December 30 2002 at 11:41 AM


EXTRACT (Appendix to a letter by Dr David Healy to the MCA - for full article please go to the url):


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.

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.

Van Putten T (1975). The many faces of akathisia. Comprehensive Psychiatry 16, 43-47.

Healy D, Farquhar GN (1998). Immediate effects of droperidol. Human Psychopharmacology 13,

Rothschild AL, Locke C (1991). Re-exposure to Fluoxetine After Serious Suicide Attempts by Three Patients: The Role of Akathisia. J Clinical Psychiatry 52, 491-493.

Wirshing WC, Van Putten T, Rosenberg J, Marder S, Ames D, Hicks-Gray T (1992). Fluoxetine, akathisia and suicidality: is there a causal connection? Archives of General Psychiatry 49, 580-581.

Lipinski JF, Mallya G, Zimmerman P et al (1989). Fluoxetine induced akathisia: clinical and theoretical implications. Journal of Clinical Psychiatry 50, 339-342.

Hamilton MS, Opler LA (1992). Akathisia, suicidality and fluoxetine. J Clinical Psychiatry 53, 401-406.

Bonnet-Brilhault F, Thibaut F, Leprieur A, Petit M (1998). A Case of Paroxetine induced akathisia and a review of SSRI induced akathisia. European Psychiatry 13, 109-111.

Marsalek M (1998). Do antidepressants increase risk of suicide? Ceska A Slovenska Psychiatrie 94, 272-281.

Lane RM (1998). SSRI-induced extrapyramidal side effects and akathisia: implications for treatment. J Psychopharmacology 12, 192-214

Diagnostic and Statistical Manual TR (2001). American Psychiatric Association, Washington D.C."

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