(This is the second of a two-part series. Part one appeared in the May issue of Psychiatric Times, p20-Ed.)
At the 2000 annual meeting of the American Foundation for Suicide Prevention, Herbert Y. Meltzer, M.D., gave a special lecture on decreasing suicide in patients with schizophrenia. During the lecture, Meltzer, recent winner of the foundation's annual research award, discussed the high rate of suicide in patients with schizophrenia.
Meltzer reported that studies have shown that the conventional neuroleptics have little, if any, effectiveness in preventing suicide, but there are data indicating that atypical antipsychotics may have a preventive effect on suicide.
Clozapine and Suicide
Meltzer, Bixler Professor of psychiatry and pharmacology at Vanderbilt University School of Medicine and director of Vanderbilt's division of psychopharmacology, said 14 studies have found that clozapine (Clozaril) can improve cognition, particularly in verbal learning and some areas of memory (Manschreck et al., 1999; Meltzer and McGurk, 1999; Meltzer and Okayli, 1995). It may also improve insight, but take away the feeling of hopelessness (Pallanti et al., 1999).
Meltzer continued, "That raises the question: Is there evidence that the newer antipsychotic drugs, which improve cognition, could decrease the suicide rate in schizophrenia? I will give the background about how we came to look for this with clozapine...the prototype of an atypical antipsychotic drug."
Reviewing the history of clozapine in relation to typical neuroleptics, Meltzer explained that in the 1960s the first investigators who used the drug noted its lower extrapyramidal side effects. Later, its lack of a significant effect on prolactin secretion was noted.
In 1975, however, when clozapine-induced agranulocytosis was detected, clozapine "was withdrawn completely, but then reintroduced on a compassionate need basis. Over the next decade, it became clear that it virtually never produces tardive dyskinesia, that it is efficacious in up to 60% of neuroleptic-resistant patients in terms of improving positive symptoms, and that it's efficacious in treatment-resistant bipolar disorder and major depression," he explained. (According to the Physicians' Desk Reference , "There are no reports of tardive dyskinesia attributable to clozapine alone. Nevertheless, it cannot be concluded without more extended experience that clozapine is incapable of inducing this syndrome" -- Ed.)
Meltzer next reported that while his group was working with several hundred patients with schizophrenia in Cleveland from 1985 to 1994, he observed that the use of clozapine resulted in much improved long-term outcome.
"For example," he said, "the part- or full-time employment rate increased from 15% to 40%, [and there was] a great deal of improvement in patients' relationships with their families, better compliance and fewer rehospitalizations. There was a perception I had, but wasn't quite sure of, that it reduced suicidality."
To answer that suicidality question, his group did a study of 88 neuroleptic-resistant patients (73 with schizophrenia and 15 with schizoaffective disorder) on whom they had very complete data. The patients had received treatment with typical neuroleptics elsewhere for at least two years. The researchers then treated them with clozapine and prospectively evaluated them for suicidality for six months to seven years (Meltzer, 1999; Meltzer and Okayli, 1995).
"We did as careful a retrospective and prospective data collection as we could from the patients, informants and medical records about suicidal ideation and suicide attempts, and, of course, we were seeing these patients every week during the course of treating them with clozapine to draw blood," he said, noting that it is his strategy whenever possible to use clozapine monotherapy.
The results of the comparison showed that "we went up from 45% [having] no suicidal ideation or attempts to over 75% [with clozapine]. The amount of command hallucination-induced self-harm went down dramatically."
"Most importantly," he added, "there were 22 patients in the two years on typical neuroleptics, that is, 25% of the sample, who had made either a low-lethality or high-lethality suicide attempt, and that went down to three patients, 3.4%, who made a low-lethality attempt, all within the first several months of clozapine treatment. And one of the key points about clozapine is that it can often take many months for it to work in this patient population. So overall, we saw approximately an 85% decrease in suicide attempts during the course of the two years on clozapine."
Meltzer added that the weekly contact patients were receiving as well as other nondrug factors could have contributed to the decrease in suicidality.
"It may well have been that these people didn't get optimal [psychosocial] treatment prior to study entry," he said, adding that psychosocial treatment was emphasized in his clinic.
Corroborating evidence for clozapine's role in decreasing suicidality was found when Meltzer and colleagues looked at the suicide rate in patients enrolled in the Clozaril National Registry.
"This [registry] provided a good database about people who had suicided while on clozapine versus those who had discontinued clozapine," explained Meltzer. "The rate in terms of life years of clozapine exposure was estimated to be about 0.04% to 0.08%, roughly 40 to 80 [people] per 100,000...certainly a lot lower than the 200 to 700 per 100,000 that one expects in schizophrenia in general So I would say that [these] data [are] strongly supportive that there could be a clozapine effect. [But] it certainly doesn't rule out that it's still the weekly contact."
Other corroborating pieces of evidence of clozapine reducing suicide came from a study on a subgroup of patients with schizophrenia and schizoaffective disorder who received clozapine and other services from the Texas Department of Mental Health and Mental Retardation (Reid et al., 1998) and a Boston University epidemiologic study of suicide (Walker et al., 1997).
"It keeps coming up, a diminished rate [of 80%] in the people who are still on clozapine," said Meltzer.
Meltzer also called for a re-evaluation of the risk/benefit assessment of suicide risk without clozapine versus mortality due to clozapine-related agranulocytosis.
One in 10,000 patients treated with clozapine dies due to agranulocytosis, he said, whereas approximately one in 10 patients with schizophrenia commits suicide.
Other Atypicals and Suicide
Meltzer next described the two-year International Clozaril/Leponex Suicide Prevention Trial (InterSePT), which he proposed and is now conducting with funding by Novartis Pharmaceuticals Corp., the makers of branded clozapine. The study is taking place in 11 countries and involves 69 centers in the United States, Europe and the Southern Hemisphere (Meltzer, 1999).
"A 900-patient study was powered to find a 20% difference between Clozaril and olanzapine [Zyprexa] which is, along with risperidone [Risperdal], the most widely used atypical antipsychotic drug. Patients in the study had to have at least one serious suicide attempt or very serious ideation and were prevented from making an attempt during the three years prior to entry into the study. The treatment is open but raters are blinded. Clinicians are able to treat these patients with other medications if they feel they are indicated, trying to reduce the suicide rate in all groups. The olanzapine group is also seen weekly. All the patients were admitted to the study no later than 16 months ago, and hopefully in about a year, I'll be able to come back and tell you whether there was any difference between the two drugs as well as what else we found out, because there's an enormous number of additional studies going on as part of this trial. At the very least, we will learn a lot more about the epidemiology, cross-cultural issues and biological issues concerning suicide in schizophrenia."
Meltzer said there are also data on some of the other atypicals reducing suicide rate.
"I have reviewed data from the manufacturer of Seroquel [quetiapine] about the rate of suicidality during treatment with Seroquel, Haldol [haloperidol] or Risperdal. They studied a total of 2,185 patients. The [suicidality] rate on Seroquel and Risperdal was significantly lower than [on] haloperidol."
Although not discussed by Meltzer, an article examining the impact of atypical antipsychotics on suicidality in patients with schizophrenia has been published (Keck et al., 2000). The authors reviewed the available literature regarding the efficacy of clozapine, risperidone, olanzapine, quetiapine and ziprasidone (Geodon) in the treatment of depression, hostility and suicidality in patients with schizophrenia. Co-occurring depression, in particular, has been associated with suicidal ideation, suicide attempts and suicide.
These studies "suggest that treatment with clozapine or olanzapine may significantly reduce suicidality in patients with schizophrenia," the authors said in their conclusion.
Meltzer said he was optimistic about most of the atypicals, including olanzapine, risperidone, ziprasidone and quetiapine, since all have advantages over the typical neuroleptics on cognitive function (Meltzer and McGurk, 1999).
In summary, Meltzer said that when he approached the treatment of schizophrenia with the object of trying to reduce suicidality, he realized it cannot be dissociated from trying to improve outcome in general.
"All these key features of cognition, psychosis, substance abuse, etc., [are key] in order to improve quality of life. The atypical antipsychotic drugs appear to be one of the key ways that we can achieve that," he said. "Whether there is a difference between clozapine and the other atypicals remains to be determined."
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