Coleg Meddygaeth Prifysgol Cymru University of Wales College of Medicine
Adran Meddygaeth Seicolegol / Department of Psychological Medicine
Adran Cymru y Gogledd / North Wales Department
Pennaeth Adran / Head of Department
Yr Athro /Professor Michael J. Owen
Bangor
Dr. D. Healy (Cyfarwyddwr)

Dear Sarah Wark,

Many thanks for your letter of February 25^th and the invitation to discuss the issues on the 25^th of March. To facilitate such a meeting it seems helpful to outline some of the key questions to do with interactions between SSRIs and suicide on the one hand and SSRIs and dependence on the other.

Before proceeding, however, I note that the MCA haven’t answered the questions I posed in my recent letters. I specifically asked for information on what the basis was for the MCA linking the benzodiazepines with aggression and suicide. I asked this because there appears to be a much greater evidence base for making these claims about the SSRIs. Given MCA/CSM reluctance to make comparable statements about the SSRIs, I suggested that in the absence of comparable evidence it would be appropriate either to revise the previous MCA statement about the benzodiazepines or to revise the current statements about the SSRIs – or else to make it clear what basis there is for distinctions between these drugs. I raised a similar question about dependence on the benzodiazepines. Both sets of questions remain unaddressed.

Agitation
The MCA now appears to concede that there is a great deal of evidence pointing to an excess of suicidal acts on SSRIs. This must be explained somehow. I think the most likely explanation is that SSRIs induce what is often termed agitation in the US but is more often termed akathisia in Europe. You concede that SSRIs produce agitation. The SSRI market authorisation holders concede that their drugs produce agitation and akathisia.

There is abundant material from the clinical literature including material from scientists and other personnel working for the SSRI market authorisation holders that akathisia/agitation can lead to suicide. The most recent edition of DSM IVTR notes that akathisia can precipitate suicide. This points to a general consensus in the field that there is such a link. (Appendix 1 contains a history of this issue).

But in addition to this general consensus, there is such obvious face validity to the idea that akathisia/agitation would lead to suicide that I would hate to be facing Kirsty Wark trying to defend the position that giving a drug which has been demonstrated in a dose dependent way to produce agitation even in healthy volunteers (and suicidality in some of those reports), and that may have led to suicide in one, that such a drug was not remotely likely to make depressed patients suicidal.

Am I to understand that in our healthy volunteer study when two of our volunteers became agitated and suicidal that their suicidality had nothing to do with their agitation? Would the MCA like to interview our two healthy volunteers?

Am I to understand that in Pfizers’ Hindmarch study where all volunteers taking sertraline appeared to become agitated/apprehensive that Pfizer discontinued the study without any concerns that this agitation/apprehension might lead on to something like suicide? Can anyone in the MCA tell me what kind of agitation would not lead to concerns that if prolonged or severe it could result in suicide?

Quite apart from suggesting something that flies in the face of common sense, am I to presume the MCA position has now become one of asking me or others to prove that agitation leads to suicidality? Perhaps the agency could suggest how this should be done? While we work this one out, I would note that in the case of reasonable suspicions about a potentially lethal side-effect, even where causality is not proven, the statutes of most regulatory authorities require warnings. Are you telling me that the MCA regulations are more lax than those of other countries?

You may be interested to know that I have talked on the platform of a market authorisation holders for new antipsychotics and with their encouragement have said that because particular agents are less likely to cause akathisia than other antipsychotics they are less likely to lead to suicide. Perhaps you would like to charge me, or the market authorisation holder in question, with inappropriate promotion?

Another of the market authorisation holders of one of the newer antipsychotics has also claimed that their agent is less likely to be associated with suicides and suicide attempts than older antipsychotics and spokespersons for the market authorisation holder have indicated that this is probably likely to be so because it is less likely to be associated with akathisia. It turns out that this agent is associated with a significant rate of akathisia and that there is also apparently an excess of suicides on this agent than on older antipsychotics or placebo.

In a letter copied to the MCA, I have recently drawn Alan Milburn’s attention to the fact that the market authorisation holder in question has withheld data on the number of suicide attempts in their clinical trials. My understanding is that prescription only status for medication exists in great part so that clinicians will be able to get data like this from companies. It is difficult to see how we could practise evidence-based medicine otherwise. But the company has flatly refused to provide it. In your letter you haven’t addressed the many issues associated with this point, even though it is germane to our discussions about the SSRIs.

In addition to agitation, there are two other mechanisms that may bring about this excess of suicides, one being psychotic decompensation on SSRIs and the other being emotional indifference/lability on SSRIs. (I enclose evidence on both these mechanisms in Appendix 2).

Suicidal Behaviour
On the issue of suicidal behaviour, the MCA now appears to concede that the figures that I’ve provided produce a significant association between SSRIs and suicidal acts.

Some mysterious original trial data are then invoked to minimise this problem. We perhaps need to consult our respective notes on what the original trial data is. I have photocopies of a great deal of this – and I am not relying on company reports of what this data means, as the MCA appears to have done on previous issues. When I communicate with others I am limited to reports prepared by the FDA, which have their inaccuracies, or other public domain documents, but I only use these because I have access to the underlying data and can verify the point. I have also seen a considerably larger trial dataset than the material that I’ve presented the MCA with, and as far as I can see the larger the dataset gets, the more significant any associations become.

As I understand it, each of the SSRI market authorisation holders has in fact several hundred suicidal acts in clinical trials undertaken on tens of thousands of patients. It should, therefore, be entirely possible to settle the issue of suicidality for each of these drugs individually in a manner that would avoid the pitfalls of pooling data that your letter alludes to – if the MCA asked the market authorisation holders to provide the data. Has the MCA asked for the data, in the light of the data-pooling problems that have been mentioned? If not, in the light of the excess of suicidal acts on SSRIs that the MCA now concedes is present, why not?

While I can appreciate MCA concerns about the hazards of pooling data, I am perplexed about the fact that the data presented for paroxetine on its own are significant and these have seemingly been ignored. Can you explain to me, whether there is any basis – other than saving paroxetine’s skin by invoking patient exposure years – that has stayed the MCA hand on the issue of putting warnings on paroxetine?

A) Patient Exposure
In raising the issue of patient exposure time, the MCA’s consultants appear to have fallen into a simple trap and come to an erroneous conclusion. I am happy to concede that in the case of some side effects of drugs, making an assessment in terms of the length of exposure to the drug is appropriate. But in the case of SSRI-induced suicidality, which has been closely tied to the first few weeks of exposure to the drug, the use of patient exposure years becomes a means for market authorisation holders to dilute the apparent problem.

It will be obvious even to someone with no experience of the field how this happens. Patients, who become agitated or suicidal on the drug, drop out of the clinical trial in the course of the first few weeks – roughly 5% do this. This leaves patients in the trials who are suited to the drug. Calculating suicidal acts in terms of exposure, when patients doing well may be left on the drug for up to a year, becomes a means of minimising the problem. Whether this minimisation happens because of deceit or because of incompetence is less clear to me. Is there an alternative to either of these options?

It becomes harder to resist the deceit option when we consider the market authorisation holders categorisation of washout suicidal acts as placebo suicidal acts. In addition to this, I presume the MCA must be aware that in the course of handling their data for registration purposes in Germany and presumably also in Britain, Lilly against a background of approximately 8000 patients entered into their trials reported six suicides on placebo, of which one occurred during the washout period, while four occurred weeks or months after the trial was over and only one was actually on placebo. If you do not have the data on this, I can provide it. Can the MCA tell me why a company should do this? Can you tell me whether the MCA are prepared to let Lilly and other market authorisation holders get away with it – now that it has been brought to your attention?

Deceit or incompetence aside, I presume the MCA is bound by the International Committee for the Harmonisation of Regulatory Submissions which require the data to be presented both in terms of absolute numbers as well as in terms of exposure. Have the market authorisation holders presented the data to the MCA in both forms? As the MCA has now appeared to concede that there is problem when the data is calculated in the terms of absolute numbers, given that there is little justification for the use of patient years in this context, I find it very hard to see how the agency would not at least warn about risks - even if any warnings include statements to the effect that a causal association has not been conclusively demonstrated.

Sweden
Your letter then draws my attention to a publication by Carlsten et al in 2001, noting a significant reduction in suicide rates in Sweden following the introduction of the SSRIs. The key figure behind this data is Goran Isacsson. The MCA may be interested to know that I invited Dr Isacsson to a symposium I chaired for the British Association for Psychopharmacology two years ago where he presented this argument and essentially these data. I can tell you that the overwhelming view in the symposium seemed to be that Dr Isacsson’s contention that the fall in suicide rates in Sweden was linked to SSRI use was improbable.

I could draw MCA attention to the fact that for example since the SSRIs were introduced suicide rates in Ireland have increased and there is more convincing data linking this increase to SSRIs, as in the article by Donovan et al 1999 (Archives of Suicide Research), which shows a statistically significant increase in suicides on SSRIs compared to non-SSRI antidepressants during this period, than there is linking any fall in suicide rates with SSRI use in Sweden. I could draw MCA attention to data from others countries, but lets stick with Sweden.

Now I am sure the MCA will be aware that Prozac – or Fontex as it is there - had difficulties getting a licence in Sweden owing to Swedish perceptions of an adverse risk benefit ratio, and that it has minimal sales there. That like Fontex, Zoloft only came onto the market there in 1996, and has had rather minimal sales. You probably also know that citalopram has accounted for something like 50% of SSRI market there. Someone within the MCA may also know that suicide rates began falling in Sweden before the introduction of SSRIs, and a host of factors such as immigration and educational campaigns about suicide, as well as simply a regression to the mean from an extraordinarily high level of suicides are likely to have something to do with this. It is in fact hard to see how SSRIs can have had much to do with falling suicide rates in Sweden, given that the suicide risk in depression stems from hospitalised depression and SSRIs have never been shown to work for these patients.

But let’s assume SSRIs might have something to do with this fall. How could this happen? My contention has never been that suicide is an inherent hazard of SSRI drugs that cannot be managed by good clinical practice. My argument has always been that the appropriate level of warnings and education of clinicians can minimise these hazards.

What are the warnings like in Sweden? Well from the early 1990s, Swedish warnings have stressed that the risk of suicide may increase in the early stages of treatment. They explicitly warn that SSRIs may lead to psychotic decompensation and it is textbook knowledge that psychotic decompensation is linked to suicide.

But rather crucially, these warnings which were stronger than British warnings appeared against a general clinical understanding in Sweden that antidepressants as a group, and not just SSRIs, can provoke suicidality in the first weeks of treatment. The MCA may be interested to know that I have Arvid Carlsson the recent Nobel Prize Winner, and creator of the SSRIs, a Swede, on videotape stating categorically that it is well known that antidepressants can trigger suicidality in some people.

In my previous meeting and in correspondence with the MCA, I’ve also drawn attention to the fact that Ulrich Malt a professor of psychiatry from Oslo writing up an RCT with sertraline reported that: "One patient on sertraline committed suicide, and three others reported increasing suicidal ideation which prompted premature stop of the treatment, in contrast to just one case on mianserin and none on placebo. Since the introduction of the tricyclic antidepressants, it has been known by clinicians that TCA could increase suicidality in the first week. For this reason a close supervision of depressed patients given TCA was recommended". He went on to say that the new antidepressants (SSRIs) would it seemed also require monitoring during the early phases of treatment.

I think this MCA example of Sweden rather proves my point about the importance of creating an appropriate climate in which antidepressants are used if they are to be used safely.

How Big a Problem?
I thought your letter struck a few odd notes when it mentioned that actually my figures might be even more significant than I had made them out to be. Does the MCA think I am under some obligation to prove that these drugs cause suicide? I have to put it to the MCA, through you, that it is the market authorisation holders in the first instance who have a legal, moral and scientific duty to prove there is not a significant problem and it is the MCA’s role to ensure that that a majority of disinterested assessments of the evidence would be likely to support such a claim.

My hunch is that most disinterested observers would agree there are grounds for concern – and that is all I need to establish. But let’s push this point just a touch further. We are teetering on the brink of proving a general excess of suicidal acts on SSRIs compared to placebo. It had never been my intention to prove this, as there is a real risk that many disinterested observers would conclude that proof of this point should lead to the use of these drugs being restricted by more than warnings. I’m afraid that it is the response from both the MCA and the market authorisation holders that has pushed the argument in just this direction.

I think the MCA and its experts now have a real dilemma that the best statistical brains in the world can’t rescue you from. It’s this. I am happy to endorse the claims of the market authorisation holders that SSRIs can reduce suicidality in some patients, if not the impression these market authorisation holders give that there would be no more suicides in Britain if everyone just took SSRIs. I would imagine the MCA would endorse some limited claims in this area also. But if SSRIs reduce suicidality in some and we still end up with an excess of suicidal acts no matter what way the data is calculated – in terms of absolute numbers or patient exposure years – where does that leave the MCA in terms of its causal assessments?

Against this background, I would respectfully suggest to the MCA that no matter which way you massage the data, using patient exposure years or original trial data, you cannot establish that SSRIs are not likely to cause suicide. And if the MCA cannot do this, I have to ask why doesn’t the MCA let people know that it cannot do this? Alternatively, please show me how you think you can do it.

The only way you could conceivably minimise the problem facing you is to deny that SSRIs save anyone from suicide. But the market authorisation holders of the SSRIs have sold these agents heavily on the back of claims that they will lower suicide rates. As the data from controlled trials now clearly indicates, while a smaller lucky subset of patients may be made less suicidal, reducing suicidality cannot be a general effect of these agents, what I would ask you does the MCA plan to do about what must now be categorised as inappropriate promotion – viz. claims that these agents will lower suicide risks?

Withdrawal & Dependence
I am happy to stand by my statements about withdrawal and dependence being synonymous. You can check my recent The Creation of Psychopharmacology from Harvard University Press, for a history of these terms and the social contexts in which they arose. The meanings behind these terms have changed so often that it would be possible to prolong a debate endlessly, by simply shifting from one set of definitions to another when the going gets sticky. Under the 1994 WHO definitions for example both the benzodiazepines and SSRIs cause dependence and WHO as of 1998 still talk about SSRIs causing withdrawal.

I suggest cutting to the chase. Lets accept the subset of definitions put out by WHO in 1998 or DSM IV that the MCA now seems comfortable with. My point was that using these definitions, the benzodiazepines do not produce dependence.

I don’t mind whether the MCA re-categorises the benzodiazepines to non-dependence producing. But if the MCA is not prepared to do this, I would very much appreciate being informed of the basis on which the agency is distinguishing between the benzodiazepines and SSRIs. I cannot find any RCT or other systematic evidence to indicate that on any of the points outlined in your letter there is a difference between the benzodiazepines and SSRIs.

In recent months, paroxetine, sertraline and venlafaxine have all promoted themselves heavily for anxiety disorders with literature contrasting themselves to the dependence producing benzodiazepines. There is a clear implication, however one defines dependence, addiction or withdrawal, that the SSRIs are doing something different to the benzodiazepines. As the MCA has not provided me with any basis for distinguishing between the benzodiazepines and the SSRIs, I wonder could I ask the agency to indicate what it is prepared to do about these misleading claims currently being given by the market authorisation holders to patients and general practitioners up and down the country?

The likely reaction from most people in the street will be that we are playing with words here. The problem many patients face however is that many of them simply cannot stop the SSRI they have been put on. As the MCA concedes that withdrawal reactions happen on SSRIs, and that these can be severe, the agency must logically concede that there are some people that cannot stop treatment and others yet to begin who will not be able to stop treatment.

I don’t care whether being unable to stop treatment is called addiction, dependence or something else but I do think that the MCA has a moral obligation to ensure that the labelling and the education of physicians as regards these drugs makes it clear to the patients about to start these drugs that some people may not ever be able to stop, once they start. I can’t imagine that anyone thinks the British labelling of the SSRIs currently reflects this.

I can, however, imagine that the MCA response on this point will be that unless some group like the Royal College of Psychiatrists were to lobby to get a new set of words put into the labelling to specify whether patients can be guaranteed being able to stop a drug, that the agency would feel under no obligation to do anything. If this is the logic of the MCA position, could you tell me exactly what such a group would have to do to bring about such a change?

Your letter asks for evidence I have on the point of people being unable to stop treatment. There is abundant RCT evidence that has in some sense passed through the MCA of patients who have had serious problems halting SSRIs. On the basis of trial designs which involved a re-randomisation to placebo and an interpretation of the difficulties that these patients had as new illness episodes, the MCA authorised market authorisation holders to claim a benefit in the long term treatment of depression, even though the market authorisation holders had prior trial data, which indicated that the withdrawal symptoms even in healthy volunteers include anxiety, agitation, violent dreams and possibly even suicide.

As long as 6 years ago, one of the market authorisation holders, fearing the competition of another, was paying psychiatrists like me significant fees to sample our opinions on withdrawal problems from antidepressants. It would appear that at least in part on the basis of these surveys, this market authorisation holder then ran an advertising campaign about problems with withdrawal from antidepressants confident that clinicians would know which SSRI antidepressants were being referred to – despite advice from me at least that this would be a bad idea. How much evidence do you need?

The Credibility of the MCA
The position of the MCA is now so much at odds with both the facts on the ground and the clinical data, that I have to ask whether the agency makes any assessment as to whether handling issues in this manner is likely to lead to an erosion of the public trust in Government with the consequences we now perhaps see in the MMR case?

If the MCA is not worried about this issue, I am. Consider the sequence of events. I write about healthy volunteer data, the MCA responds with studies you call epidemiological that a secondary school student could have told you were not epidemiological studies. I seek clarification of the healthy volunteer issues, the MCA responds by giving me the assessment the market authorisation holders have made of their own studies. I draw attention to further data, and the MCA responds by selectively citing data from Sweden that few people other than the market authorisation holders cite, data that are necessarily by their very nature inconclusive.

I count 25 questions in this letter to add to the unanswered questions from the previous letter. I would appreciate if this letter along with the enclosed revised copy of the draft paper I sent you earlier could be forwarded to the members of the CSM: Professor AM Breckenridge, Professor I Weller, Dr M Armitage, Professor T Barnes; Professor J Caldwell, Dr R Calvert, Dr T Chambers, Professor J Chipman, Professor J Darbyshire, Dr M Donaghy, Dr J Forfar, Professor M Langman, Dr A Mackay, Professor J Midgley, Professor K Woodhouse, Dr P Wilkie, Dr P Wright.

Yours sincerely,

David Healy MD FRCPsych

Director, North Wales Department of Psychological Medicine

Uned Hergest, Ysbyty Gwynedd, Bangor, Gwynedd LL27 2PW

Ffôn: (01248) 384452 Ffacs: (01248) 371397

Hergest Unit, Gwynedd Hospital, Bangor, Gwynedd LL27 2PW

Tel: (01248) 384452 Fax: (01248) 311397

APPENDIX 1                        SSRIs & MECHANISMS OF SUICIDE: 1

Agitation/Akathisia
The evidence that SSRIs cause agitation comes directly from the clinical trial programs run by the market authorization holders, where approximately 5% of patients have dropped out because of drug induced agitation. Rates of drop-out for agitation are significantly greater than for placebo.

These clinical trial findings in depressed patients are corroborated by the results from healthy volunteer studies. In these phase 1 studies, the companies generally code akathisia to agitation or to hyperkinesis. The critical point that emerges from these studies is how the market authorization holders can argue that their drugs do not lead to suicide against a background of their drugs causing agitation severe enough to lead to drop-outs from clinical trials at an up to 5% rate - in addition to all the less severe forms of agitation caused – and to agitation at an approximately 25% rate, occurring in a dose dependent fashion, in healthy volunteers. These data were all in place from the 1980s. In their early clinical trial program with Prozac, Lilly and their investigators specifically noted the emergence of akathisia/agitation and arranged for the concomitant administration of benzodiazepines to minimize this problem.

The fact that SSRIs cause akathisia has been conceded by company reviewers and by regulators and and a link between akathisia and suicide has been recognized by DSM-IV and company reviewers.

It has been long recognized in the medical community that akathisia can cause suicidality and this fact has been extensively documented in the medical literature.

The first emergence of this link came with reserpine, a psychotropic agent with comparable efficacy to SSRIs in trials for anxious depressives done in the 1950s (Davies and Shepherd 1955). This drug however led to suicide – and did so in the hypertensive patients to whom it was being given rather than in the psychiatric patients to whom it was also prescribed in higher doses (Healy and Savage 1998). It can be noted that despite causing suicide, reserpine is still prescribed to and can be effective for depressed patients (Price et al 1987).

Reserpine led to a state that could appear within hours or days of treatment commencing. This was characterised as follows:

"increased tenseness, restlessness, insomnia and a feeling of being very uncomfortable" (Achor et al 1955),

"the first few doses frequently made them anxious and apprehensive... they reported increased feelings of strangeness, verbalized by statements such as ‘I don’t feel like myself’ .. or ‘I’m afraid of some of the unusual impulses that I have’" (Faucett et al 1957).

Sarwer-Foner and Ogle (1955) describe the case of CJ who on the first day of treatment reacted with marked anxiety and weeping and on the second day "felt so terrible with such marked panic at night that the medication was cancelled".

Such reactions were interpreted by some as evidence in favour of the then current theory that patients with essential hypertension had a suppressed rage close to the surface (Faucett et al 1957). A description by Ayd (1958), however, seems to point to something else - "they had motor restlessness which made their muscles taut, compelled them to pace the floor and did not permit them to sit without moving their legs".

Akathisia was later confused with tardive dyskinesia. It was retrieved from the realm of the dyskinesias by Theodore Van Putten in 1975 who wrote that akathisia was a drug-induced psychosis, which had extremely bizarre characteristics with suicidal overtones. His descriptions make it clear that there are similarities between akathisia and symptoms such as anxiety, restlessness and agitation.

In 1983, Shear et al. reported suicide associated with akathisia with treatment of depot fluphenazine.

In a 1985 paper, Schulte linked akathisia with psychotic acts of murder and suicide. He wrote, "The following five cases are reported to bring attention to the potential for severe violence, as a result of akathisia, following such administration of a neuroleptic (major tranquilizer) for acute psychiatric symptoms."

In another 1985 paper, Drake and Ehrlich reported further on the link between akathisia and suicide attempts.

With the advent of the SSRIs, evidence emerged regarding SSRI-induced akathisia and suicidality. A rechallenge study conducted by Rothschild and Locke in McLean Hospital brought this out clearly. The authors described Prozac-induced emergent suicidality associated with akathisia in several patients. In order to test whether the emergent suicidality was coincidental or was associated in a cause and effect way with Prozac, they withdrew Prozac, then re-administered it and all three cases after having made a previous serious suicide attempt on Prozac experienced the exact same effect on rechallenge. "All three patients developed severe akathisia during treatment with fluoxetine and stated that the development of the akathisia made them feel suicidal and that it had precipitated their prior suicide attempts."

Wirshing and Van Putten described a further set of patients who became suicidal during treatment with Prozac as follows: "[n]one (of the patients discussed) had a history of significant suicidal behavior; all described their distress as an intense and novel somatic-emotional state; all reported an urge to pace that paralleled the intensity of the distress; all experienced suicidal thoughts at the peak of their restless agitation; and all experienced a remission of their agitation, restlessness, pacing urge, and suicidality after the fluoxetine was discontinued."

This article was followed up by the peer-reviewed article, "Akathisia, Suicidality and Fluoxetine," by Hamilton and Opler which ties SSRI-induced akathisia to suicidality, "[t]he proposed link between fluoxetine and suicidal ideation is explained by fluoxetine-induced akathisia and other dysphoric extrapyramidal reactions," and provides an extensive history of drug-induced akathisia causing suicidality:            

"Several reports already exist in the literature documenting the development of EPS [extrapyramidal symptoms] in association with fluoxetine, but without necessarily linking this to an increased incidence in suicidal ideation. Specifically, Lipinski et al. first reported the occurrence of akathisia in five patients treated with fluoxetine. Bouchard et al. reported that EPS developed in several of their patients while they were being treated with fluoxetine and in other patients the baseline levels of EPS worsened during fluoxetine treatment. Symptoms noted included bradykinesia, cogwheel rigidity, and akathisia. Tate reported that a patient who had previously tolerated haloperidol alone had an increase of EPS (including parkinsonism and akathisia) when fluoxetine was added. Stein reported a case of tardive dyskinesia that developed when a low dose of haloperidol was added to fluoxetine. In the case reported by Teicher et al., four of the six patients described complained of an inner restlessness which Opler has previously argued could reflect that they were experiencing akathisia. Wirshing et al. recently reported that five patients treated with fluoxetine experienced ‘agitation, restless motor movement, dysphoria, pacing, an internal sense of desperation, and suicidal ideation,’ and they too suggest ‘that fluoxetine-induced akathisia can lead to suicidal ruminations.’

A separate clinical literature suggests that akathisia can at times lead to emergence of suicidal ideation. Akathisia is defined as an ‘inner sense of restlessness’ and an ‘inability to sit still.’ Patients who experience this often give reports such as ‘I feel like I’m jumping out of my skin.’ As akathisia is a common side effect of neuroleptic medications, information regarding subjective response to akathisia exists primarily, although not exclusively, in the literature on schizophrenia. In 1974 Van Putten et al. noted that nine schizophrenics treated with high-potency neuroleptics showed ‘behavioral toxicity’ associated with akathisia. Three of these patients developed de novo suicidal ideation. Schulte reported five cases of violent behavior, including completed suicides, as a result of akathisia in patients treated with neuroleptics. Shear et al. reported two cases of completed suicide by jumping in patients who the authors argue were suffering from akathisia. Drake and Ehrich also reported two cases of suicidal ideation secondary to akathisia. In one case the patient stated that he did not intend to die but that he would do anything to escape the intolerable feeling of restlessness. Drake and Ehrlich noted that these patients were unable to distinguish the akathisia from the ongoing symptoms of their psychiatric illness. Weiden reported that the use of prochlorperazine for nausea in a patient receiving chemotherapy led to akathisia which was very distressing to the patient. In 1986 Weddington and Banner successfully used chlorpromazine and metoclopramide to treat intractable hiccups but found that after 3 days of treatment the patient became restless, felt like he was ‘going crazy,’ and began obsessing about suicide. During a crossover study involving haloperidol and BW2344-U (which is characterized by the absence of dopamine receptor affinity), Shaw et al noted that during haloperidol treatment the patients experienced a clinical decline characterized by severe akathisia and an increase in violent behaviors as well as suicidal ideation and homicidal thinking. None of the symptoms were present with BW2344-U. In a 1987 review article, Van Putten et al. cite several studies in which it was noted that akathisia leads to suicidal ideation or homicidal thinking. They called this the ‘behavioral toxicity’ of antipsychotic medication. By 1988 Hermesh et al. began studying the use of propranolol to treat akathisia because of the authors’ familiarity with the above literature and their concern that akathisia might lead to suicide attempts."

The Lipinski article was also referenced by Bonnet-Brilhault and colleagues in a 1998 article on paroxetine induced akathisia as follows:

"Since the publication in 1989 of the article by Lipinski et al., reporting the occurrence of akathisia in five patients treated with fluoxetine, there have been several reports of akathisia associated with other selective serotonin reuptake inhibitors (SSRIs) such as sertraline, and, lately, paroxetine. In addition to the discomfort felt by patients, the most notable secondary complications are non compliance and suicidal ideation or behavior."

The association between akathisia and suicidality and its implications is, perhaps, best expressed by Roger Lane in 1998 when he was working for Pfizer:

"It may be less of a question of patients experiencing fluoxetine-induced suicidal ideation, than patients feeling that ‘death is a welcome result’ when the acutely discomforting symptoms of akathisia are experienced on top of already distressing disorders. Hamilton and Opler (1992) stated that the term ‘suicidal ideation’ to describe the apparent suicidality associated with akathisia was misleading as the ‘suicidal ideation’ reported in patients receiving fluoxetine was a reaction to the side-effect of akathisia (i.e. unbearable discomfort and restlessness) and not true suicidal ideation as is typically described by depressed patients experiencing suicidal ideation."

The recognition of a link between akathisia and suicide is not confined to the US/UK. In 1998, Marsalek noted:

"Suicidal ideation and behavior can sometimes emerge in persons with obsessive or panic features who take antidepressants or neuroleptics. Typical for such state is rapid development, impulsive and/or obsessive characteristic of suicidal ideation, an independence of the course of depression, severe tension and anxiety, an intense violence of suicidal fantasies and attempts, and their prompt disappearance after the discontinuation of the antidepressant. . . . There is clinical evidence of the link between akathisia and suicidal tendencies. . . . The reduction or the discontinuation of antidepressants or neuroleptics, and the treatment with benzodiazepines or beta blockers should be recommended when the drug-induced suicidal tendencies are recognized."

Finally, as with SSRI-induced akathisia, DSM-IV TR also acknowledges the association of akathisia and suicidality:

"The subjective distress resulting from akathisia is significant and can lead to noncompliance with neuroleptic treatment. Akathisia may be associated with dysphoria, irritability, aggression, or suicide attempts."

There is no textbook, reference work or peer reviewed trial anywhere saying that akathisia or agitation do not predispose to suicidality.

References
Davies D L, Shepherd M (1955). Reserpine in the treatment of anxious and depressed patients. Lancet 117-121

Price LH, Charney DS, Heninger GR (1987). Reserpine augmentation of desipramine in refractory depression: clinical and neurobiological effects. Psychopharmacology 92, 431-437.

Healy D, Savage M (1998). Reserpine exhumed. British Journal of Psychiatry 172

Achor R W P, Hanson N O, Gifford R W (1955). Hypertension treated with rauwolfia serpentina (whole root) and with reserpine. Controlled study disclosing occasional severe depression. J.A.M.A. 159,. 841-845

Faucett R L, Litin E M, Achor R W P, (1957). Neuropharmacologic action of rauwolfia compounds and its psychodynamic implications. A.M.A. Archives of Neurology and Psychiatry 77, 513-518

Sarwer-Foner GJ, Ogle W (1955). Psychosis and enhanced anxiety produced by reserpine and chlorpromazine. Canadian Medical Association Journal 74, 526-532.

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