AKATHISIA: SHINING A NEW LIGHT ON AN EXCEPTIONALLY COMMON, MUCH OVERLOOKED, AND HIGHLY CONSEQUENTIAL SIDE-EFFECT SYNDROME (ESPECIALLY ITS PROMINENT CAUSATION OF TREATMENT-REFRACTORY PSYCHIATRIC ILLNESS)
(MY MONOGRAPH)
PRELIMINARY NOTE
I had been on a journey of discovery for over 27 years - - until my retirement from psychiatry 8 years ago - - regarding the diagnosis, treatment, prevalence, and enormous importance of akathisia. It began with two articles, one by Zubenko et al. in 1984 (50) and the other by Adler et al. in 1987 (51) describing a new medicine for it, clonidine. So I tried it and found it much more effective than propranolol (Inderal) or benztropine (Cogentin), the 2 primary treatments then, and I suspect, still now. In a continuing adventure, I came to know that akathisia is far more prevalent, far more consequential -- especially for achieving treatment success vs. our all-too-usual therapeutic failures and partial successes now -- and far more important to good psychiatric care than we presently realize. My discoveries brought an enormous enhancement to my patients’ responses to medication, and I suspect that new discoveries have not come along these past 8 years to negate or much diminish what I learned then about dealing with treatment resistance and failure.
I have written an experiential account as I have no expertise in research, but I believe more scientific studies would bear me out. I believe what I have found is quite original, as I have never seen any reports in the literature showing more than a hint of what I have discovered about akathisia and its importance. I know my findings are valid for I have seen them confirmed over and over with my patients. At present, psychiatry incorrectly believes that akathisia consists only of restlessness and perhaps some dysphoria and/or anxiety that has essentially been reduced to a somewhat minor problem due to the new antipsychotics, and even less so, from the SSRIs and SNRIs which have hardly been recognized as causes of akathisia, even though I found they bring on as much as do the antipsychotics. Therefore, it is essentially seldom noticed, much less dealt with. But I saw it in the very large majority of my patients on psychotropics -- 88.5% of 243 subjects and then 86.2% of 87 in 2 studies I performed -- with far more symptoms and consequences than just restlessness and dysphoria – so much more so that I gave this new picture a new name -- ‘expanded’ akathisia -- to encompass the many new symptoms I was finding that seemed to not be part of the ‘limited’ akathisia we presently confine ourselves to. With my new diagnostic and treatment methods, I achieved a 90 and then
2
79% success rate (by my criteria), far greater than the usual 30-45% (109) we can now expect (up to a “theoretical cumulative remission rate” in STAR*D of 67% after trying up to 3 more switches and/or augmentations). (108)
Perminder Sachdev, in his book, Akathisia and Restless Legs, (164) presents a large list of psychiatric medicines reported to cause akathisia (p 211) (the limited kind) with which I agree, and others not mentioned such as lamotrigine and valproate that cause it, too -- and prominently. And as for akathisia’s ‘expanded’ symptoms, several are more significant in my opinion than the two presently recognized by the Barnes Akathisia Scale (restlessness and “distress related to restlessness”) (83) with some having been noted over the years but which were then essentially forgotten which I then ‘rediscovered’. A glaring example of this forgetting is, to me, the most consequential one -- its constant ability to immediately exacerbate and bring back psychotic symptoms, which has been mentioned, but very cursorily, in the DSM-IV and -IV-TR (Appendices, p 745 and 801 resp.) and in several other papers but which was then dropped in the DSM-5 but then reinstated in the -5-TR [P 813-14] perhaps indicating just an oversight -- or a renewed realization! And what I discovered that has remained almost completely unrecognized is that it can do exactly the same with depression!
I have described these and many other symptoms in this paper to improve our recognition, understanding, and treatment of akathisia and its consequences for which there is an almost complete lack of knowledge. The present protocol we use for the problems it creates is to increase and/or augment our medications when treatment is not going well and even to start right off with multiple meds as argued for by Fava and Rush. (109) However, I have found we need to go much more often in the opposite direction and keep medication regimens as minimal and doses as low as possible to better deal with this dose-related, extremely common, side-effect. We need to always look for the occurrence and impact of akathisia, to always consider the benefits of less, not more, medication, and to use the medicines I have come to prefer to treat it. This means a major change in our treatment procedures for most mental illnesses. Therefore, I feel I need to extensively explain my discoveries to give support for this new look at diagnosis and medication management.
As my major point, I believe unrecognized and therefore untreated akathisia is the primary reason why psychiatry’s record is so mediocre for achieving the successes needed to gain the satisfaction presently lacking, or nearly so, with so many of our patients and their families who must bear the burden of our shortcomings, not to mention our own feelings of frustration and inadequacy. As Thomas Insel, the former director of NIMH, wrote, “The unfortunate reality is that current medications help too few people to get better and very few people to get well”. (114) I believe I know how to change much of that reality!
I hope you will find interest in what I have written about akathisia. It likely is quite surprising and therefore likely quite difficult to believe, so I expect there will be much resistance to what I have to say.
3
I do not mean to sound grandiose, but I believe these discoveries are really quite revolutionary, which, if they became well-known and part of the usual practice of psychiatry, would make a very great difference for a very great number of patients throughout the world -- likely tens, if not hundreds, of millions of people who are now being unsuccessfully or poorly treated with psychiatric meds.
William Drucker, MD.
AKATHISIA: SHINING A NEW LIGHT ON AN EXCEPTIONALLY COMMON, MUCH OVERLOOKED, AND HIGHLY CONSEQUENTIAL SIDE-EFFECT SYNDROME (ESPECIALLY ITS PROMINENT CAUSATION OF TREATMENT-REFRACTORY PSYCHIATRIC ILLNESS)
ABSTRACT
In over 27 years I learned a great deal more about akathisia than seems to have ever been recognized before. My journey began in 1988 when I read two reports, as noted above, from Zubenko et al. and then Adler et al. on using clonidine for it. This embarked me on an adventure that led to a whole new understanding of the symptoms, ubiquity, treatment, and great importance of akathisia -- an adventure which turned out to be of enormous value to my patients, greatly increasing their therapeutic success rate plus giving them much greater physical and psychological comfort than previous med regimens had provided. My expanded akathisia is far more common than we presently perceive -- about 85% of all my patients suffered from it (Here, by “it”, I mean my expanded concept of akathisia.), and just about all our psychotropics cause it -- antipsychotics, antidepressants, and mood stabilizers. “It” is far more symptomatic than just the restlessness and attendant anxiety and dysphoria the Barnes Scale and psychiatry recognize. And there is a much better treatment for it than we presently use. I believe if my colleagues try my discoveries, they will find the same successes I came to expect for my patients.
Here, I would like to emphasize an important point: colleagues to whom I’ve described my discoveries and treatments will tell me they haven’t seen any or many patients with the akathisia I see. My response is, if I find akathisia in so many of mine while always using the lowest possible number of medications and dosages, it tells me my confreres are employing the usual very limited view of it. After seeing and successfully treating so many patients who suffer from akathisia, (my kind) I know it is there in great abundance, and causing manifold important consequences.
I believe my discoveries are quite original and eye-opening as they will explain many patient complaints that have gone unexplained and untreated or poorly so.
In this paper I hope to provide a better understanding of all this, what to look for, and then how to treat it.
INTRODUCTION
Akathisia, meaning “without sitting”, was coined by Lad Haskovec in 1902 (1) from the Greek, kathisis (a sitting) and ‘a’ (without), who observed such severe restlessness in 2 patients that they “could not remain seated”, and in one or both, “pins and needles in the fingers”, “clonic seizures of the diaphragm and spasms
4
of the larynx”, “hot feelings throughout [the] body”, “fleeting pains in the legs” and elsewhere, and “trembling and a feeling of agitation in [the] whole body”. (2) Since 1988, when I first used what I believe is a better treatment for it, clonidine (Catapres), and then its congener, guanfacine (Tenex), I have come to see akathisia as far more prevalent with far more symptoms and far more consequential than we realized, then or now. As the late Theodore Van Putten, a past leading investigator (with associates) stated, (3) “…we believe that a far greater sensitivity to akathisia by the treatment community is warranted.” Having made some very surprising and, I think, very important discoveries here, I highly agree.
I hope I can convey how valuable akathisia is to the successful pharmacologic treatment of our patients, how important it is to always be aware of its many manifestations, and then how to deal with them. With this knowledge, I believe we can achieve much greater success in our medication efforts than we can now expect. Of course, my akathisia includes all the many symptoms I gradually discovered (many of which I just rediscovered after years of being forgotten). But in the literature, akathisia is almost exclusively limited to just restlessness plus anxiety/dysphoria except for a few occasions when mention is made of some of these other symptoms. So do keep in mind the divergence between my much broader list and the much more restricted one commonly accepted in the field.
As per Sachdev, (4) akathisia was recognized by Freyhan in 1957, (5) early on in modern psychopharmacology to be a side-effect of the new antipsychotic, chlorpromazine (Thorazine), though he did not connect this to Haskovec’s description until 2 years later. (6)
As for cause, Sachdev states, (7) “The pathogenesis of akathisia is incompletely understood, and many competing hypotheses exist.” It was -- and in large degree still is -- considered to be part of the extrapyramidal syndrome (EPS) or parkinsonism brought on by neuroleptics blockading dopamine receptors in the extrapyramidal region. As per Brown, (8) “…Akathisia is a well-known manifestation of the early phases of the idiopathic Parkinsonian syndrome…” Therefore, the main treatment first given was anticholinergics which usually work well for EPS, but from what I and others have seen (see below), not so well for akathisia. However, others have written favorably about anticholinergics for it (below}. The classic EPS symptoms of bradykinesia, coarse and slow tremor (pill-rolling), rigidity, decreased facial expression, and postural instability are not really a part of the akathisia picture except for tremor, which is not pill-rolling but more of a tremulous, twitching, and shaking. As per Sachdev, (9) “The majority of patients with akathisia do not have EPS”, and “Akathisia should not be considered another symptom of parkinsonism”. Weiner and Luby (10) in 1983, stated, “The association of akathisia with extrapyramidal dysfunction is questioned.” I believe akathisia and EPS are separate but connected in some ways, probably through the dopamine system.
So what causes akathisia? It remains uncertain and complicated. Fleischhacker et al. (11) stated, “The underlying pathophysiology of akathisia … may not involve, primarily, nigrostriatal dopamine pathways”, and “Central nor-adrenergic mechanisms may be involved in the pathophysiology of [akathisia)”. Blaisdell (12) wrote,“[It] likely arises from complex interactions in subcortical and possibly spinal dopamine/norepinephrine ”
5
and Kane et al., (13) “…It seems likely that a complex interplay of several neurotransmitter systems underlies [akathisia’s] complex pathophysiology”. I see it as a hyperactive/hypersensitive state due to the actions of our meds in various neurologic systems.
AKATHISIA-INDUCING MEDICATIONS
I believe almost all our psychotropic medication groups cause akathisia with only benzodiazepines and perhaps stimulants and L-methylfolate (Deplin) not doing so. Moreover, I find antidepressants and mood stabilizers bring it on as frequently as antipsychotics, a claim which will likely be disbelieved.
Sachdev lists many medicines implicated in causing akathisia (14) with which I agree. His tabulation includes the antipsychotics, both first (FGA) and second generation (SGA) (only 2 of which, risperidone and clozapine, were on the market when his 1995 book came out), the antidepressants -- SSRIs and TCAs -- and the mood stabilizers, lithium, carbamazepine, and valproate. To this I would add buproprion, SNRIs, and lamotrigine (the last 2 not on the market in 1995). Lamotrigine is, perhaps, the worst inducer as it seems to often cause a particularly refractory form no matter what the dose, which has led me to not prescribe it except for those without a history of such difficulty from it. I have found akathisia to occur with all the SGAs except clozapine, with which I have no experience, and so little (or none) with the new SGAs, asenapine (Saphris), lurasidone (Latuda), iloperidone (Fanapt), and brexpiprazole (Rexulti), that I cannot judge. Iloperidone’s manufacturer claims the Barnes Scale’s akathisia rate to be equal to a placebo’s, but, as I noted above, the Barnes is not an adequate measure for me as it limits itself only to restlessness and dysphoria. The same no akathisia claim was made for quetiapine with which I’ve had much experience and have long found to bring on its share. Sachdev also lists buspirone (Buspar), of which I am uncertain.
By and large, SGAs are thought to bring on less akathisia than FGAs (15) and I agree. Aripiprazole (Abilify) and lurasidone have been noted to cause a good deal of it even with our present limited recognition. One study by Nelson et al. (16) found a 25% akathisia rate plus an additional 12% “restlessness” -- which to me is just akathisia -- when aripiprazole was used as an adjunct to antidepressants. I am uncertain as to how much akathisia is caused by it. I have noted some patients seem to suffer less or no akathisia when its dose is raised into the 20 - 30 mg per day range. My experience is that akathisia is a dose-related phenomenon, but perhaps aripiprazole’s partial agonism of D2 receptors ameliorates that. I think the FGA, perphenazine (Trilafon) isn’t too problematic for causing it, and at least 1 study by Peluso et al., (17) comparing FGA and SGA extrapyramidal motor effects, found no significant difference in akathisia rates between the two.
Within a year of its introduction in 1988, fluoxetine (Prozac) was noted to cause it (18,19) and the same for sertraline (Zoloft). (162) The DSM-IV-TR acknowledges the ability of SSRIs to cause an akathisia that “appears to be identical to…Neuroleptic-Induced Acute Akathisia.”(15), and the -5-TR (p 814), (but, again, not the DSM-5),
6
similarly states, “…akathisia that appears to be identical in phenomenology and treatment response to akathisia induced by antipsychotic medication …”. Since blocking serotonin reuptake can be anti-dopaminergic by increasing serotonin, I am not surprised. I see SSRI-induced akathisia all the time. I suspect tricyclics (TCAs) cause less akathisia than SSRIs but still a fair amount. When I am trying to ease a refractory akathisia due to an SSRI, I will, at times, substitute a TCA and think I see some further alleviation. I have no knowledge of the MAOIs, nor are they noted by Sachdev.
I see mirtazapine (Remeron) as causing akathisia, based on numerous patients so affected by it, even though it has been claimed by Poyurovsky et al. (20,21) and others (22,23) to ease it. But patients of mine have been on it, alone, in extremely low doses and still suffered from considerable akathisia. And others have reported the same. (24,25,26)
Patterson (27) describes akathisia in 2 patients on buspirone and Ritchie et al. (28) write of 1 given 5mg TID who also suffered from it. I’ve had a fair number with a history of buspirone use from previous doctors who felt it helped their anxiety (which akathisia commonly causes), so I continued it along with akathisia-causing psychotropics. Because they were on both at the same time, I could not tease apart akathisia causation, but my guess is buspirone is OK.
I think L-methylfolate causes no akathisia, though my experience is with only 5 patients. Similarly, my exposure to gabapentin (Neurontin) is limited, but 1 patient had no akathisia, 1 endured a fair amount, and 1 found that terminating it while continuing 2 other akathisia-generating psychotropics stopped or greatly eased akathisia symptoms of hot and cold feelings, numbness, cramps, and shooting pains, which indicated my anti-akathisia treatment sufficed against 2 causative agents but could not block it from 3.
Sachdev also lists calcium channel blockers, which have antidopaminergic effects, as a cause of akathisia (29) (which, therefore, is not a surprise). A patient of mine on 30 mg of the calcium blocker, nifedipine, and no psychotropics suffered numerous akathisia symptoms, only one of which, restlessness, is presently seen as akathisia, but also felt pinpricks in toes, muscle spasms in knees and hands, electric shocks, hot sweats, cold feelings, numbness in feet and hands, and itching and crawling feelings on the back and scalp -- all of which I classify as part of it. I began both guanfacine and a psychotropic, and almost immediately, likely before any akathisia from the psychotropic would have begun, it eased significantly.
MEDICATIONS FOR TREATING AKATHISIA
As to the utility of anticholinergics, Sachdev writes, (30) “Only a proportion of akathisics derive benefit [from the anticholinergics]”. Lima, et al. (31) state, “At present, there is no reliable evidence to support or refute the use of anticholinergics… for akathisia,” and Fleischhacker et al. (11) similarly say, “The efficacy of anticholinergic agents…is far from established.”
7
But other studies support their use. Sachdev delineates the pros and cons of it, (32) and Hirose (33) cited himself and a number of other researchers who had found parenteral anticholinergics good at blocking akathisia. (Perhaps this route works better). I long ago stopped PO anticholinergics because of inefficacy.
The literature also has numerous positive and negative articles on beta-adrenergic blockers for akathisia, many of which are delineated by Sachdev. (34) Beginning in 1983, the beta adrenergic blocker, propranolol, began to achieve prominence, (35), (36) but Poyurovsky and Weizman in 2001, (37) wrote, “…beta-blockers, anticholinergics, and benzodiazepines show only a modest treatment efficacy…”. Bratti et al. (38) state these same meds are “often inadequate for treating… akathisia”, and Sharma et al., (39) “Presently, there is no definitive treatment of akathisia.” Lima et al., (40) in a Cochrane Review, claim, “There are insufficient data to recommend beta-blocking drugs for akathisia”, and “These drugs are experimental for this problem…”.
As with these authors and as with anticholinergics, which probably are even less effective, I do not think propranolol is all that beneficial for akathisia. However, soon before I retired, I became more open to its possible value, having 1 patient with a history of good results from it, which returned when I restarted it, and then another, very resistant to all my usual anti-akathisia meds, who had a better response to it than to those agents.
Trazodone (Desyrel) has been mentioned as being useful, (41), (42) and I employed it to a fair degree as a soporific without feeling it helps akathisia. I do not think it causes it, either, at least at the lower doses used for insomnia. However, one patient did suffer mild akathisia from just 50 mg without taking any other medication.
Sachdev discusses other medicines that have been tried for akathisia, (43) including clonidine which had quite favorable results but with supposedly problematic side-effects -- which I have not found to be all that problematic.
I am reasonably certain I found a better treatment for akathisia than the two medications we usually use, even though propranolol has been generally accepted as the medicine of choice. With my preferred treatment , I have been able to enormously improve my understanding of akathisia and with it, my ability to gain much more success in dealing with my patients’ underlying mental illnesses than we can presently expect.
My ever-expanding understanding of akathisia began when I first tried clonidine, an alpha 2A partial adrenergic receptor agonist, in 1988, first approved by the FDA as an anti-hypertensive in 1974. After a few years, I changed over to guanfacine, a more selective 2A agonist than clonidine. (44) Guanfacine has gradually become my first choice as it usually is just as effective -- but not always -- while being less likely to cause as much of clonidine’s somnolence (which does not seem to be so troublesome, anyway, as other authors have claimed), xerostomia (dry mouth), orthostasis, sexual dysfunction, and other side-effects such as withdrawal rebound hypertension.(45), (46) It is about one tenth as potent as clonidine for hypertension which is reflected in its tablet sizes of 1 and 2 mg vs. 0.1, 0.2, and 0.3 mg for clonidine, and I use the same strength ratio when
8
prescribing it for akathisia. Guanfacine’s half-life is 12-24 hours vs 6-24 for clonidine, but I do not think there is any appreciable difference in their duration of action for akathisia which seems to run about 3-5 hours, thus usually requiring a TID, or more, dosage schedule.
How do clonidine and guanfacine counter akathisia? As per Goodman & Gilman, (47) “The alpha 2A receptor plays a major role in inhibiting norepinephrine release from sympathetic nerve endings and suppressing sympathetic outflow from the brain…”. By agonizing these receptors, they reduce “…both the firing rate of norepinephrine autoreceptors and the presynaptic release of norepinephrine” (48) from the locus coeruleus where CNS norepinephrine is synthesized, thus “decreas[ing] adrenergic neurotransmission from [it]”. (49) This action, with its beneficial effect on akathisia, may reveal at least some of akathisia’s causation.
As I noted above, I did not discover clonidine’s use for akathisia. The first recognition of its possibilities was in 1982, when Freedman et al., (61) which included Adler, wrote, “One might also postulate that clonidine would be useful … in cases of severe akathisia.” Its actual use was first described in 1984 by Zubenko, et al. (50) and then repeated in 1987 by Adler et al. (51) in 2 small studies of just 6 patients each, both with quite favorable results. All 6 of Zubenko’s group “demonstrate[d] substantial improvement”, with 4 achieving “complete remission”, and Adler’s 6 hospitalized patients realizing “significantly lower akathisia and anxiety”. (I consider anxiety to be a major inherent symptom of akathisia which I think they did not.) But both these studies seem to have only minimally been taken note of by the psychiatric community, including, surprisingly, by any of the 9 authors of these two positive papers as they almost never reported on any follow-ups I could find. Two (other) articles (by the same two authors et al.), one by Zubenko’s group (52) a month after his first in 1984, using clonidine for bipolar disorder, stated, “one patient’s akathisia also appeared to respond to clonidine”. The second was by Adler and his same group (nearly), (53) also in 1987, treating 12 patients with propranolol and 6 with clonidine. They felt both medicines were effective for akathisia, but clonidine also ameliorated anxiety while propranolol did not (which could be an indication of clonidine’s possible greater utility against akathisia). However, clonidine caused noticeable somnolence and hypotension while propranolol did not. After that, only a few other reports using clonidine for akathisia seem to have been written.
After this, clonidine for akathisia is mentioned in various review articles (11), (12), (13), (54-57) and books such as Sachdev’s, (2) (p 271) sometimes favorably and sometimes not, and usually just as a second or third choice. Somnolence and hypotension were its significant problems but not according to some, (58), (59), (60) including myself who has treated far more patients with clonidine and guanfacine (I would estimate ~500 over 27 years) than any of the afore-mentioned reports without that much side-effect difficulties. Moreover, after a month or so, I will often find the sedative effect to ease and sometimes the orthostasis, too. Freedman et al. (61) found blood pressure decreased by a mean of 9.3 mm Hg with clonidine up to a dose of 0.9 mg/day in 8 schizophrenics which seems fairly small, especially for this moderately large dose of clonidine. Finally, Fleischhacker et al. (11) revealed mixed feelings about clonidine, referring at one point to Zubenko’s 1984
9
report, that it was “striking…that all patients experienced improvement, with four achieving complete remission of akathisia”, but further on, that “clonidine…does not appear to offer any advantages over the beta-blockers at this time”. With such a strongly positive first statement, I’m surprised they did not call for further investigation.
Thus, the usefulness of clonidine seems to have been forgotten. Also, and importantly, these reviews and Sachdev’s book have a very limited perception (by my criteria) of what akathisia consists of -- basically just restlessness and sometimes anxiety/dysphoria -- so they miss the many symptoms I am constantly detecting (described above and below). These are also usually well-controlled by clonidine and guanfacine (and 2 other medicine families yet to be discussed) which the other more usually used akathisia medications are perhaps not alleviating so well, such as the anxiety for which propranolol did not succeed, as noted above. But I am reasonably pleased with my results and find neither somnolence nor hypotension to be that much of a problem, especially with guanfacine which they did not explore. I think clonidine’s and guanfacine’s xerostomia is a larger difficulty. (Biotene works pretty well here.)
The advantages of clonidine and guanfacine over beta-blockers are quite evident to me. With these meds, sometimes in combination, I came to realize just how prevalent and multi-symptomatic akathisia is and how beneficial they can be for all its manifold effects.
Clonidine and guanfacine have a few other side-effects such as bradycardia and the above-mentioned withdrawal hypertension, but I have not seen these being much of a problem, though I have not been that diligent in looking for them. The PDR lists other possible side-effects such as anxiety, agitation, depression, nausea, vomiting, muscle and joint pains, vivid dreams, nightmares, and restlessness, but it states these and other listed symptoms may just be from other medicines the subjects were concomitantly taking. Moreover, many of them are part of my expanded definition of akathisia which these meds help alleviate, not cause. I have not noticed such problems from them except for an occasional GI upset. An important consideration is if they cause depression. It is mentioned as a “less common” possibility by Goodman & Gilman (p 854) and also in the prescribing information for the extended release form of clonidine, Kapvay, but I have not seen this in the many times I have used them.
Around 2004, I added a new and very valuable anti-akathisia medicine, ropinirole (Requip), a D2/D3 dopamine receptor agonist with a half-life of 6 hours and Tmax of 1-2. It is for the treatment of Restless Legs Syndrome (RLS), which I learned shares many symptoms with akathisia which then led me to try it. (It is also approved for Parkinson’s). Hettema and Ross (62) also noted the shared symptoms between akathisia and RLS and successfully used ropinirole to treat tardive akathisia (TA) in one patient at a dose of up to 18 mg/day, well beyond my usual range of 1-4. The addition of ropinirole has helped me discover new and very important akathisia symptoms, not to mention its value when clonidine and guanfacine are not as effective as wished for or are causing problematic side-effects. I found the main difficulty with ropinirole to be nausea which
10
occurs about 50% of the time, but half of this time can be eased by taking it with food. Orthostasis can also occur.
Ropinirole’s efficacy can make a good case for a dopamine factor in the causation of akathisia.
Pramipexole (Mirapex) is another dopaminergic medication also approved for RLS and Parkinson’s disease, but I have not used it. It has a stronger selectivity for D3 than ropinirole, (63) but I cannot say if this will make any difference for akathisia. My guess is it would work as well as ropinirole and perhaps even better. As per the PDR, its dosage range is 1½ - 4½ mg/day and its half-life, 8-12 hours. Rotigotine (Neupro), another similar dopaminergic medication, applied as a patch, was approved for RLS and Parkinson’s, but I haven’t tried it, either.
These agents carry some risk of causing or exacerbating psychotic symptoms and mania, especially in patients with Parkinson’s disease, RLS, and bipolar disorder. (64), (65), (66) I haven’t noted this consequence in the hundred fifty or so I’ve had on ropinirole, though virtually none had concomitant Parkinson’s or RLS as best I could tell. The same goes for the reported increased risk of compulsive disorders, pathologic gambling, and ‘sleep attacks’ noted especially with pramipexole when used for Parkinson’s.
Another risk is the dopamine agonist withdrawal syndrome from a too rapid cessation which many of my patients have let happen. It has a number of psychological and physical symptoms including anxiety, depression, agitation, irritability, orthostasis, nausea, and sweating, (67), (68) but since many of these are part of the now returned akathisia, I cannot differentiate one syndrome from the other.
More recently, I found benzodiazepines to be quite helpful for akathisia, and I am not alone here. (69), (70), (71), (72), (73) Sachdev (74) sees their value, stating, “[They] are effective anti-akathisia drugs in some patients”. At times, they seemed to work even better than my others but, generally, still needed to be used in combination with them.
To me, it is unfortunate that what I see as the best medicines for treating akathisia have gone unrecognized all these years, while the two, propranolol and anticholinergics, which I and other authors believe are not so effective (as I noted above) have remained the treatments of choice.
INCIDENCE/PREVALENCE OF AKATHISIA AND ITS LIMITED PERCEPTION
Though incidence/prevalence estimates for akathisia go as high as 70-90% (for the FGAs), most seem to range from single digits to the 30s (for the SGAs). (3), (75), (76), (77), (78), (79) Van Putten found it in 45% of his patients on FGAs. (76) Barnes and Braude (80)reported a prevalence rate of 48% from the FGAs in 82 schizophrenic outpatients who were showing “restless movement characteristic of akathisia” with about 33% having chronic akathisia. Kane et al., (13) in 2009, reported its incidence rates from dopamine receptor antagonists to range from 21 to 75% and its prevalence, between 20-35%. They state FGAs have a “consistently
11
higher [incidence]” than SGAs, (with which I agree as I stated above), and the DSM-IV and -IV-TR put akathisia prevalence at 20-75%, (81) with FGAs causing the most.
But with my diagnostic criteria for akathisia, only with outpatients as my subjects compared to the above reports which most likely came from inpatients on much higher doses than mine, plus on FGAs in the older studies vs. mine essentially on SGAs and many on SSRIs from which akathisia is hardly recognized, my incidence/prevalence rates were 88.5% of my patients seen over 8¼ months in my first study and 86.2% in a second seen over a year. (Both described below). One would expect my practices to cause lower akathisia rates, but instead, they are much higher than those in the large majority of these other studies. So I definitely find much more akathisia than other investigators who use only the Barnes where akathisia is just restlessness, the accompanying “distress related to restlessness”, and, perhaps, some separate anxiety/dysphoria.
Therefore, my perception of it is much more extensive than what the psychiatric community currently believes it to be. Using my diagnostic list (below) I find akathisia to be extremely common and arising from nearly all the psychotropics except for the benzodiazepines -- which, as just mentioned, can often be very helpful -- and perhaps, the stimulants. If my frequency estimate is correct, what I have learned about its diagnosis and treatment should be of great value to the tens of millions now on psychotropics, most of whom I suspect are suffering considerably from unrecognized akathisia without benefit of what I believe is the very effective treatment I have been able to give my patients.
I realize my findings and experiences with akathisia will likely meet with considerable skepticism -- as they should -- but there is some recognition in the field (as per personal communications and various articles such as the Van Putten et al. one above) that we have for years been overlooking the pervasiveness and importance of what is to me an extraordinarily common and extraordinarily consequential side-effect. So my goal is to provide understanding and support to my findings to help lead us to a much better response to akathisia than we have given it so far.
Though restlessness is a significant feature of akathisia, I believe it is not its most important, as it likely is not the greatest cause of a patient’s discomfort or distress unless it is fairly severe. Restlessness can be fairly low on a patient’s list and, as I have found, is often not even thought of (perhaps thanks to my low dosing).
The Barnes Scale and our present perception of akathisia shows its inadequacy to me in a study by Rosenheck et al. (82) Including the Barnes, they looked at 309 schizophrenic/schizoaffective patients over a year in VA med centers to compare the benefits and costs of haloperidol vs. olanzapine. They found just 9.6% of patients on haloperidol and 5.8% of those on olanzapine to have moderate to marked akathisia. But haloperidol is known to cause much akathisia, especially with its final mean dose of 14.3 mg/day, about 3-10
12
times greater than my usual for my few outpatients on it. Yet, I find at least an 85% rate for akathisia (extended) from medicines much less likely to cause it than haloperidol!
I think the universal reliance by the research community on the limited symptoms of the Barnes (83) has contributed to our ongoing lack of awareness of akathisia’s many other features, its high frequency, and the major impact it has on treatment success, though this scale (published 1989) just reflects the limited understanding existing before it of only restlessness and to some extent, agitation and dysphoria. But then, it did lock in this restricted perception of it.
Since the beginning of neuroleptic, antidepressant, and bipolar therapy in the 1950s, akathisia has been noted to bring on, or at least be associated with, a wide variety of symptoms. (see below) But many of its manifestations seem to have been ignored or given little acknowledgement and then forgotten but which I have rediscovered over the past twenty-five plus years, thinking they were originally found by me -- and probably some were. However, I think I am the first to have put many of its symptoms into one assemblage of akathisia as opposed to isolated and infrequently perceived ones described over the years and to have been the first, or nearly the first, to recognize just how great is akathisia’s frequency, how pervasive it is no matter what psychotropics (almost) we are using, how profound is its impact on our patients’ mental illnesses, and so importantly, how successful we can now be in ending its destructive consequences.
I should now present my akathisia symptom list. I would like to add here, I believe we need to specifically ask the patient about these symptoms rather than just rely on their inadequate spontaneous reports. Otherwise, the diagnosis runs an increased chance of being missed.
I believe the following are all part of the akathisia syndrome -- all of which are quite, to very, uncomfortable, if not worse. I see the first 2 as its most important features, yet they have hardly been recognized. Importantly, akathisia is intermittent and comes and goes as it will.
1. Exacerbation, persistence, or return of underlying psychotic symptoms, especially paranoia, nightmares, and hallucinations which turn on and off rapidly, closely tracking with other waxing and waning akathisial features.
2. Exacerbation, persistence, or return of underlying depressive symptoms from major depression, bipolar, or schizoaffective disorder. These also come and go rapidly, again tracking closely with other akathisial symptoms.
3. On and off day or night restlessness/antsiness that derives from uncomfortable muscle and other body sensations and can be somewhat relieved by movement. (Seen as marché à pieds, tapping or flexing and extending hands, feet, or toes, rocking, abducting, adducting, swinging, crossing, and uncrossing the legs
13
and arms, twirling the ankle, tossing in bed, feeling a need to take a long walk, etc.) Can be confused with ADHD.
4. On and off nervous/anxious or “edgy” feelings. Can precipitate panic attacks.
5. On and off irritability, anger, and/or agitation. (I believe these are just secondary to the increased anxiety and restlessness of akathisia or its exacerbation of depression and/or psychosis.)
6. On and off headaches. (Often felt as sudden sharp stabs, blows, aching, or strange feelings in head.) Strange or weird physical feelings commonly go with akathisia.
7. On and off muscle cramps, spasms, stiffness, and tightenings (including in larynx which can be confused with an anticholinergic-responsive dystonia). My patients often call them Charley horses.
8. Spontaneous tremors or shaking of legs or hands typically starting while at rest (vs. a lithium intention tremor resulting from a muscle action). Feeling tremulous or “shaky” internally.
9. On and off twitches and myoclonic jerks. (Could lead to dropping objects or the leg suddenly giving out which could be mistaken for a dizziness due to an orthostasis from clonidine or guanfacine.)
10. Muscle, joint, bone, or other areas of aching that can be felt deep down. These may be more continuous, i.e. less intermittent than the other symptoms. Again, can be labeled as a Charley horse.
11. Bruxism or feeling need to “click” the teeth.
12. Dizziness or lightheadedness. Can be confounded with orthostasis from clonidine and guanfacine, but akathisial dizziness often occurs when sitting or lying down.
13. Feeling an urgency to breathe, a restlessness in breathing, or feeling unable to “breathe in a leisurely relaxed manner”. (84) Can cause grunting, gasping, sighing, snorting, dyspnea, etc.
14. A tardive dyskinesia-like picture (such as tongue protrusions or eyebrow movements I’ve seen in 2-3 patients). Perhaps TD is related to, or part of, akathisia.
15. Paresthesias: (These are very common.)
On and off unusual itchiness on or deep under skin or scalp, under the skull, in brain, or in back of throat and often difficult to get at.
On and off crawling (formication) on or under the skin, or as if you’ve run into a spider web.
On and off hot or burning feelings on or under the skin, or in some part of the body. (can be quite intense)
Hot and/or cold flashes and feelings, hot and cold sweats and chills. (can be confused with menopause)
14
On and off numbness or tingling occurring most anywhere but most commonly in the hands and feet. (can be confused with diabetic neuropathy)
Sudden needle sticks, bee stings, or bites on the surface or penetrating deep into the body. (can be mistakenly attributed to bed bugs)
Touch sensations as if pushed on by a thumb or being gripped or suddenly punched.
On and off sudden electric shocks in part of or throughout the body.
On and off shooting pains that could be attributed to disc problems and arthritis.
Feeling pressure or aching, especially in the head. (can be confused with a headache or migraine)
On and off stabbing pains, especially in head, joints, sides, back, and chest (including precordium, confusing it with angina, but is often while at rest.)
‘Icky’ feelings on or under skin. (can make one feel need to shower, dig at, rip off, or crawl out of skin).
Weird sensations such as water running down neck, blood flowing in the veins, tingles or tickling in brain or that the head might explode, pulling or drawing sensations on a part of the body, strange sensations in muscles and joints that can make one want to crack the knuckles, strange feelings in viscera. (“My stomach feels strange. It’s like I’m churning inside.”) (76)
16. Dysesthesias: A touch or gentle brushing feels as if sandpaper were abrading the skin.
My guess is many of us have heard any number of these complaints for which we had little answer, so we would either ignore them, refer our patient for an evaluation, or try treating them in various and usually unhelpful ways. Some treatment attempts I have seen are: augmenting with a second medicine, switching to a new one, or increasing the dose when the exacerbation or return of depression or psychotic symptoms is mistaken for a relapse; adding benzodiazepines for akathisial anxiety and dysphoria (which can be quite beneficial for all its symptoms); adding analgesics (which can ease some of the sharp, aching, stinging, burning, shooting, or shock-like pains); adding soporifics, an antihistamine, or an external skin cream for the pruritus (both of which seem to be helpful at times); adding an antihistamine or anti-cholinergic which I find are usually unhelpful for the various muscle tightenings, cramps, twitchings, and spasms attributed to EPS.
Another aspect of this lack of recognition is that I’ve often noted that many of my akathisia symptoms are mentioned separately from ‘Akathisia’ in the adverse events list in the PDR or on Prescribing Information (PI) sheets for the different psychotropic medicines. Some of the independently listed side-effects I have seen are: headache, myalgia (from akathisia’s muscle cramping, tightening, stabbing, and aching), abdominal and back pain (from akathisia’s pinprick, stabbing, shooting, and shock-like pains), agitation, anxiety, insomnia (due to akathisia’s restlessness, anxiety, paresthesias, and pains), tremor, twitching, shakiness, sweating, paresthesias, rash (from akathisial itching leading to an itcher’s rash), cough (from itching in the throat or “restlessness of respiration”), (84) EPS (from akathisial tremors, stiffenings, myoclonic jerks, or spasms), rapid
15
mood swings (from akathisia rapidly turning an underlying mood disorder on and off), and finally, psychosis and depression (from akathisia’s exacerbation of the underlying illness). I have often seen ‘restlessness’ listed in addition to akathisia which makes no sense to me as this is what akathisia essentially means!
I suspect that more frequently than not, these separately listed symptoms are just due to akathisia, as I have basically seen them all respond nicely to my medicines. And if all these independently listed adverse events in the PI sections are just part of unrecognized akathisia, as I believe they usually are, one can get a sense of just how pervasive and unrecognized akathisia is.
In the same way, many times have I heard a medicine being described as “activating”, which, to me, likely is just a manifestation of the agitation, insomnia, and restlessness that is integral to akathisia and not the positive activation one hopes to achieve. As Freyhan (85) put it in 1958, in referring to akathisia, “What [patients] experience is not an increase of drive but a disturbing sensation of being driven”.
There is another important relevance for akathisia that extends beyond psychiatry. I have seen a large number of medical and dental problems occurring in many patients on psychotropics that are not recognized by their doctors as coming from akathisia which could easily be diagnosed and treated as such without putting their patients (and our health system) through additional tests and procedures with their dangers, discomforts, and, likely, the wrong medicines. I have had a fair number of patients who were referred to the neurologist for feared seizures, paresthesias, numbness, or various pains (as happened to one character in the movie, “Garden State”, who was on lithium, Depakote, Paxil, Zoloft, and Celexa, seemingly all at the same time, suffering “intense headaches”, “like a lightning storm in my head for a split second”, and “like a surge of electricity”, referred to the neurologist who found nothing wrong with him), the cardiologist (when stabbing or stinging pains occur in the precordium or substernum), the rheumatologist or orthopedist (for pains in joints, bones, neck, or back), the gynecologist (for pelvic pains or hot flashes mistaken for menopause), the diabetologist (when burning, tingling, or numbness in the extremities or elsewhere are thought to be from a diabetic neuropathy), and the dentist for their bruxism. And I have seen a few patients who I am pretty sure were incorrectly diagnosed with fibromyalgia due to their sharp pains, spasms, and aching in their muscles and joints. Yet all these symptoms frequently come from akathisia and will usually respond to my akathisia meds.
As I previously mentioned, there are many symptoms noted by other researchers over the years as being part of akathisia that were subsequently forgotten which I then ‘rediscovered’, thinking I was the original finder. Sachdev lists a number of them in his book and devotes a section to one of its most important consequences, an exacerbation of psychosis (p 125-7). He cites (p 8) Sarwer-Foner and Ogle, (86) who, at the very beginning of the psychopharmacologic era, described “…a psychotic process, further deterioration of a psychotic process, or enhanced anxiety” resulting from chlorpromazine and reserpine which I suspect was due to akathisia, (though the authors made no mention of this possibility). He also cites (p 127) Van Patten
16
et al. (87) as the “first to suggest that neuroleptic-induced exacerbations of psychosis may result from akathisia”.
I have found the exacerbation of psychosis and depression to be akathisia’s most important and basically constant symptom, by which I mean one can expect to see this just about every time akathisia turns on in patients who suffer from either of these conditions. I see these exacerbations to be ‘consequence’ symptoms that will occur when the patient already has the underlying depressive or psychotic illness as opposed to anxiety, which, as I stated, I think of as being one of akathisia’s inherent symptoms. The relapse of psychosis and/or depression frequently leads to a misdiagnosis of the real cause of the difficulty and with it, a wrong and often harmful treatment that brings on more of the akathisia that has created the relapse in the first place.
Van Putten et al. described the akathisia-induced relapse of psychosis in at least three papers (76), (87), (88) and stated in a couple, it “… can be associated with dramatic exacerbations of psychosis,” and in another, “…the exacerbations of psychosis were often sudden and dramatic.” This last quote emphasizes a very important aspect of akathisia that I constantly see and noted in my symptom list. It will turn on and off quite suddenly (or at least, rapidly), and when it does, the exacerbation, be it of psychosis or depression, turns on and off just as quickly with it. This rapid relapse and recuperation is a major sign for me that akathisia, and not a relapse of the illness itself, is the root cause of it. The patient will feel as if on a “roller coaster” of mood swings or psychotic experiences and, at times, will give this description to me. I, in turn, have learned to make this an important term with my patients to investigate the cause of a relapse. An additional most important point is that I have found that relapses and exacerbations of psychosis or depression come far more oftenfrom the onset of akathisia than from a developing refractoriness of the underlying illness! This has given me a much greater success in treatment than I believe we usually can expect, for I am able to direct my efforts to the correct target.
Numerous other authors besides Van Putten et al. have noted exacerbation of psychosis from, or at least associated with, akathisia. Brown wrote, (8) “It [akathisia] is frequently mistaken for anxiety, agitated forms of depression [perhaps from just a worsening of it], psychosis, and delirium”, and “It is not unusual to see the akathisia thus misidentified being treated with increasing doses of neuroleptic medication, often with disastrous results”. Van Putten (89) cited Fouks et al. (90) as stating, ”[Akathisia is] often associated …with bizarre mentation”, which I take as a psychotic symptom. Lipinski et al, (91) in a review of beta-adrenergic antagonists used for akathisia, came to an “inferential” determination that psychotic symptoms were improved by treating the neuroleptic-induced akathisia, and Nishikawa et al., (92) that, “tardive akathisia is easily misdiagnosed as an aggravation of psychotic symptoms”. Chien and DiMascio, (93) Barnes, (94) and Shen (95) wrote of this same very important consequence. Shen also stated that an exacerbation due to akathisia can lead the treating physician to “increase (my emphasis) the dosage of neuroleptic drugs, and further aggravate the patient’s problem”. Raskin (96) made the same point and recommended, “…decreasing (my emphasis) the dose of the drug being used…” Friedman and Wagner (97) understood this, too, writing,
17
“[Akathisia] often causes dramatic changes in behavior which may be misinterpreted that more, rather than less, medication is required”. Duncan et al. (98) found “statistically significant decrements in BPRS positive symptoms…” after treatment of akathisia, and that … “the effect of akathisia in exacerbating psychopathology is large.” Finally, this assertion and caution is also made in the DSM-IV, -IV-TR, (81) and -5-TR (p 813) stating, “Worsening of psychotic symptoms … may lead to an increase in neuroleptic medication dose, which may exacerbate the problem” (of akathisia and/or psychosis). But this warning is buried in the appendix or the very back of the manual, helping it to be overlooked. And as I wrote above, the limited warning in the -IV and -IV-TR was then entirely left out of the -5 (but returned in the -5-TR), revealing some diminished perception of akathisia’s importance. So it appears many authors in the past recognized this consequence, but it seems to have been somewhat forgotten -- a major mistake, in my opinion -- in the face of this very frequent and very important side-effect!
Akathisia’s ability to worsen depression is hardly recognized, if at all, in the literature. (But Brown, above, (8) seems to have, though in a limited way.) It appears virtually no one has made this connection as was made numerous times for psychosis, nor is it in the DSM-IV or -IV-TR as it is with psychosis (and again, not in the -5 or -5-TR). The closest I could find, aside from Brown, was Van Putten et al. who ascribed an association between akathisia and depression, perhaps causative, stating, “Akathisia is often experienced as anxiety and depression.” (3) I find when treating a depressive disorder that if akathisia begins, it will almost always quickly bring the depression back or exacerbate it just as it does to psychosis. Perhaps this missed connection in the literature is due to the common perception that antipsychotics are the predominant cause of akathisia instead of equally sharing that causative role with antidepressants and mood stabilizers as I have witnessed countless times. And I find these 2 medication families will treat depression just as well as the antipsychotics will treat psychosis if it weren’t for the akathisia they also constantly engender!
I do not think akathisia will bring on either depression or psychosis de novo. When I have a straight schizophrenic on an antipsychotic who is suffering from akathisia, I do not see him/her going in and out of depression (as will a schizoaffective with depression). I will only see a relapsing psychosis coming and going along with the akathisia. Of course, depression can gradually develop in a schizophrenic from the frustration and hopelessness due to an untreated akathisia.
I see this capability of creating on and off relapses as an inherent symptom of akathisia -- its most important symptom -- a physiological reaction that is part of the akathisial syndrome, itself, which is evidenced by the quickness of the activation and then the equally quick return to where the mental state was before, when the akathisia eases. This switch is a major diagnostic tool for determining the real problem in the treatment, for I do not think these rapid changes would occur if we were facing only an inadequacy of our medicines. They would be more gradual and without such a characteristic roller coaster pattern. Moreover, if the relapse is ended by my akathisia-treating meds, as I find it usually is -- assuming they are working well
18
and without gaps in their coverage -- that makes the akathisial cause a near certainty!
As a brief aside, my feeling is that the rapidity of the turning on and off of akathisia, and with it, its psychotic and depressive relapses, may shed some light as to akathisia’s source. It makes me wonder if -- but my knowledge is very limited here -- there might be some rapid changes in neuron membrane permeability to various ions leading to changes in neurotransmission that is behind it.
FORGOTTEN OR IGNORED AKATHISIA SYMPTOMS
Numerous other seemingly forgotten akathisia symptoms have been noted in the literature over the years that I constantly see in my patients and which further substantiate my discoveries.
As I have stated, anxiety is a major and very frequent symptom of akathisia which I think is too often ignored. The Barnes Scale gives weight to “distress” that is “related to restlessness”. I see this ‘distress’ as just anxiety due directly to akathisia and not to its restlessness. Hirose (33) gives some variation to my idea that anxiety is an inherent symptom of akathisia. He says akathisia’s anxiety is, “the most common variant expression of [the] inner restlessness of akathisia,” -- i.e., it is just another expression of the restlessness Sachdev states, “tension was described by 52.5% of our patients [with akathisia]… in the mind and (or) body”. (99) Van Putten writes of akathisia bringing on “strong affects of fright, terror, [and] anxiety.” (76) Numerous others in the past, such as I noted above with the Sarwer-Foner and Ogle article, (86) have described anxiety as a symptom of akathisia and that it can reach to panic levels and even terror. More recently, Nelson (104) ascribes “tension [and] panic” to it. And again, as per Van Putten (89) citing Fouks et al., (90) akathisia is “often associated with severe anxiety…”. (translated from the French)
I rank the intermittent, usually out of the blue rapid onset of anxiety (Its quick onset supports my view it is an inherent symptom of akathisia.) as one of akathisia’s major features that can help me increase my index of suspicion that akathisia is occurring. My patients will, at times, describe this as a feeling of “desperation”.
Sachdev and Kruk (105) found “coarse tremors” and “myoclonic jerks” in the legs to be due to a
neuroleptic-induced akathisia in about 5-10% of 100 inpatients as did Braude et al. (78) and Ritchie et al. (28) who observed myoclonus and akathisia from buspirone. I see these same symptoms from all my causative meds, but likely because of my early recognition and treatment, they are often limited to much milder, but, nevertheless, irritating muscle twitches, especially in the eyelids, cheeks, arms, and thighs. Other forms of muscle involvement such as cramps, (also noted by Fouks) spasms, and stiffenings are quite common with the akathisia I see.
Sachdev and Kruk (105) saw “a feeling of pins and needles” from akathisia in 12.5% of 100 inpatients, and Fouks et al., (90) noted“fourmillements” (tingling).
19
Sachdev states, (99) 12.5% of his patients “experienced paraesthesiae” from akathisia. To me, this rate is quite low. In 1992, before the SGAs, Decina et al. (100) reported 23% of 60 consecutively admitted psychiatric inpatients on neuroleptics suffered “subjective painful sensory symptoms” who did not have them at admission which they attributed to the treatment and which I would specifically attribute to akathisia. My estimate for paresthesias is 30-40%. They are sudden, usually sharp, stinging, or like electric shocks (as felt in “Garden State”). I typically ask my patient about bee stings, bites, shocks, or pinpricks. In the present national concern over bedbug infestations, many of my patients claim they are being bitten, but generally this stops after I begin treatment for akathisia. With so many people on our meds, I can wonder how much of our bedbug problem is only this!
There are various other paresthesias I commonly see with akathisia that have been described before. Astra Zenica, in a pamphlet on quetiapine (Seroquel) entitled “Recognize Akathisia”, (pamphlet #237575, June 2006) mentions the “sensation of skin crawling or jumping out of one’s skin” (i.e., wanting to). I find feeling bugs crawling on or under the skin, along with itching, to be one of the most common symptoms of akathisia, and again, not only due to the antipsychotics but from almost all the psychotropics. Burke et al. (101) saw rubbing of the face and hair and scratching from akathisia, which they thought of as an expression of “stereotyped movements” but which I suspect is just part of its paresthetic itching and crawling. In the same way, Barnes attributed scratching and face and thigh rubbing to “complex hand movements” (94) due to akathisia. Kim et al. (102) write of “paresthesias and various unpleasant sensations”. Fouks et al., (90) as translated in Van Putten, (89) write of “peculiar bodily sensations”, Van Putten and Marder, (88) of a patient who felt “worms crawling on my bones”, and Van Putten, of “vague somatic complaints”, all due to akathisia.(76) The vague somatic complaints I see usually entail weird or strange sensations such as being touched or pulled on, including internally, feeling water running down a part of the body, blood coursing through the veins, an inflated balloon inside, tingles, or numbness within the head, the brain being pulled on or ‘tickled’, etc. Freyhan (85) described “pulling and drawing sensations in the extremities” as did Barnes. (94) I see them occurring most anywhere on the body. Though many of these unpleasant sensations might be diagnosed as tactile hallucinations, I am quite sure they are more likely to be symptoms of akathisia because when I treat them as part of it, they typically resolve.
Head-banging has been seen with identified akathisia (76), (84) and sometimes where it was not mentioned (106) but which I suspect was present. I haven’t seen head-banging with my patients, but my guess is it’s from the itching, pulling, and other very uncomfortable feelings from akathisia inside the head of which they would complain and which I think I was able to deal with before injury occurred. I did have a couple patients who slashed their arms due to akathisia which I was then able to stop. (I can only wonder if akathisia is behind many of these self-mutilations, head-banging episodes, and agitation, we read of.)
20
Breathing can be affected by akathisia. Kruk et al. (107) write of “irregular respirations, dyspnea, grunting or gasping, and abnormal chest and esophageal movements” from TA and dyskinesia. Hirose, (84) in 5 patients, noted a restlessness in breathing and difficulty “breath[ing] in a leisurely relaxed manner”, with gasping, sighing, and dyspnea, and Kim et al. (102) noted “difficulty breathing”. Similar problems are reported by others. (101), (94), (103) I suspect these symptoms reflect the spasms, cramps, and tightenings I see from akathisia but have seen only a couple patients with such breathing difficulties. I’ve had a couple to a few with laryngospasm who responded to my akathisia medications and not so well to an anticholinergic, the usual therapy for this dystonia.
These papers reveal that some of the numerous symptoms I saw from akathisia have been recognized by others but were then apparently forgotten. I believe they are very much a part of this syndrome and can help us recognize just how frequent and important akathisia is to our patients’ comforts and our medication efforts. I think the field has only caught glimpses of what I have noted, leaving major gaps in our understanding of its significance and how to better treat it. This goes especially for its exacerbation of psychosis and depression and likely increase of anxiety and agitation.
I now need to show its frequency and that with my treatment protocols, how much of a difference we can make in relieving its many harmful, painful, and discomforting consequences.
RESULTS OF MY TREATMENT STUDIES
With so many people now on psychotropics and the high rate of akathisia from them, I believe there are millions who are greatly affected and harmed by it without recognition!
Of course, such an assertion needs support, so in order to test it and my claim for a much greater success rate from my treatment methods than we presently have, I carried out 2 studies on the results I saw with my patients. Since I had neither the knowledge nor time while at my regular work duties to properly do statistical studies nor use the rating scales such as the Hamilton Scale for Depression (HAM-D) or Montgomery-Asberg (MADRS), they were not done. My grading came from my own classification, and I counted only those patients who followed, or acceptably followed, my prescribed regimens at least long enough for me to make a reasonable judgment as to their responses to my treatment. I did my best to be as objective as I could and, if anything, leaned toward being harder rather than easier on myself with my scorings. But I cannot say no biases or other inaccuracies occurred, so more proper studies must be done to confirm or refute my findings.
I did not use the Last Observation Carried Forward (LOCF) method, for it does not allow for the exclusion of noncompliant patients who were not evaluable or who dropped out prematurely, though I suspect accepted statistical methods do say LOCF is the best way to deal with this universal problem in clinical research.
21
I did 2 investigations of my outpatient population, the first lasting a little over 8 months and the other just under a year. I included 100% of my patients except the aforementioned ones for whom I could not determine a response to my medicating efforts.
In my first, I evaluated all of the 241 individual patients I saw at least twice over an 8¼ month period. Nearly 100% were suffering from depression, be it from my most common diagnosis, major depressive disorder with psychotic features, then schizoaffective disorder, then major depressive disorder without psychotic features, then bipolar disorder, and finally, the few who had a straight schizophrenia where mood state does not play much of a role. Of these 241, 217 (90.0%) had akathisia by my diagnostic criteria and 24 did not. (20 of these 24 were compliant and 4 were not) Thirty-one of the 241 were, in my judgment, too irregular or refused to try my prescriptions to include in my evaluation of their response to my illness-treating and anti-akathisia medications, though I was still able to judge that 27 of these 31 did suffer from akathisia and just 4 did not (the 4 mentioned above who were not compliant), so I was still able to put them into my ratios for having it or not. Therefore, I evaluated 190 (241 - 20 compliant patients without it - 31 noncompliant ones) for their reaction or lack thereof to my treatment for their illnesses and akathisia. (I evaluated the treatment responses of my 20 compliant patients without akathisia separately as they did not need akathisia meds like the other 190, which placed them in a different group and which, interestingly, had a noteworthy response I will discuss below.)
My akathisia medications were guanfacine, clonidine, ropinirole, and an occasional benzodiazepine, plus I gradually lowered the illness-treating meds when needed (which I shall also discuss below) so as to attack the akathisia coming from both too much of the psychotropic medicine causing it and not enough of my anti-akathisia medicine for treating it. Because of inadequate response or side-effects limiting tolerance to a given akathisia medicine, a good number of my patients were taking more than one at the same time. When I performed these studies, I was no longer using propranolol, but since then, I tried it a couple times when nothing was working, and it seems there can be some patients for whom it is more beneficial than for others.
For grading the reactions to my medication protocol, I used the following 4 categories:
‘Excellent’ for those who felt essentially completely relieved of their underlying illness and akathisia with its recurring depressive and psychotic symptoms, though some would still hear an occasional voice, see flitting shadows, or feel a couple hours of mild depression and/or psychotic symptoms here and there when akathisia would still break through. One hundred thirty-six of the 190 (71.6%) were in this category.
‘Pretty Good’. These still had some residual symptoms of akathisia and underlying illness but generally would feel alright day and night with only occasional and mild occurrences of depression, psychotic symptoms, and akathisia. Thirty-five of the 190 (18.4%) I put into this category.
22
‘Fair’ for those who had a modest to moderate degree of improvement, yet still had a good distance to go before reaching the next level. Fourteen of the 190 (7.4%) were here.
‘Poor’. These did no better, or almost no better, than when they began. Five of the 190 (2.6%) did poorly.
I consider my top 2 groups to have been therapeutic successes -- 71.6% excellent and 18.4% pretty good, equaling 90.0%. (It is just coincidence this 90.0% success rate is the same as the above 90.0% of my patients who experienced akathisia.) These results are considerably better than what has usually been found in treating mental illness. For example, in 1 of the STAR*D study reports by Rush et al., (108) just 36.8% achieved remission (by the QIDS-SR) after completing the first treatment step, with a cumulative total of 67%, reaching it after up to 3 more medication switches or augmenting steps. Other investigations reveal similar limited outcomes. (109),(110), (111) One of these studies (110) showed that out of 108 of 215 patients (50.2%) who were classified as full responders with a score ≤ 7 by the HAM-D-17, only 19 (17.6%) really had no residual depressive symptoms, at all, by the SCID-P. So at least some of the 108 should, perhaps, be called only moderate successes. And then there is the 2010 article by Fournier et al. (112) that made such a stir in the news about the ineffectiveness of antidepressants for the treatment of mild to moderate depression to call attention to our shortcomings.
For schizophrenia, we see the same results. Naber and Lambert, (113) writing on the CUtLASS and CATIE studies, remark that medications gave “only limited improvement of psychopathology and quality of life”.
Clearly, there is much room for improvement, but of course I must leave it to further research to determine if my diagnostic and treatment discoveries will resolve or, at least, improve this great shortcoming.
As an additional but telling point, as noted above, I gave response grades to my 20 compliant patients who did not suffer from akathisia and only needed illness-treating medications. I scored 13 as having an excellent and 7, a pretty good response to them, putting all 20 in my therapeutic success group! This gives indication that when akathisia is absent, our illness-treating medicines can work quite well, which is substantially different than our present perception of their inadequacies which is essentially blind to the impact of akathisia. This adds weight to my contention that the difficulty with our alleged mediocre meds may primarily be the unrecognized akathisia they bring with them! (I have more evidence of this below.)
About a year after concluding my first study, trying to be as certain as I could as to the validity of my findings, I ran another on all my patients, again not using the LOCF. It might be of value to note, of the 241 in my first study, 159 (65.4%) were either still seeing me when I began my second count or had returned at some point before or during it to restart. Considering the nature of my patient population -- the homeless mentally ill living on or near our Skid Row -- this might say something about the validity of my discoveries as it seems to me to be a fairly high percentage for such clientele as these.
23
In this second nearly yearlong study, I saw almost the same number as the first who saw me at least twice, 246 vs. 241, with a diagnostic breakdown like the first. I counted only new patients to avoid a positive bias from the continuing ones. These, too, had to make 1 or more return visits to allow me a reasonable sense of their response to my regimens. Therefore, I evaluated just the 87 new patients (246-159 ongoing ones). Nearly 100% suffered depression. This time I added intermediate response rankings between the 4 in my first study to give 7, as I felt 4 left me with too broad a categorization, making it more difficult to gain an accurate picture of the results. Of these 87, 11 compliant patients and 1 noncompliant did not experience akathisia, leaving 75 (86.2%) who did, essentially the same percentage as my first study where 90.0% suffered from it. Nine of these 87 were too irregular or unwilling to follow my recommendations to include them, but as before, I was able to determine that 8 suffered akathisia and 1 did not, so these 8 could be included in the 86.2% who had it. Eleven compliant patients did not suffer akathisia, so I evaluated 67 (87 - 11 compliant ones without it - 9 noncompliant) for their response to my illness plus akathisia meds.
I put 34 in the ‘excellent’ response group, 10 in a new ‘pretty good to excellent’ grade, 9 in ‘pretty good’, 6 in my new ‘fair to pretty good’ rank, 7 in ‘fair’, 0 in a new ‘poor to fair’ group, and 1 in ‘poor’. I think it reasonable to classify my top 3 groups as successes (34 + 10 + 9 = 53) for a success rate of 53 ¸ 67 = 79.1%, lower than the 90.0% in my first study but still comparable and still much better than what we usually can expect to see.
I do not claim my 2 studies to have been properly scientific, but if they are decently true, these success rates merit further investigation as they are quite exceptional compared to what we presently have!
As in my first study, I also evaluated the response to illness-treating meds, alone, in my 11 compliant patients who had no akathisia, and almost like then, 10 of these 11 did very well (90.9% vs. 100% in study 1 with 20 patients) with 7 excellent, 3 pretty good to excellent, and 1 poor. So again, this indicates when akathisia is not present, the response to our medicines is very good. The treatment problem seems to be the akathisia they cause and not ineffectiveness!
Though some of akathisia’s importance has been recognized at times, it is evident to me that the extensiveness of its symptoms, ubiquity, and impact remains very under-recognized despite its playing such an extremely important role. It is seen as a movement disorder with accompanying dysphoric feelings that can sometimes be quite intolerable and is part of the extrapyramidal syndrome caused almost exclusively by the antipsychotics (much less for SGAs than for FGAs) and to some extent, the SSRIs. I maintain it is much more than that. It is a multi-symptom reaction engendered by nearly all our psychotropics which consists of paresthesias, dysesthesias, muscle spasms, twitches, myoclonic jerks, hot and cold flashes, bruxism, and more, in addition to restlessness, plus -- and this is a big plus-- it almost invariably worsens the illness due to its exacerbation and prolongation of psychotic, anxiety, and depressive symptoms -- this last group going quite unrecognized in the field. Dealing with the akathisia I see has made a pronounced and profound difference in
24
the comfort, happiness, and well-being of my patients. (A note of caution: I’ve had a number of them who stopped their meds because they felt so well they thought they did not need them anymore, of course to learn they did!)
ADDITIONAL CONSIDERATIONS ON THE UNDER-RECOGNITION OF AKATHISIA
I am quite surprised by what I see to be psychiatry’s very diminished awareness of the presence and importance of akathisia. After all, we began connecting it to our medications 60 years ago and should be more cognizant of it by now. This lack of recognition, even when coming from the FGAs, let alone the other psychotropics, was noted by Weiden et al. (115) in 1987, well into the neuroleptic era even before SGAs were available. They found 20 of 27 inpatients at the Payne Whitney Psych Clinic with researcher-diagnosed akathisia were misjudged by the clinical staff, 9 of whom were completely missed. Chung et al. (116) state, “Akathisia has been relatively neglected”, and Shen, (95) “[There is a] great chance of overlooking this condition”. Van Putten et al. (3) state, “[It] often goes undiagnosed”, and as I already quoted from them, “We believe that a far greater sensitivity to akathisia by the treatment community is warranted.” (3)
But even these, who have been more attuned to akathisia than most, had only a limited understanding of it in my judgement, seeing just a part of its full presentation and consequences, primarily its restlessness, dysphoria, anxiety, and agitation, all of which are important but not a full portrayal, by far -- and essentially only seeing it as coming from the antipsychotics.
Not having akathisia in mind or just a limited recognition of it speaks to the adage we heard in training, “You cannot make a diagnosis unless you think of it” -- and my addendum -- and you know its symptoms!
To this same point of under-recognition, Zimmerman et al. (117) found that a significant factor in our failure to find side-effects was our common practice of making a “global inquiry” about their presence rather than a direct one with specific symptoms in mind, so discovery requires a spontaneous report which is unlikely with the mentally ill. With 300 depressed outpatients, using a 31 item list from the self-administered version of the Toronto Side-Effects Scale, his group found 20 times more side-effects listed by the patients on this questionnaire compared to those recorded by their physicians. And even with frequently occurring or very bothersome ones, it was still 2-3 times more! (The Toronto Scale is not aimed specifically at akathisia.)
Zimmerman also cites several studies with similar results to his when comparing detailed questioning to an open-ended or self-reported exploration of side-effects. (118), (119), (120), (121), (122) Though these studies do not deal with akathisia, per se, and just 2 of them relate to psychiatric patients, my experiences with akathisia show the same finding as did Zimmerman, and so I feel it best to actively pursue its symptoms and not leave it to the patient to volunteer them. As I brought up above, with colleagues who have shown some interest in my discoveries, they tell me they see it only in a fraction of the patients I do – perhaps because of this ‘open-ended’ method or perhaps from not wanting to ‘lead their patients on’. I believe if we do not seek, too often, we shall not find! With my 85% incidence/prevalence rate, from what I have seen, akathisia truly pervades the
25
whole treatment process. Hirose (33) felt this non-recognition came partly from the clinician’s “failure to consider akathisia during antipsychotic therapy”, and I would add, from other psychotropic medicine families as well!
There are other reasons why akathisia is so frequently missed: (1). As I showed with my long symptom list, many of them are not recognized as being part of it. I believe I have discovered a whole new roster of hitherto unknown, or hardly known, signs and symptoms that belong to the syndrome. To review: some are paresthesias such as itching, tingling, numbness, and crawling revealed by scratching, brushing, or rubbing (the so-called “stereotyped movements” as labeled by Burke et al. (101) and thought to be part of TA); tremors, sudden sharp pains or shocks, intermittent chills and hot feelings causing the patient to put his/her jacket on and then take it off; complaints of headaches, bruxism, strange bodily sensations, and most important, becoming sad, moody, agitated, and/or getting nightmares and sleeplessness from returning depression and/or psychosis due to akathisia. (2). The PDR and PI sheets often separate the side-effect of ‘restlessness’ from akathisia even though, as I said above, this is what akathisia essentially means. (3). Akathisia typically occurs only intermittently and can be more quiescent than active.
At the beginning of my adventure, I never imagined just how many symptoms of this syndrome I would find (or rediscover) and how important its effects would turn out to be. As I continued to use clonidine, guanfacine, ropinirole, propranolol, and finally, benzodiazepines, I saw an ever-expanding number of them which these medicines could ease, usually completely or significantly, though I must forewarn, they usually require 3 to 4 tailored doses per day and even more. ER forms, which exist for most, may greatly help. (Formulary limitations at work prevented me from using them.)
IMPROVING AKATHISIA RECOGNITION AND OUTCOMES
Improving treatment outcomes requires a major change in the way we deal with a patient not doing as well as desired. We must keep akathisia in mind whenever our efforts are failing or falling short, and when we do, I aver that very frequently, akathisia, never thought of as the core problem, will be found to be just that. I expect this idea will be met with much disbelief.
If my patient had been doing well and is now relapsing, I first look for a change in compliance and alterations in medication doses and schedules which can easily trigger off akathisia. When a patient presents with a compromised or lost success, the onset or return of akathisia is a very likely cause. Therefore, I ask him/her to go through the regimen, including the illness meds, dose by dose, and will often find some change has been made which has restarted the akathisia and with it, a return of the illness. I find a relapse or insufficient response seldom lies with an inadequacy of the illness-treating medicines. They usually work and hold, as I saw in my 2 studies when akathisia was not a factor in 20 and then 11 patients who did very well except for only one of them.
26
But on the other hand, akathisia can break through its medication coverage, even with good compliance. Though much better than what we now use, my meds are not perfect. If on akathisia medicines and compliance is good, I would estimate that about 80% of the time a relapse of the illness will come from a recurrence of the akathisia and not from a recurrence of the underlying condition. The patient or doctor may attribute such problems and reactions to a psychological cause such as family or life difficulties, anniversaries, mistreatment, or that ‘everyone has their ups and downs’, etc., but I have found, very commonly, it is just akathisia to blame.
As discussed above, a highly effective and probably the easiest way to get at the akathisial cause of a relapse vs. a poor response to the illness medicines is to ask if there is a roller-coastering of depression and/or psychotic symptoms. To emphasize what I said just above, akathisia will typically bring with it an immediate and concurrent relapse of the underlying illness that begins and ends just as soon as the akathisia does. My patients essentially never appreciate on their own the swings akathisia brings but will see them only as a continuing condition. But they may drop some hints of their switches by saying “I go up and down” or “I have mood swings” which gives me the clue I seek. Then I find they can fairly easily begin recognizing these changes.
As I said, I can usually easily determine whether it is akathisia or the illness breaking through by investigating if akathisia symptoms are tracking -- from minute to minute -- with the intensification or remission of the psychotic or depressive ones. A detailed history of the dosing times and amounts of the anti-akathisia meds taken greatly help determine the cause to be akathisia as I will usually see an improvement 20 to 30 minutes after ingestion or the illness returning in about 3-6 hours as these meds wear off. I can then determine the timing of these cycles and improve the dosing schedule.
The existence of the improved state when the akathisia episode has turned off, tells me the illness-treating med(s) are working well, and inadequate response is not the problem but akathisia is! This experience reinforces my 2 studies when I had a very high success rate (20 out of 20 and then 10 out of 11) when akathisia was absent and the illness-treating medicines were all that were needed. When akathisia is not present, but the illness still is, illness symptoms will be steady and not roller-coastering. This tells me the illness meds are to blame. It is an easy and quite consistent way for me to differentiate between the two causes of relapse or poor results (akathisia vs. inadequate medication).
I know my findings will meet resistance -- as they should. Perhaps it is because we are so used to thinking of a relapse or poor response to be only due to the illness breaking through or not responding to our meds. Only one cause seems to be considered in medication management -- the illness is not being adequately controlled. But there are really two, and I have found the much more likely cause of relapse or poor response is inadequately treated or unrecognized akathisia, not a refractory underlying illness! The proper target is the med-caused akathisia, not some inadequacy in their effectiveness! You could have both, but I find this is not common.
27
There is another reaction that is recognized as akathisia and is called ‘withdrawal akathisia’. An abrupt or too rapid cessation or decrease of the psychotropics that cause the akathisia can greatly exacerbate it and make it more refractory or cause it to begin when it was not there before. Though our field basically recognizes it only from the neuroleptics, what seems to me to be this very same phenomenon also derives from the antidepressants but has been given the separate name of ‘Anti-Depressant Discontinuation Syndrome’ without realizing it to be what I believe it is -- a withdrawal akathisia. It brings on many of the same symptoms as my expanded akathisia has, such as burning, tingling, electric shocks, dizziness, muscle aches, chills, tremor, headache, insomnia, disturbing dreams, irritability, anxiety, and agitation. (123), (124), (125), (126), (127) However, antidepressant withdrawal does cause various GI reactions such as nausea, vomiting, and diarrhea which I do not see in withdrawal akathisia. Therefore, I would speculate an antidepressant withdrawal brings on 2 or more separate neurological and physical activations.
I have seen withdrawal akathisia many times when my patients have run out of, lost, stopped, or too steeply decreased their medications. I will see it begin within 1-3 days which a re-start of the withdrawn med(s) will then quickly resolve. This form of akathisia often seems to be more severe than what existed before, as it commonly will overwhelm my previously effective anti-akathisia agents even if they are still being taken after the psychotropic medicine(s) have been discontinued or reduced too fast. And the reaction can last a couple, and even more, months as it slowly eases (or perhaps becomes a TA). But restarting the terminated medicine, as with the Antidepressant Discontinuation Syndrome, will typically quickly end the withdrawal reaction and bring the patient back to where he/she had been before.
I can wonder, as have others, if akathisia is why some patients (especially adolescents and young adults) have attempted or thought of suicide when treated with SSRIs (128), (129), (130), (131) or antipsychotics. (132) My guess is they suffered a return or exacerbation of depression and/or psychosis due to akathisia either while taking their medicines or soon after stopping or too quickly decreasing them, resulting in suicidal thoughts or actions due to their great discomforts and/or fright from increased or recurring depression or psychosis.
This brings me to two other conditions with quite similar presentations to akathisia, one of which led me to successfully try ropinirole for it, of which I previously made mention.
The first is Restless Legs Syndrome (RLS). In 2004, I attended a seminar on it soon before the FDA’s approval of ropinirole, a dopaminergic agent, and was quite surprised to learn many of its symptoms were essentially the same as those I was seeing with akathisia. At that symposium, such complaints as aching, creeping, itching, crawling (even under the skin), pulling, prickling, pins and needles, numbness and tingling were listed in addition to restless legs. In subsequent lectures, especially those given by Dr. Mark Buchfuhrer who specializes in treating RLS and has written papers (133) and books (with others) (134) on it, I learned of other RLS symptoms I was seeing with akathisia such as muscle cramps and spasms, twitches, myoclonic
28
jerks, painful paresthesias such as electric shocks, burning and cold feelings, and sudden pin jabs, stings, and “bites”, as my patients with akathisia frequently called them, often believing they were victims of bedbugs. Hirose (33) lists a number of these same symptoms in akathisia, plus aching feelings, though he states many are absent with akathisia but present in RLS, with which I disagree, as I frequently see them in akathisia, too. In the booklet, “Restless Legs Syndrome: Diagnosis and Treatment in Primary Care, 2008” (135) a patient (p 2) describes the feeling of “water running underneath my skin”, and another, of “worms or bugs crawling deep in my muscles” (p 2), which, along with other strange and unpleasant bodily sensations and paresthesias, I also see with akathisia.
Though RLS generally occurs only when going to sleep or on lying down, it can become a 24 hour condition which akathisia almost always is. And as with RLS, akathisia is often exacerbated or triggered by lying down or going to bed. Also, RLS can occur elsewhere than in the legs such as the arms (135), (136) and even abdomen. (137) Because of these similarities, I knew I should try ropinirole for akathisia, and when I did, I found it as beneficial as clonidine and guanfacine.
The second condition is withdrawal from opiates, which also looks quite similar to the akathisia I diagnose. Mu opiates (the ones used clinically and have abuse potential) potently stimulate mu opioid receptors in the amygdala and locus coeruleus which then inhibit noradrenergic neurotransmission. (138) There are a host of symptoms shared by both opiate withdrawal (49), (139), (140), (141), (142) and the akathisia I see. They are: restlessness, anxiety, irritability, muscle twitches and aches, tremors, and alternating feelings of hot and cold with sweats and shivers. A patient of mine who had gone through heroin withdrawal a few times also endorsed itching, crawling, myoclonus, clammy sweats, sudden sharp stabbing pains, and muscle spasms, all of which I see in akathisia. However, opiate withdrawal also includes GI distress, rhinorrhea, yawning, a flu-like syndrome, and other symptoms which I do not.
Since these 3 different conditions -- Antidepressant Discontinuation Syndrome, RLS, and opiate withdrawal -- have so much in common with my form of akathisia, perhaps from this we can derive a better understanding of all 4 and their causation and treatment.
Though many of my akathisia symptoms are easy to spot, elaboration of some from my list above may further help their recognition. And it bears repeating -- these symptoms are intermittent.
1.) Exacerbation, persistence, or return of underlying psychotic symptoms
As I have stated, this is a very common and clearly enormously important symptom of akathisia which was first noted in 1956 by Sarwer-Foner and Ogle (86) at the very start of the psychopharmacologic era and then by others, some of whom I have already listed. (8), (87), (91), (93), (94), (95), (143) And as I already noted, the DSM-IV and -IV-TR, Appendix B, also acknowledged this, (81) but it was then surprisingly and unfortunately (to me) deleted from the DSM-5 (but then restored in the -5-TR).
29
This phenomenon can make it uncertain as to whether you are dealing with a refractory or relapsing psychotic (or depressive) illness or just akathisia. I went through this many times before I understood it, leading me to increase doses or add new meds without much or any benefit, and, at times, with harm. Also, to complicate matters further, there often are brief and temporary misleading improvements from these changes that would direct me further down this wrong path. I believe this phenomenon is an important cause of the polypharmacy and poor success rates we so often see, which, until I understood what was occurring and how to deal with it, I was a victim of, too.
2.) Exacerbation, persistence, or return of underlying depression
What I’ve said about akathisia-generated relapses and treatment resistance of psychosis applies to depression relapses and resistance as well, though as I mentioned, the literature (and the DSMs) do not seem to recognize this at all. A 2013 article (144) listed about 25 possible reasons for antidepressant resistance such as differences in metabolism, age, smoking, medical issues, lack of exercise, various genetic variations, the HPA axis, thyroid abnormalities, etc., but left out akathisia which I see as the most important cause, by far!
Akathisia’s capacity to exacerbate, prolong, and re-ignite an underlying depressive illness occurs all the time -- in my experience, just about every time the akathisia turns on -- which makes it extremely frequent! And as with psychosis, it does this very rapidly. Sometimes I will see this occurring right before my eyes into either an up or down mood, depending on the direction, on or off, akathisia is going. Increasing the problematic meds or adding new ones will usually just bring on more akathisia, and with it, worse or continuing depression. Of course, more antidepressants can occasionally be needed, but I seldom see this, which reinforces my contention that our medicines work better than we give them credit for. I believe a relapse of a treated depression (or psychosis) on its own is not very common if the medicines have already been effective for awhile. (There may be an exception here with bipolar breakthroughs, especially of mania.)
Differentiating whether the depression (or psychosis) is coming from the underlying illness vs. the akathisia is not difficult. A continuing underlying illness requires the condition to be ongoing and persistent, even without the ups and downs akathisia will bring. When the patient suffers from both illness and akathisia and the akathisia is quiescent, the depression will still be there. Otherwise, the depression will wax and wane as the akathisia does. If the depression is responding to the meds, I find the patient, if asked about this, will likely be able to recognize this difference.
I am quite certain this recurring exacerbation of an underlying depression does not result from the patient’s emotional reaction to the akathisia or from exogenous life problems. If it did, it would not arise as quickly nor be as severe (such as with returning psychotic symptoms or suicidal ideation) as when akathisia is the cause.
30
3.) Restlessness or antsiness
As I have pointed out, the restlessness of akathisia is the main symptom by which it is generally known (though anxiety/dysphoria gets some attention) with many papers describing it, especially in the legs. Hirose and others have also written of unusual locations for it such as in the back of the neck, (143) larynx, (1) and diaphragm, (84) as I have already mentioned. He states “[The patient] could not respire leisurely nor stop breathing at any time”. Walters et al. wrote of restlessness in the arms as the principal manifestation of neuroleptic-induced akathisia. (145) I will occasionally find it in such places. A patient told me he “felt restless” from his upper chest to the top of his head when the dose of one of his meds was increased which then resolved upon dose reduction. So we should probe for it by asking if our patient feels restless, antsy, the need to get up and walk around, restlessness in other parts of the body besides the legs or trunk, or feels so only when in bed, one of the most common times of exacerbation as I have already mentioned.
Interestingly, though my patients will frequently endorse restlessness, it does not show itself that often, even when they actively affirm it. This may be because of its intermittency. I would say less than half my patients will manifest it while I am with them, but a good 60-80% will endorse it when asked.
ADHD, frequently comorbid with other psychiatric disorders, (146), (147) will be felt as a restlessness in about 2/3 of adults who suffered it in childhood (148) but in a more subdued form, yet with fidgeting, difficulty sitting still, and feeling “restless inside”. Several times, I thought these patients had akathisia only to be told they had been feeling these symptoms since childhood. So I first ask if their present meds had brought on increased fidgetiness, foot twirling, or rocking over and above their ADHD background. And to be more certain about cause, I check for other akathisia symptoms.
4.) On and off nervous/anxious feelings
One of the most common symptoms of akathisia is anxiety which is also widespread in just about all the mental illnesses. So how do we know if akathisia is the source? Again, just look for concomitant akathisia symptoms and the roller coaster of depression, anxiety, and/or psychotic symptoms generally coming out of the blue without any reason. I also ask if my patient feels calmer and more relaxed 20-30 minutes after taking the akathisia med(s).
My patients will call these meds “anxiety” and, especially, “sleeping pills”. Clonidine and guanfacine can have a soporific effect, (more so with clonidine) so a little causal exploration may be needed. But I find akathisia is quite a bit more apt to be the reason for anxiety or insomnia than some other explanation.
A benzodiazepine may have a combined action against akathisia and of other causes of anxiety.
5.) On and off irritability, anger, and agitation
31
As noted in my Akathisia Symptom List, I believe this is just due to the hard-to-bear akathisia features and the illness exacerbations it creates. I do not think these symptoms are inherent in akathisia, but it is quite common and can be very disruptive and dangerous, so we need to be alert to the akathisia behind it. I recall a very agitated patient who was violent to objects but was not psychotic and could relate to his unexplainable rage and the akathisia symptoms I inquired into. When I acutely treated him for this, he calmed down within minutes and did very well for the next couple of years or so until I retired, hoping his next doctor in the clinic, to whom I had explained this, would understand his reaction as I had. So I caution the physician not to misdiagnose the source as a relapse of the illness when akathisia may very well be to blame.
6.) Headache
The causes can be difficult to differentiate. I can be more certain of an akathisial origin if there are intermittent sudden sharp head pains, strange feelings there, and/or other akathisia symptoms. Akathisia can intrinsically cause this or maybe bring on the tension and dysphoria that will cause a headache, and if it quickly responds to my akathisia meds, that surely gives me more confidence as to its origin.
7.) Muscle cramps, spasms, stiffness, and tightenings (dystonias)
These are fairly common. There are differences between EPS dystonias and those from akathisia. With the SGAs and my low doses, I virtually did not see EPS anymore. I think an EPS dystonia is generally more severe, painful, and probably more dramatic and frightening than one due to akathisia, but akathisia’s cramps and spasms are still significant. EPS will cause jaw locking, spasmodic tongue protrusions, laryngo-pharyngeal spasms, twisting or hyperextension of the neck and trunk, and oculogyric effects. The pulling feelings, spasms, muscle cramps, tightenings, and twistings from akathisia seem to be more uncomfortable than painful but can be painful, too. Finger, calf, and thigh cramps and spasms are the usual dystonias I see from akathisia. My patients often call them Charley horses. I have had a few who suffered mild laryngospasms for whom benztropine did not work well but which ended when I treated for akathisia.
8.) Tremors
An EPS hand tremor is commonly continuous and pill-rolling, probably occurring along with other Parkinsonian symptoms such as wooden facies, muscle rigidity and ratcheting, slowed movement, and akinesia. Akathisia does not seem to show such symptoms but can cause a rapid tremoring of the extremities. Patients will tell me they feel “shaky” inside. I do not know if those with EPS tremors feel this.
32
Akathisia tremors generally seem to start from a resting position as opposed to the intention tremor from lithium. Lithium-induced ones will respond to beta-blockers, but those from akathisia have a more limited response to them. Conversely, I do not find clonidine or guanfacine to do much or anything for a lithium tremor.
I wonder if the rabbit syndrome with its rapid tremoring of the lips is really due to akathisia and not EPS. I last saw it many years ago before I even knew of clonidine, but I recall it not responding well to anticholinergics. Perhaps it would respond better to an akathisia medicine.
9.) Twitches and Myoclonus
Twitches, usually around eyes, arms, and thighs, are fairly common with akathisia, but the more severe myoclonic jerks of arms, legs, and trunk, less so. Nishimatsu et al. (72) write of a polysomnogram-documented nocturnal myoclonus that “decreased remarkably” after akathisia was blocked with clonazepam. Myoclonus and twitches from akathisia can cause the patient to drop something or fall. Several of mine went to the ER in the mistaken fear it was a serious event. But a note of caution: since the alpha adrenergic agonists are antihypertensives that can also cause bradycardia, it is important to be alert to orthostasis. So if the patient falls or loses balance, I see if it were preceded by an orthostatic lightheadedness/dizziness vs. myoclonus.
11.) Bruxism
Dentists are finding bruxism to be an increasing problem, one that I suspect parallels the great increase in psychotropic usage. Dr. Ivan Lapidus of the UCLA School of Dentistry, a while back told me, “We see tons of bruxism with all the SSRIs, the SNRIs, and the anticonvulsants, especially Tegretol, Trileptal, and Lamictal” (which we also use as psychotropics and which cause their share of akathisia). They also saw “sharp pains in the jaw and electric shocks” (more akathisial symptoms) with them. I have had a number of patients who told me their grinding stopped or was greatly reduced when I treated their akathisia. Amir et al. (149) describe two cases where nocturnal bruxism, coupled with akathisia, responded to propranolol.
12.) Dizziness and other symptoms that may cause medical concern
Dizziness is fairly common from akathisia. Its cause can be confounded with an orthostasis from my akathisia meds. At first, I attributed dizziness to them, but then I noted it was often present along with the akathisia before I ever added my medications, or it would improve or end when I began or increased them. With further exploration, I found dizziness would often occur while the patient was seated or lying down, which would strongly rule against orthostasis. So I see if dizziness eases when my guanfacine or clonidine is working well or occurs when not standing. Of course, a blood pressure is warranted. Hypotension from my meds is not that much of a problem, generally not occurring below 0.6 mg clonidine or 3-4 mg guanfacine/day.
33
Similarly, when patients experience fairly common precordial chest pains, I ask if they are sharp, sudden, and not radiating as would occur from akathisia vs. typical angina, or if they happen when at rest vs. upon exertion, or end soon after an akathisia med is taken, or only begin when my meds have worn off and other akathisia symptoms are also returning. More often than not, really much more often than not, I am able to determine that these and other worrisome symptoms are due to akathisia and not to a medical problem. I ask the reader to consider how much trouble, anxiety, and cost can be prevented when akathisia is kept in mind and treated.
15.) Paresthesias
It seems some paresthesias, such as sharp pains and numbness, will focus onto old areas of injury or other physical difficulties such as arthritis, making it uncertain as to whether akathisia or exacerbation of the old injury or condition is to blame. Again, the coincidence or absence of these pains and discomforts with akathisia symptoms plus the response to akathisia meds will likely resolve the question. I’ve seen a good number of such cases, and in general, I would say much or most are from akathisia.
MANAGING AND TREATING AKATHISIA
Treatment difficulties can come from the limited duration of medication action of 3-5 hours and from the varying intensities of akathisia throughout the 24 hours requiring varying doses and times of administration.
If dosings become too complicated, a chart of the medication schedule is much easier to follow than directions on a bottle. And hopefully, the use of extended release forms can greatly diminish this problem.
Another major treatment difficulty occurs because your patient was put on excessive doses of illness meds due to the common misunderstanding of the real cause of a poor response, and now you need to deal with this. The caution is dose reduction must be done slowly to avoid a withdrawal reaction or confuse the doctor as to whether the treating meds have now gone too low vs. the problem still being akathisia.
The difficulties I have described are good reason for keeping the illness-treating med doses as low as possible which can surprisingly be much lower than presently believed. (see below) Akathisia is dose related and can become more treatment refractory as psychotropic doses increase.
The need to adjust akathisia meds is probably the most frustrating part in my treatment as they can fairly quickly lose their efficacy. Though I believe my meds are usually superior to propranolol, they are not perfect, and a breakthrough of akathisia is fairly common. This can be helped by a gradual increase in their doses along with a gradual decrease in the illness medications. Extended release forms may make a big difference, too, but as I mentioned above, formulary limitations blocked me from using them.
Here are my dosing strategies for the 3 akathisia med families I use. (I leave out propranolol as I have hardly used it.) I usually begin with guanfacine vs. clonidine because it seems less prone to cause grogginess or dizziness and usually -- but not always -- will work as well. GI distress seems minimal for both, their
34
xerostomia has a fairly effective OTC treatment, (Biotene) and grogginess will often ease with time. I begin guanfacine at 1 mg, or a comparable clonidine at 0.1 mg, BID but provide directions for a TID schedule because BID is frequently not sufficient to prevent a coverage gap in the afternoon, when going to bed, or, very commonly, in the middle of the night. Given acutely, these medicines, including ropinirole, generally take only 20-30 minutes to begin working. Their action can last less than 3-5 hours, especially when akathisia is severe, regardless of the listed half-lives of 12-24 hours for guanfacine, 6-24 for clonidine, and 6 for ropinirole. I have some patients who need 7-8 doses per day (but some, only 1). They are willing to follow this because of the return of the underlying illness and/or akathisial symptoms if they do not.
Ropinirole is my usual second option, but I find it is as effective as clonidine or guanfacine. Nausea and sometimes vomiting occur roughly half the time which food eases about half of those times. Sometimes I need both families.
I should say something about pramipexole, another dopaminergic agonist like ropinirole used for RLS and Parkinson’s, but I haven’t tried it (though I should have). It likely would have the same or perhaps even better value for akathisia. A number of studies have found pramipexole (up to ~ 4.5 mg/d) (150), (151), (152), (153), (154) and the less studied ropinirole (155) to be quite helpful as adjunctive treatment for refractory unipolar and bipolar depression, but no mention of akathisia was made in any of these papers as a possible reason for their treatment value. Aiken (63) reviewed 24 studies on pramipexole’s general use in psychiatry and found a very strong effect size of 0.6 to 1.1 at a mean dose of 1.6 mg/day in the 3 placebo-controlled trials in his review that examined its benefits just for treatment-resistant depression. But again, no mention of akathisia was made in any of these 3 (151), (152), (156) as a possible cause of the treatment resistance.
From my use of ropinirole, I suspect pramipexole’s adjunctive benefit for depression is really due to a probable effectiveness against an unrecognized akathisia. Studies also show pramipexole to be of adjunctive value to antipsychotics in the treatment of schizophrenia. (159), (160) My guess as to why is the same -- its likely effectiveness against akathisia. For all I know, it might be better where ropinirole is not working so well, just as occurs with clonidine vs. guanfacine. Pramipexole seems to cause less nausea, vomiting, and dizziness than ropinirole and may also be more effective for RLS. (157)
You might ask if ropinirole and pramipexole have an inherent antidepressant effect in addition to their likely akathisia benefits. Perhaps so, possibly from the same dopaminergic action (158) that may ease the akathisia. I’m not able to judge, having used it only when akathisia was the problem.
My recent discovery of the effectiveness of the benzodiazepines for akathisia has opened a new and valuable treatment option for me along with my others. At times, I saw they could be quite beneficial, and as with clonidine, I am not the first to have found this family helpful for akathisia, (101), (69), (70), (71), (72), (73), (74) though Poyurovsky et al. (37) did not think too highly of them. Lima et al. (161) gave a limited approval, stating,
35
“…the use of benzodiazepines may reduce the symptoms of antipsychotic-induced acute akathisia.” Because of abuse potential, I first see how my patient does with my first 2 choices which usually are sufficient. Generally, I will choose lorazepam or clonazepam which have a lower risk of abuse than diazepam and alprazolam, but rarely, I found I needed to use 1 of these for the patients who would respond only to them. Importantly, if my added benzodiazepine has been helpful for combating a refractory akathisia, I have not seen an abuse problem developing. I think there is a similarity between benzodiazepines used for akathisia and the safe use of the stimulants for ADHD and ADD when these medications are judiciously and justifiably given.
I have already spoken of propranolol and that I abandoned it many years ago, but soon before my retirement, I tried it again with some success on a couple occasions when I had an insufficient response from my other medicines plus dose reductions of the akathisia-causing meds. So it is an option to keep in mind.
I should now describe how I decrease psychotropic doses to ease akathisia. It’s an important tool for abating it. Happily, I commonly find I can decrease the treating meds to extremely low, yet still effective doses. I have found if a patient is very sensitive to akathisia, he/she is usually also very sensitive to the beneficial effects of the illness-treating medications, giving me the room to greatly lower the doses to significantly ease the resultant akathisia. These decreases must be done gradually to avoid inducing a withdrawal akathisia and also to minimize the risk of going below a needed blood level of illness-treating medicine and, perhaps, to avoid inducing a TA.
To give a sense of how low doses can go, I will list my successful regimens where I finally achieved control of both illness and akathisia. These patients were on just one illness-treating medicine for their major depressive or schizoaffective disorders along with akathisia treatment, and who I thought had reached a successful stability. My guideline for a listing here is that my average daily doses were less than the smallest tablet made – except for 1 schizoaffective patient on just 1 mg risperidone/day and 1 with major depressive disorder on 10 mg imipramine/day, both of whom I felt I should include because these doses were so low. My guess is these regimens are quite unheard of, yet they worked well for the following 26 patients: with fluoxetine, I had 4 on 5 mg/day, 1 on 5 mg 5 days/wk, 1 on 5 mg 4 days/wk, 1 on 10 mg 5 days/wk, 1 on 5 mg 2 days/wk, and 1 on 10 mg one day and 5 mg the next. With sertraline, I had 1 on 12.5 mg/day, 1 on 12.5 mg 5 days/wk, 1 on 12.5 mg 4 days/wk, and another on 12.5 mg every fifth day. Continuing, I had 1 schizoaffective patient on 1 mg aripiprazole twice/wk, another on 12.5 mg quetiapine 5 days/wk, and 2 on 12.5 mg/day (1 was a major depressive).Another schizoaffective was on perphenazine, 1 mg/day on 5 days/wk and 2 mg on the other 2 days. Two with major depression were on buproprion, 1 on 75mg every other day and another on 37.5 mg once every 10 days! I had 3 patients on 12.5 mg lamotrigine/day, 1 on mirtazapine at 3.75 mg/day, 1 on 3.75 mg every 4 days, and finally, 1 on 5 mg nortriptyline once every 10 days!
36
I am sure these would all be considered extremely low doses for their illnesses, (and keep in mind that anti-akathisia meds can still need to be quite high). And yet, this is what worked for these patients for both their illnesses and akathisia that had plagued them until we had reached these levels. As I’ve said, some patients -- maybe much more than some -- are very sensitive to akathisia but fortunately, then usually quite sensitive to the beneficial effects of the illness meds, too. I found it easier to slowly increase the treating meds to help prevent akathisia from the start rather than having to decrease them once it had begun.
I believe these low dose regimens show just how important it is to be aware of at least some patients’ sensitivities to dose. We all know the old medical maxim to ‘start low and go slow’. I suspect it applies more often than we realize with psychotropics. Another benefit of this is that this lessens the risk of going right past an effective regimen where the akathisia is minimal or nonexistent.
These low dose regimens tell me our medicines are frequently much more powerful than we give them credit for (as can be seen from the 100 and 90.9% success rates I had in my 2 studies with psychotropics, alone, when akathisia was absent) and that we can have more room than we realize to decrease doses when needed. Soon before retirement, I started new patients with the smallest pill denominations available, and this method seemed to work well, but I did not have enough opportunity to be sure. If my discoveries are correct, this will likely change the way we think about our medication regimens.
Occasionally, I have been uncertain as to whether I was dealing with a continuing akathisia or if my diminishing doses became too low to control the illness, so I would increase the illness medications a little and see if the illness improved or not. If not, then akathisia was still the likely problem, and I would retry a reduction again. Frequently -- more often than not -- I found this direction was still called for.
The determining factor that tells me the illness-treating meds are effective is that when the akathisia is quiescent, the patient will be feeling well or at least pretty well. Then I know my medicine does not need an increase and, if anything, may need a decrease to further reduce the akathisia. But there are times when patients are persistent about having an increase, and though I will tell them this could be one of the “worst things” I could do, I may give in to their wishes for the sake of the relationship and their learning. Usually, they are worse off for an increase, but as I said above, an increase in the illness medicine can still misleadingly, but only temporarily, improve a poor response that is due to akathisia which is then followed by a new recurrence beginning in days, weeks, or months as akathisia breaks through again with a renewal of the psychotic or depressive symptoms which could then be wrongly treated with another dose escalation or augmentation.
Patients on their own can take the medication process in two wrong directions at the same time. If results are not going as they wish, they might increase their illness meds on their own (perhaps in the false belief that more is better) and then, to make matters worse, decrease those fighting their akathisia, incorrectly believing they were the cause of their relapsed or persistent illness. To discourage this, I will tell patients if
37
they feel a relapse coming on and must deal with it on their own, to “first try increasing your akathisia medicine, not the illness one(s)”. This erroneous action happens fairly often. It is a natural reaction for patients -- and their doctors -- to do this when they feel the treatment isn’t working as well as desired. And since the basics of akathisia treatment seem to be somewhat difficult for patients to grasp, (and both patients and doctors to believe) they can wrongly decide which medication should go up and which should go down. When I have made symptoms better by a re-lowering of the illness-treating medicines after such an increase and/or re-increasing the ones for akathisia, I will remind the patient, “Less illness medicine can help you feel better, not worse!”
I should add here that I have not felt the literature’s frequent differentiation between acute and chronic akathisia to be of importance as I do not think this matters for its recognition or treatment.
I suspect the two processes -- the roller coaster mood and/or psychosis pattern due to akathisia and the temporary misleading improvement in mental status resulting from an increase in the illness-treating medicines -- to be major reasons for a misdiagnosis of refractory psychosis or depression. From this follows the cycles of ever-increasing doses, med changes, and augmentations that lead to polypharmacy and the search for new medicines and new medicine families. I suspect unrecognized akathisia is a major, if not themajor, cause of polypharmacy -- much discussed in recent years and generally felt to be inadvisable. The physician tries to deal with breakthrough or continuing illness symptoms by adding a second and third medication without recognizing what I see as the likely akathisia behind them. I have dealt successfully with numerous such cases by asking if my patient had been doing or feeling better or no worse before the illness meds had been changed, increased, or new ones added. Usually, I find he/she can give me a pretty good idea as to what regimen I can safely (and gradually) return to -- now with akathisia meds in addition.
If we medicate in what I think is the better way where I saw a 90 and 79% success rate in my 2 studies, I believe we will see much fewer refractory and resistant cases and much less polypharmacy. But my studies need validation, which, if I am proven right, should bring on a major change in our too often poorly performing medication protocols of first increasing the dose or looking for a new medicine or med combination when our patient is not doing well.
A good example of a cause of polypharmacy is in my previously mentioned Fava and Rush article (109) which advocates for a large list of augmentation and combination medications “right from the start of treatment” for major depression to improve poor treatment results while not recognizing akathisia at all as a problem, much less, the problem, as I see it to be. Interestingly, they do recommend pramipexole, ropinirole, benzodiazepines, and even opiates as part of their response to resistant depressions -- but without connecting these meds to their effectiveness against akathisia. (I have not spoken of opiates, but I have had some indication they might ease it, too, just as they can ease a difficult RLS.) As I stated, akathisia is, by far, my most common cause of persistent psychotic or depressive symptoms and not some inadequacy of our
38
medicines. I must repeat, though, I only saw outpatients who will not be as severely ill as inpatients from which many study populations are drawn.
To determine if akathisia is playing a role in our treatment efforts, we just need to ascertain whether the on and off depressive and/or psychotic symptoms are co-occurring with the on and off of akathisia signified by some of the symptoms on my list, especially anxiety, restlessness, itching, crawling, and numbness, which may be the most common. Then in addition to my akathisia meds, if I think I have some room to maneuver, I may also begin easing the dose of the treating medicine to attack the akathisia coming from this cause, as I noted before.
A good time to investigate for akathisia is when our patient is lying down to sleep which can worsen it, or in the middle of the night when he/she is awakened by it. When I add akathisia medicines at bed and/or in the night (ER forms could ease this.) sleep usually comes on or returns in 15-25 minutes.
A word of warning: I find it usually takes a fair number of adjustments to get things right. The breaking through of the illness between doses of my akathisia meds occurs often, so it is most important to establish the almost hour by hour details of the response to the akathisia meds unless the ER ones can resolve much of this titration difficulty.
A related issue is that many times, patients have told me either the illness or akathisia medicines were not working only for me to discover they had been working well, or at least adequately, when they were taking my meds as prescribed, who then regained their stability or improved mood when they returned to what they were supposed to be taking and when they were supposed to be taking them. A note of caution here: It was not unusual in these cases for my patients to say they had been “taking my meds as prescribed” but could not give me any dosing details which meant they likely were not! I would estimate such dosing changes in illness- and/or akathisia-treating medications -- and not a loss of efficacy -- to be the cause of a relapse as much as 50 to 70% of the time when the response had previously been good. I will tell patients to ‘’first think akathisia’ to help keep them from making the kinds of alterations they should not.
Another incorrect attribution patients and likely their doctors make is not to recognize the akathisia behind many of their emotional difficulties which they may blame on ‘stress’ or ‘life problems’. These problems may be severe, but I still recommend seeing if akathisia is the real culprit, especially if hallucinations, nightmares, or paranoia have also returned which increases the likelihood akathisia is the source. The same can be said for physical symptoms which may be attributed to diabetes, fibromyalgia, old injuries, back or joint difficulties, menopause, bedbugs, etc. Very often, it is just akathisia, and even if the patient feels the meds are working well, I frequently find akathisia to be still giving them added trouble.
39
Another possible akathisia presentation is agitation and violence which I described above with one case. I suspect many more patients than we realize have experienced this untreated dangerous symptom which could be avoided if we just recognized and then treated the akathisia that is likely behind at least some of the episodes as was noted in section 333.99 of the DSM-IV and -IV-TR and the -5-TR (p 813) where it stated, akathisia could result in “[a] worsening of psychotic symptoms or behavioral dyscontrol (my emphasis) …”. (81)
The exacerbation of illness symptoms caused by akathisia -- depression, hallucinations, nightmares, agitation, anxiety, insomnia, etc. -- will generally ease as a group with its successful treatment, but different parts can ease at different rates, especially the insomnia, perhaps because of its worsening upon lying down. This will require more targeted treatment and/or med reduction.
Because of the unrecognized impact of akathisia, I have come to question much of the research results and remedies regarding many of the important medication issues in psychiatry, especially those regarding the high numbers of patients refractory and resistant to treatment. Hopefully, I have also clarified and provided new understanding for other issues such as how to improve sleep, what is behind the physical complaints that can bring unneeded referrals, is unrecognized akathisia the reason why pramipexole is of significant value for depression and psychosis, is akathisia behind some or much of the increased suicidality seen especially in younger populations, what is the commonality between the causes of the Anti-Depressant Discontinuation Syndrome, RLS, opiate withdrawal, and akathisia? With my recognitions, I believe I am not faced with such a troubling degree of limited gains and frustrations in my medication efforts as seems to be the case in our field. Instead, I am able to routinely treat many patients who I think would elsewhere be considered much more problematic. I have found I can achieve remission or near remission due to my recognition of the enormous role akathisia (my kind) plays in treatment resistance and the indispensable role my akathisia medications and procedures play in resolving it. But at the same time, I wish to emphasize it can require diligence and attentiveness to determine the proper regimens for many.
As a result of my discoveries, I now believe psychosis and depression are not so difficult to deal with (not to say it is easy), and with this knowledge, I feel I do not have to face anywhere near the number of limited gains and constant disappointments my colleagues do. But my methods will require a readiness to ‘think outside the box’ of ever-increasing doses, med switches, and augmentations that we have put ourselves in
SUMMARY AND CONCLUSIONS
I have tried to give the reader an understanding of a new and no doubt controversial perception of a very poorly recognized but extremely important side-effect syndrome that I believe occurs almost all the time with almost all our psychiatric medicines. I think because we have missed, forgotten, or ignored the constant illness relapses akathisia brings with it, we just weren’t tuned in to what it could do. For about 27 years I was
40
on a journey of discovery of this syndrome, one that was both an adventure and surprise for me -- adventure like any voyage of discovery and surprise because even though akathisia was noted 60 plus years ago at the very start of the psychopharmacologic era, its ubiquity and profound importance for treatment has remained unrecognized and even became less appreciated as we switched to the new antipsychotics. As I noted above, this diminishment is reflected in the DSM-5 vs. the DSM-IV and -IV-TR but then restored in the -5TR.
I think we can all agree that treatment resistance is the major problem psychiatry faces today, and I believe I have found the answer -- or at least a significant part of the answer -- as to what is occurring. We have been pursuing the wrong target all these years with the resultant inadequate response of psychiatric illnesses to our medicines which led us to think our medicines were inadequate and not that the highly frequent akathisia they bring with them is what is so consequential.
I think we may have become so imbedded in the goal of finding a better medicine or medicine combination that we have not recognized the correct target is elsewhere. I believe the ‘true target’ is akathisia with the numerous symptoms I have described (vs. the usual perception of just restlessness and some anxiety/dysphoria), especially what I consider is its most important and relevant -- the intermittent and immediate exacerbation of the underlying illness we are trying to treat -- so important because the false picture of inadequate medication it creates has led us down the wrong treatment path over and over again, thus prolonging our patient’s suffering -- not to mention ours!
I believe our medicines work quite well once you have treated the akathisia they cause, as I showed in my 2 studies. This akathisia creates what is probably a not unusual phenomenon in medical care where a side-effect or an overdose -- as with insulin or digitalis -- brings on what appears to be a worsening of the illness itself! This is what akathisia does just about every time it turns on -- generating the ‘roller coaster’ effect on mood and/or psychosis as it comes and goes. To treat the illness, we must also recognize and treat the akathisia and not make it worse with more and more of the offending medicines! A balance needs to be searched for and found!
The psychotropics that treat the 3 major mental illnesses of depression, bipolar disorder, and psychosis seem to bring akathisia with them as a very common and, perhaps, inherent consequence. This could be the reason why so many of my patients suffered from it -- 85%, which is far greater than presently recognized. None of this has been perceived, leaving us in our present difficulty of an approximate 35-45% success rate -- possibly up to 67% (108) after much effort. I believe there will be no way out of this conundrum as long as we continue to search only for new medications and combinations since they will all likely cause akathisia, except, perhaps for the antipsychotic, clozapine, with all its dangers and difficulties that discourage use, and the newly approved anesthetic/antidepressant, esketamine, with its issues that will discourage use, also. Moreover, clozapine may achieve response in only 40% of patients with treatment resistant schizophrenia (163) which still leaves much to be desired.
41
I hope there will now be others who wish to explore the truth or non-truth of what I have discovered. I know it goes very much against the grain of present treatment thinking and must be replicated at least a few times before it can gain even some acceptance. To that end I should give a forewarning to anyone who wishes to explore my findings further: do recognize that looking into the akathisia I see requires significant attention to details such as just when meds were taken, missed dosings, whether doses were cut or consolidated, the correlation of dosings with the start or end of another bout of akathisia, etc., but if what I have found is true, it will be worth it.
Of course, my discoveries need to be verified. When I first wrote up my findings, I thought I would see interest in them from the academic psychiatric community but was surprised to find this interest was not there. Perhaps my discoveries are too far outside the box to be acceptable. I hope this paper can change that and encourage a further look at what I have seen. I have done my best to impart the knowledge I have acquired in as concise a manner as I could.
REFERENCES
1. Haskovec L. Akathisie. Arch Bohemes Med Clin. 1902; 17: 704-8
2. Sachdev, Perminder. Akathisia and Restless Legs 1995; Cambridge Univ. Press. As per translation p 355-9
3. Van Putten T, May PR, Marder, SR. Akathisia with haloperidol and thiothixene. Arch Gen Psychiatry 1984
Nov; 41: 1036-39
4. Sachdev, Akathisia and Restless Legs 1995, ibid, p 88
5. Freyhan FA. Psychomotility and parkinsonism in treatment with neuroleptic drugs. Arch Neurol Psychiatry
1957; 78: 465-72
6. Freyhan FA. Therapeutic implications of differential effects of new phenothiazine compounds. Am J
Psychiatry 1959; 115: 577-85
7. Sachdev, Akathisia and Restless Legs 1995, ibid, p 210
8. Brown P. Review: drug induced akathisia in medical and surgical patients. Int J Psychiatry Med 1988 May;
18(1): 1-15
9. Sachdev, Akathisia and Restless Legs 1995, ibid p 142-3
10. Weiner WJ, Luby ED. Tardive Akathisia. J Clin Psychiatry 1983 Nov; 44(11): 417-9
11. Fleischhacker, WW, Roth SD, Kane JM. The pharmacologic treatment of neuroleptic-induced akathisia. J
Clin Psychopharmacology 1990 Feb; 10(1): 12-21
12. Blaisdell GD. Akathisia: a comprehensive review and treatment summary. Pharmacopsychiatry 1994 Jul; 27 (4): 139-46
13. Kane JM, Fleischhacker WW, Hansen L, Perlis R, Pikalov 3rd, Assunção-Talbott S. Akathisia: an updated
review focusing on second-generation antipsychotics. J Clin Psychiatry 2009 Apr21; 70(5): 627-43
14. Sachdev, Akathisia and Restless Legs 1995, ibid, p 98-105, p 211
15. DSM-IV-TR, Appendix B, § 333.99, p 801
16. Nelson JC, Thase ME, Trivedi MH, et al. Safety and tolerability of adjunctive aripiprazole in Major
Depressive Disorder: a pooled post hoc analysis (studies CN 138-139 and CN 138-163). Prim Care
Companion J Clin Psychiatry 2009; 11(6): 344-52
17. Peluso MJ, Lewis SW, Barnes TR, Jones PB. Extrapyramidal motor side-effects of first- and second-
generation antipsychotic drugs. Br J Psychiatry 2012 May; 200(5): 387-92
18. Maany I, Dhopesh V. Akathisia and fluoxetine (letter and comment). J Clin Psychiatry 1990; 51: 210-12
19. Lipinski JF Jr, Mallya G, Zimmerman P, Pope HG Jr. Fluoxetine-induced akathisia: clinical and theoretical
implications. J Clin Psychiatry 1989; 50: 339- 42
20. Poyurovsky M, Pashinian A, Weizman R, Fuchs C, Weizman A. Low-dose mirtazapine: a new option in the
treatment of antipsychotic-induced akathisia. A randomized, double-blind placebo- and
propranolol-controlled trial. Biol Psychiatry 2006 Jun 1; 59(11): 1071-77
21. Poyurovsky M. Acute antipsychotic-induced akathisia revisited. Br J Psychiatry 2010 Jan; 196(2): 89-91
22. Hieber R, Dellenbaugh T, Nelson LA. Role of mirtazapine in the treatment of antipsychotic-induced
akathisia. Ann Pharmacother 2008 Jun; 42(6): 841-6
23. Wilson MS 2nd. Mirtazapine for akathisia in bipolar disorder. J Clin Psychopharmacol 2005 Aug; 25 (4):
394-5
24. Markoula S, Konitsiotis S, Chatzistefanidis D. Akathisia induced by mirtazapine after 20 years of continuous treatment. Clin Neuropharmacol 2010 Jan-Feb; 33(1): 50-1
25. Gulsun M, Dorok A. Mirtazapine-induced akathisia. J Clin Psychopharmacol 2008 Aug; 28(4): 467
26. Girishchandra BG, Johnson L, Cresp RM, Orr KG. Mirtazapine-induced akathisia Med J Aust 2002 Mar 4;
176(5): 242
27. Patterson JF. Akathisia associated with buspirone. Journal of Clinical Psychopharmacology 1988; 8: 296-7
28. Ritchie EC, Bridenbaugh RH, Jabbari B. Acute generalized myoclonus following buspirone administration.
Journal of Clinical Psychiatry 1988 Jun; 49(6): 242-3
43
29. Sachdev. Akathisia and Restless Legs 1995, ibid, p 213-14
30. Sachdev, Akathisia and Restless Legs 1995, ibid, p 143
31. Lima AR, Weiser KV, Bacaltchuk J, Barnes TR. Anticholinergics for neuroleptic-induced acute akathisia.
Cochrane Database Syst Rev. 2006 Oct 18; (4): CD003727
32. Sachdev, Akathisia and Restless Legs 1995, ibid, p 253-9
33. Hirose S. The causes of underdiagnosing akathisia. Schizophr Bull 2003; 29(3): 547-58
34. Sachdev, Akathisia and Restless Legs 1995, ibid, p 259-71
35. Lipinski JF, Zubenko GS, Barreira P, et al. Propranolol in the treatment of neuroleptic-induced akathisia.
Lancet 1983; 2: 685-6
36. Wilbur R, Kulik AV. Propranolol for akathisia. Lancet Oct 15 1983; 2: 917
37. Poyurovsky M, Weizman A. Mirtazapine for Neuroleptic-Induced Akathisia. Am J Psychiatry (letter) 2001
May; 158(5): 819
38. Bratti I, Kane JM, Marder S. Chronic restlessness with antipsychotics. Am J Psychiatry 2007; 164: 1648-54
39. Sharma A, Madaan V, Petty F. Propranolol treatment for neuroleptic-induced akathisia. Prim Care
Companion. J Clin Psychiatry 2005; 7(4): 202-3
40. Lima AR, Bacalcthuk J, Barnes TR, Soares-Weiser K. Central action beta-blockers versus placebo for
neuroleptic-induced akathisia. Cochrane Database Syst Rev 2004 Oct 18; (4): CD009946
41. Stryjer R, Strous RD, Bar F, Poyurovsky M, Weizman A, Kotler M. Treatment of neuroleptic-induced
akathisia with the 5-HT2A antagonist trazodone. Clinical Neuropharmacology 2003 May-Jun; 26(3): 137-41
42. Stryjer R, Rosenzcwaig S, Bar F, Ulman AM, Weizman A, Spivak B. Trazodone for the treatment of
neuroleptic-induced akathisia: a placebo- controlled, double-blind, crossover study. Clin Neuropharmacol
2010 Sep-Oct; 33(5): 219-22
43. Sachdev, Akathisia and Restless Legs 1995, ibid, p 267-79
44. Goodman & Gilman. The Pharmacological Basis of Therapeutics, eleventh edition, eds: Brunton LL, PhD,
Lazo JS, PhD, Parker KL, PhD, McGraw-Hill, 2006; p 256
45. Sorkin EM, Heel RC. Guanfacine. A review of its pharmacodynamic and pharmacokinetic properties and
therapeutic efficacy in the treatment of hypertension. Drugs 1986 Apr; 31(4): 301-36
46. Saameli K, Jerie P, Scholtysik G. Guanfacine and other centrally acting drugs in antihypertensive therapy;
pharmacological and clinical aspects. Clin Exp Hypertens A 1982; 4(1-2): 209-19
44
47. Goodman & Gilman, ibid, p 169
48. Bond WS. Psychiatric indications for clonidine: the neuropharmacologic and clinical basis. J Clin
Psychopharmacol 1986 Apr; 6(2): 81-7
49. Goodman & Gilman, ibid, p 619
50. Zubenko GS, Cohen BM, Lipinski JF Jr, Jonas JM. Use of clonidine in treating neuroleptic- induced akathisia.
Psychiatry Res 1984 Nov; 13(3): 253-9
51. Adler LA, Angrist B, Peselow E, Reitano J, Rotrosen J. Clonidine in neuroleptic-induced akathisia. Am J
Psychiatry 1987 Feb; 144(2): 235-6
52. Zubenko GS, Cohen BM, Lipinski JF, Jonas JM. Clonidine in the treatment of mania and mixed bipolar
disorder. Am J Psychiatry 1984 Dec; 141(12): 1617-8
53. Adler L, Angrist B, Peselow E, Corwin J, Rotrosen J. Noradrenergic mechanisms in akathisia: treatment with propranolol and clonidine. Psychopharmacol Bull 1987; 23(1): 21-5
54. Miller CH, Fleischhacker WW. Managing Antipsychotic-Induced Acute and Chronic Akathisia. Drug Saf 2000 Jan; 22(1): 73-81
55. Tonda ME, Guthrie SK. Treatment of neuroleptic-induced movement disorders. Pharmacotherapy 1994
Sep-Oct; 14(5): 543-60
56. Sandyk R, Gillman MA, Iacono RP, Bamford CR. Clonidine in neuropsychiatric disorders: a review. Int J
Neurosci 1987 Aug; 35(3-4): 205-15
57. Sachdev P, Chee KY. Pharmacological characterization of tardive akathisia. Biol Psychiatry 1990 Nov; 28(9):
809-18
58. Amann B, Erfurth A, Grunze H. Treatment of tardive akathisia treated with clonidine: a case report. The Int’l Jrnl of Neuropsychopharmacology 1999 Jun; 2(2): 151-3
59. Nishikawa T, Tanaka M, Tsuda A, Koga I, Uchida Y. Clonidine therapy for tardive dyskinesia and related
syndromes. Clin Neuropharmacol 1984; 7(3): 239-45
60. Dollfus S. Indications for clonidine in child psychiatry. Encephale 1993 Mar-Apr; 19(2): 83-7; (article in
French but abstract in English)
61. Freedman R, Kirch D, Bell J, Adler LE, Pecevich M, Pachtman E, et al. Clonidine treatment of schizophrenia.
45
Double- blind comparison to placebo and neuroleptic drugs. Acta Psychiatr Scand 1982 Jan; 65(1): 35-45
62. Hettema J, Ross DE. A case of aripiprazole-related tardive akathisia and its treatment with ropinirole. J Clin
Psychiatry 2007 (letter) Nov; 68(11): 1814-15
63. Aiken CB. Pramipexole in psychiatry: a systematic review of the literature. J Clin Psychiatry 2007 Aug; 68(8): 1230-36
64. Singh A, Althoff R, Martineau J. Jacobson J. Pramipexole, ropinirole, and mania in Parkinson’s disease. Am J Psychiatry 2005 Apr; 162(4): 814-15
65. Stoner SC, Dahmen MM, Makos M, Lea JW, Carver LJ, Rasu RS. An exploratory retrospective evaluation of
ropinirole-associated psychotic symptoms in an outpatient population treated for restless legs syndrome or Parkinson’s disease. Ann Pharmacother 2009; 43(9): 1426-32
66. Goodman & Gilman, ibid, p 535
67. Pondal M, Marras C, Miyasaki J, et al. Clinical features of dopamine agonist withdrawal syndrome in a
movement disorders clinic. J Neurol Neurosurg Psychiatry 2013 Feb; 84(2): 130-5
68. Rabinak C, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson’s disease. Arch Neurol 2010 Jan; 67(1): 58-63
69. Horiguchi J, Nishimatsu O, Inami Y. Successful treatment with clonazepam for neuroleptic-induced akathisia. Acta Psychiatr Scand 1989 Jul; 80(1): 106-7
70. Bartels M, Heide K, Mann K, Schied HW. Treatment of akathisia with lorazepam. An open clinical trial.
Pharmacopsychiatry 1987 Mar; 20(2): 51-3
71. Donlon PT. The therapeutic use of diazepam for akathisia. Psychosomatics 1973 Jul-Aug; 14(4): 222-5
72. Nishimatsu O, Horiguchi J, Inami Y, Innami T. Sasaki A, Kondo K. Nocturnal myoclonus observed
in a patient with neuroleptic-induced akathisia. Jpn J Psychiatry Neurol 1992 Mar; 46 (1): 121-6
73. Kutcher S, Williamson P, MacKenzie S, Marton P, Ehrlich M. Successful clonazepam treatment of neuroleptic- induced akathisia in older adolescents and young adults: a double-blind, placebo-controlled study. J Clin Psychopharmacol 1989 Dec; 9(6): 403-6
74. Sachdev, Akathisia and Restless Legs 1995, ibid, p 238
75. Sachdev, Akathisia and Restless Legs 1995, ibid, p 89-92,
76. Van Putten T. The many faces of akathisia. Compr Psychiatry. 1975 Jan-Feb; 16(1): 43-7
46
77. Ayd FJ. A survey of drug-induced extrapyramidal reactions. JAMA 1961 Mar 25; 175: 1054-60
78. Braude WM, Barnes TR, Gore SM. Clinical characteristics of akathisia: a systematic investigation of acute
psychiatric inpatient admissions. Br J Psychiatry 1983 Aug; 143: 139-50
79. Halstead SM, Barnes TRE, Speller JC. Akathisia: prevalence and associated dysphoria in an in-patient
population with chronic schizophrenia. Br J Psychiatry 1994 Feb; 164: 177-83
80. Barnes TR, Braude WM. Akathisia variants and tardive dyskinesia. Arch Gen Psychiatry 1985: 42: 874-8
81. DSM-IV and -TR, Appendix B, § 333.99, p 745 in -IV and 801 in -IV-TR
82. Rosenheck R, Perlick D, Bingham S, et al. Effectiveness and cost of olanzapine and haloperidol in the
treatment of schizophrenia: a randomized controlled trial. JAMA 2003 Nov 26; 290(20): 2693-2702
83. Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry 1989; 154: 672-6
84. Hirose S. Restlessness of respiration as a manifestation of akathisia: five case reports of respiratory akathisia. J Clin Psychiatry 2000 Oct; 61(10): 737-41
85. Freyhan FA. in Trifluoperazine: Clinical and Pharmacological Aspects. Lea & Febiger, Philadelphia, 1958.
chapter 5, p 195-205: Extrapyramidal symptoms and other side-effects
86. Sarwer-Foner GJ, Ogle W. Psychosis and enhanced anxiety produced by reserpine and chlorpromazine. Can Med Assoc J 1956; 74: 526-32
87. Van Putten T, Mutalipassi LR, Malkin MD. Phenothiazine-Induced Decompensation. Arch Gen Psychiatry
1974 Jan; 30: 102-105
88. Van Putten T, Marder SR. Behavioral Toxicity of Antipsychotic Drugs. J Clin Psychiatry 1987 Sep; 48(Suppl):
13-19
89. Van Putten T. Why do schizophrenic patients refuse to take their drugs? Arch Gen Psychiatry 1974; 31: 67-72
90. Fouks, Périvier, Mathis, et al. Le syndrome d’impatience. (article in French) Ann Med Psychol (Paris) 1967
May; 125(5): 719-23. (Year, month, and volume cited incorrectly by Van Putten in reference #89)
91. Lipinski JF Jr, Keck PE Jr, McElroy SL. Beta-adrenergic antagonists in psychosis: is improvement due to
treatment of neuroleptic-induced akathisia? J Clin Psychopharmacol 1988 Dec; 8(6): 409-16
92. Nishikawa T, Koga I, Uchida Y, Tanaka M. Treatment of tardive akathisia with clonidine. Kurume Med J 1990; 37(3): 185-7
93. Chien CP, DiMascio A. Drug-induced extrapyramidal symptoms and their relations to clinical efficacy. Am J Psychiatry 1967; 123: 1490-98
47
94. Barnes TRE. The Barnes Akathisia Rating Scale -- revisited. J Psychopharmacol 2003; 17: 365-70
95. Shen WW. Akathisia: an overlooked, distressing, but treatable condition. J Nerv Ment Dis 1981 Sept; 169(9):
599-600
96. Raskin DE. Akathisia: a side effect to be remembered. Am J Psychiatry 1972 Sept; 129(3): 345-7
97. Friedman JH, Wagner RL. Akathisia: the syndrome of motor restlessness. Am Fam Physician 1987 Feb; 35(2): 145-9
98. Duncan EJ, Adler LA, Stephanides M, Sanfilipo M, Angrist B. Akathisia and exacerbation of psychopathology: a preliminary report. Clin Neuropharmacol 2000 May-Jun; 23(3): 169-73
99. Sachdev, Akathisia and Restless Legs 1995, ibid, p 123
100. Decina P, Mukherjee S, Caracci G, Harrison K. Painful sensory symptoms in neuroleptic-induced
extrapyramidal syndromes. Am J Psychiatry 1992 Aug; 149(8): 1075-80
101. Burke RE, Kang UF, Jankovic J, Miller LG, Fahn S. Tardive akathisia: an analysis of clinical features and
response to open therapeutic trials. Mov Disord 1989; 4(2): 157-75
102. Kim H, Cho SY, Byun HJ, Kang UG, Ahn YM, Kim YS. Multidimensional sensory phenomena in antipsychotic-induced akathisia. J Clin Psychopharmacol 2004 Dec; 24(6): 618-23
103. Sachdev, Akathisia and Restless Legs 1995, p 356 (as translated)
104. Nelson DE. Akathisia -- a brief review. Scottish Med J 2001 Oct; 46(5): 133-4
105. Sachdev P, Kruk J. Clinical characteristics and predisposing factors in acute drug-induced akathisia. Arch
Gen Psychiatry 1994 Dec; 51(12): 963-74
106. Daniels JE, Wirth JB, Herrera DG, et al. Head banging on an inpatient psychiatric unit: a vicious circle. Harv Rev Psychiatry 2007 Mar-Apr; 15(2): 70-9
107. Kruk J, Sachdev P, Singh S. Neuroleptic-induced respiratory dyskinesia. J Neuropsychiatry Clin Neurosci
1995 Spring; 7(2): 223-9
108. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed
outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163 (11):
1905-17
109. Fava M, Rush J. Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. Psychother Psychosom 2006; 75: 139-53
48
110. Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry 1999; 60(4): 221-25
111. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using
measurement-based care in STAR*D; implications for clinical practice. Am J Psychiatry 2006 Jan; 163(1): 28- 40
112. Fournier JC, De Rubeis RJ, Hollon SD, et al. Antidepressant Drug Effects and Depression Severity. JAMA 2010 Jan 6; 303: 47-53
113. Naber D, Lambert M. The CATIE and CUtLASS studies in schizophrenia: results and complications for
clinicians. CNS Drugs 2009 Aug; 23(8): 649-59
114. Insel TR. Disruptive Insights in Psychiatry: transforming a clinical discipline. J Clin Invest 2009 Apr 1; 119(4):
700-5
115. Weiden PJ, Mann JJ, Haas G. Clinical non-recognition of neuroleptic-induced movement disorders: a
cautionary study. Am J Psychiatry 1987(Sept); 144: 1148-1153
116. Chung WS, Chiu HP. Drug-induced akathisia revisited. Br. J Clin Practice 1996 Jul-Aug; 50(5): 270-8
117. Zimmerman M, Galione JN, Attiullah N, et al. Underrecognition of clinically significant side- effects in
depressed outpatients. J Clin Psychiatry 2010; 71(4): 484-90
118. Bent S, Padula A, Avins AL. Brief communication: better ways to question patients about adverse medical
events: a randomized, controlled trial. Ann Intern Med 2006; 144(4): 257- 61
119. Wallander MA, Dimenas E, Svardsudd K, Wiklund I. Evaluation of three methods of symptom reporting in a clinical trial of felodipine. Eur J Clin Pharmacol 1991; 41(3): 187-96
120. Wallin J, Sjövall J. Detection of adverse drug reactions in a clinical trial using two types of questioning. Clin Ther 1981; 3(6): 450-2
121. Greenblatt M. Controls in clinical research. Clin Pharmacol Ther 1964; 5: 864-70
122. Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side-effects and those rated as bothersome
with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician
estimate. J Clin Psychiatry 2004; 65(7): 959-65
49
123. Schatzberg AF, Haddad P, Kaplan EM, et al. Serotonin reuptake inhibitor discontinuation syndrome: a
hypothetical definition. Discontinuation Consensus. J Clin Psychiatry 1997; 58(suppl 7): 5-10
124. Black K, Shea C, Durson S, Kutcher S. Selective serotonin receptor inhibition discontinuation syndrome:
proposed diagnostic criteria. J Psychiatry Neurosci 2000 May; 25(3): 255-61
125. Lejoyeux M, Ades J. Antidepressant discontinuation: a review of the literature. J Clin Psychiatry 1997;
58(suppl 7): 11-16
126. Zajecka J, Tracy KA, Mitchell S. Discontinuation symptoms after treatment with serotonin reuptake
inhibitors: a literature review. J Clin Psychiatry 1997 Jul; 58(7): 291-7
127. Frost L, Lal S. Shock-like sensations after discontinuation of selective serotonin reuptake inhibitors. Am J
Psychiatry 1995 May; 152(5): 8-10
128. Teicher MH, Glod CA, Cole JO. Antidepressant drugs and the emergence of suicidal tendencies. Drug Saf
1993 Mar; 8(3): 186-212
129. Wirshing WA, Van Putten T, Rosenberg J, Marder S. Fluoxetine, akathisia, and suicidality: is there a causal
connection? Archive Gen Psychiatry 1992 Jul; 49(7): 580-1
130. Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry 1991 Dec; 52(12): 491-3
131. Hamilton MS, Opler LA. Akathisia, suicidality, and fluoxetine. J Clin Psychiatry 1992 Nov; 53(11): 401-6
132. Seemüller F, Schennach R, Mayr A, et al. Akathisia and suicidal ideation in first- episode schizophrenia. J Clin Psychopharmacol 2012 Oct; 32(5); 694-8
133. Buchfuhrer MJ. Strategies for the treatment of restless legs syndrome. Neurotherapeutics 2012 Oct; 9(4):
776-90
134. Buchfuhrer MJ, Hening WA, Kushida C. Restless Legs Syndrome. American Academy of Neurology Press
Quality of Life Guide Series, 2006
135. “Restless Legs Syndrome: Diagnosis and Treatment in Primary Care”. 2008 (p 2); RLS Foundation,
Rochester, MN 55901, www.rls.org
136. Michaud M, Chabli A, Lavigne G, Montplaisir J. Arm restlessness in patients with Restless
Legs Syndrome. Mov Disord 2000; 15(2): 289-93
137. Perez-Diaz H, Iranzo A, Rye DB, Santamaria J. Restless abdomen: a phenotypic variant of restless legs syndrome. Neurology 2011 Sep 27; 77(13): 1283-6
50
138. Friedman MJ. Prevention of psychiatric problems among military personnel and their
spouses. N Engl J Med 2010 Jan 14; 362: 168-70
139. Graham A, Schultz T (eds) & Wilford B (assoc. ed.). Principles of Addiction Medicine, 2nd
Edition, American Society of Addiction Medicine (Publ) 1998
140. Mannelli P, Peindl K, Wu LT, Patkar AA, Gorelick DA. The combination of very low-dose naltrexone-c clonidine in the management of opioid withdrawal. Am J Drug Alcohol Abuse 2012 May; 38(3): 200-5
141. A.D.A.M. Medical Encyclopedia (MedLine Plus), Opiate Withdrawal, 2012 Jan
142. Wyngaarden JB, Smith LH, Bennett JC, eds. Cecil Textbook of Medicine, 19th ed., WB Saunders 1992, p 52
143. Hirose S. Restlessness in suboccipital muscles as a manifestation of akathisia. Psychiatry Clin Neurosci 2001 Feb; 55(1): 81-2
144. El-Hage W, Leman S, Camus V, Belzung C. Mechanisms of antidepressant resistance. Frontiers in
Pharmacology 2013 Nov 22; 4: 146. doi 10.3389/fphar.2013.00146
145. Walters AS, Hening W, Chokroverty S, Duvoisin R. Restlessness of the arms as the principal manifestation of neuroleptic-induced akathisia [letter]. J Neurol 1989; 236: 435
146. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States:
results from the National Comorbidity Survey Replication. Am J Psychiatry 2006 Apr; 163(4): 716-23
147. Biederman J, Monuteaux MC, Mick E, et al. Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study. Psychol Med 2006 Feb; 36(2): 167-179
148. Kooij SJ, Bejerot S, Blackwell A, et al. European consensus statement on diagnosis and treatment of adult
ADHD: The European Network Adult ADHD. BMC (BioMed Central) Psychiatry 2010; 10: 67. published
online 9/3/10; doi: 10-1186/1471-244X-10-67
149. Amir I, Hermesh H, Gavish A. Bruxism secondary to antipsychotic drug exposure: a positive response to
propranolol. Clin Neuropharmacol 1997 Feb; 20(1): 86-9
150. Sporn J, Ghaemi SN, Sambur MR, et al. Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review. Ann Clin Psychiatry 2000 Sep; 12(3): 137-40
151. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of
pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry 2004
Mar; 161(3): 564-6
51
152. Zarate CA Jr, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of
concept study. Biol Psychiatry 2004 Jul; 56(1): 54-60
153. Perugi D, Toni C, Ruffolo G, Frare F, Akiskal H. Adjunctive dopamine agonists in treatment-resistant
bipolar II depression: an open case series. Pharmacopsychiatry 2001 Jul; 34(4): 137-41
154. Cassano P, Lattanzi L, Soldani F, et al. Pramipexole in treatment-resistant depression: an extended follow-
up. Depress Anxiety 2004; 20(3): 131-8
155. Cassano P, Lattanzi L, Fava M, et al. Ropinirole in treatment-resistant depression: a 16-week pilot study.
Can J Psychiatry 2005 May; 50(6): 357-60
156. Corrigan MH, Denahan AQ, Wright CE, Raqual RJ, Evans DL. Comparison of pramipexole, fluoxetine, and
placebo in patients with major depression. Depress Anxiety 2000; 11(2): 58-65
157. Quilici S, Abrams KR, Nicolas P, et al. Meta-analysis of the efficacy and tolerability of pramipexole versus
ropinirole in the treatment of restless legs syndrome. Sleepmedicine 2008 Oct; 9(7): 715-26
158. Mah L, Zarati CA, Nugent A, Singh JB, Manji HK, Drevets WC. Neural mechanisms of antidepressant efficacy of the dopamine receptor agonist pramipexole in treatment of bipolar depression. Int
J Neuropsychopharmacol 2011 May; 14(4): 545-51
159. Kasper S, Barnas C, Heiden A, et al. Pramipexole as adjunct to haloperidol in schizophrenia. Safety and
efficacy. Eur Neuropsychopharmacol 1997 Feb; 7(1): 65-70
160. Kelleher JP, Centorrino F, Huxley NA, et al. Pilot randomized, controlled trial of pramipexole to augment
antipsychotic treatment. Eur Neuropsychopharmacol 2012 Jun; 22(6): 415-8
161. Lima AR, Soares-Weiser K, Bacaltchuk J, Barnes TR. Benzodiazepines for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev. 2002; (1): CD001950
162. Klee B, Kronig MH. Case report of probable sertraline-induced akathisia (letter). Am J Psychiatry 1993; 150: 986-7
163. Siskind DJ, Lee M, Ravindran A, et al. Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis. Aust NZ J Psychiatry 2018 Aug; 52(8): 751-67
164. Sachdev, Perminder. Akathisia and Restless Legs 1995; Cambridge Univ. Press