Study Finds Clozapine Is Most Effective Option for Preventing Second Psychosis Relapse

Among individuals with schizophrenia who experienced their first relapse while taking an oral antipsychotic, only those who switched to clozapine lowered their risk of a second relapse. These findings, based on Finnish population data, were published in Lancet Psychiatry.

“When a patient with first-episode schizophrenia has their first psychosis relapse, despite the use of a non-clozapine oral antipsychotic, continuation with the same antipsychotic strategy or switching to another non-clozapine oral antipsychotic is as unhelpful as switching to non-use of antipsychotics,” wrote Heidi Taipale, Ph.D., of the University of Eastern Finland, and colleagues. “This finding challenges the current treatment guidelines, which suggest clozapine should be used after at least two different non-clozapine antipsychotics.”

Taipale and colleagues identified 3,000 individuals in Finland who were hospitalized for first-episode schizophrenia between 1996 and 2014 and experienced a relapse within five years. To ensure the study population reflected a true “first episode,” eligible individuals had to be age 45 or under and not taking any antipsychotics in the year prior to hospitalization.

Among this group, 45.5% were not taking any antipsychotics prior to their first relapse, 32.4% were taking a non-clozapine oral antipsychotic, and 10.4% were taking clozapine; the remaining individuals were taking injectable antipsychotics or multiple oral antipsychotics. Not surprisingly, of those not taking any antipsychotic prior to a first relapse, switching to any antipsychotic therapy lowered their odds of a second relapse within two years. However, switching to clozapine was the most beneficial, with a 48% reduced relapse risk compared with staying off medication.

In patients who were taking an oral antipsychotic, switching to clozapine reduced relapse risk by 34% compared with staying on the same medication. No other treatment strategy—not even switching to long-acting injections—appeared to offer any benefit.

Finally, among individuals who relapsed while taking clozapine, those who were switched to another antipsychotic had about twice the odds of a second relapse compared with individuals who stayed on clozapine.

“Clozapine is associated with risks of rare but potentially severe adverse effects, such as agranulocytosis,” Taipale and colleagues wrote. “However, there is accumulating evidence … suggesting that clozapine is the safest antipsychotic concerning overall survival, in addition to being associated with greater symptomatic improvement, including in patients without treatment-resistant schizophrenia.”

For related information, see the Psychiatric News article “Clozapine Found Most Effective in Patients With Schizophrenia and Conduct Disorder.”

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Teens With Classmates Diagnosed With Mental Illness More Likely To Be Diagnosed Themselves

Teens who have one or more classmates with a mental disorder are more likely to be diagnosed with one themselves later in life than those who do not have any classmates with a mental disorder, according to a report in JAMA Psychiatry. The risk of a mental illness diagnosis was greatest in the first year following the diagnosis of a classmate.

Being exposed to a peer with a mental disorder may aid in “normalization of mental disorders through increased awareness and receptivity to diagnosis and treatment,” wrote Jussi Alho, Ph.D., of the University of Helsinki, Finland, and colleagues. “Similarly, having individuals with no diagnosis in the peer network might discourage seeking help for any underlying mental health problems.”

Alho and colleagues used Finnish national health and school registries to examine mental disorder diagnoses among more than 700,000 individuals born between 1985 and 1997. The cohort was followed from August 1 of the ninth grade (approximately age 16) until a diagnosis of mental disorder, emigration, death, or December 31, 2019. The researchers adjusted findings to control for a wide range of variables that might affect diagnosis—parental educational level, income, and mental health; area-level education, employment, and urbanicity; and school and class size.

Among the cohort, 47,433 individuals had a mental disorder diagnosis by the ninth grade. Of the remaining cohort members, 167,227 (25.1%) received a mental disorder diagnosis during the follow-up. There was no increased risk of a mental disorder diagnosis among teens with one diagnosed classmate across the whole follow-up, but a 5% increase with more than one diagnosed classmate.

During the first year of follow-up, teens with one diagnosed classmate had a 9% increased risk of a mental disorder diagnosis, while teens with multiple diagnosed classmates had an 18% increased risk. Mood, anxiety, and eating disorders were the most common diagnoses following exposure.

Alho and colleagues wrote that the heightened risk early in follow-up “challenges the likelihood of harmful contagion occurring without an already existing, undiagnosed disorder,” but acknowledged that for some diagnoses such as eating disorders, transmission could also occur through peer social influence.

“Prevention and intervention measures that consider potential peer influences on early-life mental health could substantially reduce the disease burden of mental disorders in society,” the researchers concluded.

For related information see the Psychiatric News article, “Teen ‘Social Media Induced’ Illness Requires Careful Workups.”

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Risks of Clozapine Decline Sharply After Six Months, May Warrant Reduced Monitoring

While clozapine increases an individual’s risk of agranulocytosis (a drop in a type of white blood cell that can be life threatening) more than other antipsychotics, the risk of a serious adverse event is minimal and drops steeply after the first year of use, according to a study published yesterday in Lancet Psychiatry. This study, which tracked nearly 62,000 people in Finland for up to 22 years, also found that the fatality rate among individuals who develop agranulocytosis is very low.

“More than half of the agranulocytosis events in patients treated with clozapine occurred during the initial 6 months,” wrote Jose M. Rubio, M.D., of the Feinstein Institutes for Medical Research in Manhasset, N.Y., and colleagues. “Notably, although purposeful, lifetime blood monitoring might be a deterrent to use clozapine for some patients and therefore lifting it from being mandatory after a cautionary period could facilitate the uptake of this underused drug.”

Rubio and colleagues studied 61,679 people who were diagnosed with schizophrenia or schizoaffective disorder in Finland, which has the highest rate of clozapine prescription worldwide. About one-quarter the individuals took clozapine, and three-quarters took other antipsychotics.

The researchers noted that antipsychotics as a class appear to be associated with an elevated risk of agranulocytosis during the initial six months of treatment. In fact, 231 individuals treated with clozapine developed the condition (1.37%) as well as 167 individuals treated with other antipsychotics (0.13%). However, the risk of agranulocytosis appeared to abate after six months among those taking other antipsychotics, while the risk of developing clozapine-induced agranulocytosis decreased steeply over time but remained elevated.

The researchers found an increased risk of agranulocytosis for those treated with higher than standard doses of clozapine, those taking it in combination with other psychotropic medication, and those with medical comorbidities. For every 3,559 individuals who initiated clozapine, only one person died due to agranulocytosis.

“Rubio and colleagues make a sensible, and cautious, call for a reduction in the frequency of blood monitoring for those on clozapine and to stop after 3 years of treatment,” according to an accompanying editorial by Jack B. Fanshawe and Belinda R. Lennox, D.M., of the University of Oxford. However, given the homogeneity of the Finnish population, “[f]urther studies in more diverse clinical cohorts are crucial to ensure any flexibility in haematological monitoring can be safely applied to these populations,” they wrote.

For related information, please see the Psychiatric News story, “FDA Reviewing Clozapine REMS to Determine if Monitoring Requirements Can Be Modified.”

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Clozapine, LAIs Found Effective in Patients With First-Episode Psychosis and Cannabis Use Disorder

Individuals with first-episode psychosis (FEP) and cannabis use disorder who were prescribed any antipsychotic were significantly less likely to be hospitalized for psychosis than similar patients who did not receive an antipsychotic, according to a report in Schizophrenia Bulletin.

Clozapine and long-acting injectable (LAI) formulations of risperidone, aripiprazole, and paliperidone were the most effective medications at preventing relapse and hospitalization due to psychosis. Clozapine was also most effective at preventing hospitalization due to substance use.

Alexander Denissoff, M.D., of the University of Turku, Finland, and colleagues noted that cannabis use is common among FEP patients. Further, continued cannabis use after a first episode of psychosis has been associated with more severe symptoms, nonadherence to antipsychotic treatment, and an increased frequency of relapse.

For that reason, “improving outcomes of FEP patients with dual disorders is of paramount importance as relapse after the index psychotic episode is associated with adverse clinical outcomes,” they wrote.

Denissoff and colleagues used Swedish national registries to track the outcomes of 1,820 individuals diagnosed with FEP and co-occurring cannabis use disorder between 2006 and 2021. The main outcome was hospitalization due to relapse of psychosis, though the researchers also looked for hospitalizations due to any substance use disorder.

A total of 1,111 of the 1,820 patients were hospitalized due to psychotic relapse. The researchers found that patients who received any antipsychotic were 33% less likely to be hospitalized due to a relapse of psychosis compared with patients who did not receive an antipsychotic. Regarding individual medications, LAI risperidone was associated with the most significant reduction in hospitalization risk (60%), followed by LAI aripiprazole (58%), oral clozapine (57%), and LAI paliperidone (54%). In contrast, LAI olanzapine, oral quetiapine, and oral risperidone were not found to prevent hospitalization due to relapse.

In the cohort, 1,143 of 1,820 patients were hospitalized due to substance use disorder. Clozapine was associated with the greatest decreased risk of subsequent hospitalization due to any substance use (86%) followed by LAI formulations of risperidone (67%) and paliperidone (63%).

“These findings encourage the early use of second-generation long-acting injectables as an important secondary pre­vention strategy to reduce rates of hospitalization in first-episode patients with comorbid cannabis use disorders,” the researchers concluded.

For related information, see the Psychiatric News article “Strategies for Reducing Cannabis Use By Patients With FEP.”

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Suicide Risk Among Patients With Depression Highest First Three Days After Discharge

Patients with depression who have been discharged from psychiatric hospitals have the highest risk of dying by suicide in the first three days after discharge, with some risk factors increasing that risk further, according to a study published this week in JAMA Psychiatry.

Of all people dying by suicide, more than half had depression, and approximately 40% had been recently hospitalized, wrote Kari Aaltonen, M.D., Ph.D., of the University of Helsinki and colleagues. Therefore, people hospitalized for depression are at significant risk of suicide following their discharge. “Such a population with a distinct high-risk period in contact with psychiatric care forms a prioritizable target for selective suicide prevention,” they wrote.

Aaltonen and colleagues used data from Finnish registers such as the Care Register for Health Care and Statistics Finland, which included information on hospital admissions, discharges, diagnoses, and causes of death. They identified all psychiatric hospitalizations for depression among participants aged 18 years and older from 1996 to 2017; patients with comorbid major psychotic disorder or bipolar disorder were excluded. Each patient was followed for up to two years after discharge. For those with multiple hospitalizations, each discharge marked the beginning of a new follow-up period.

A total of 193,197 hospitalizations occurred during the study period among 91,161 participants (56.2% female; mean age 44 years). A total of 1,219 men and 757 women died by suicide during the study period. Additional findings included the following:

• During the first three days after discharge, the suicide incidence rate was 6,062 per 100,000 person-years. The authors noted that this rate exceeded the rate within the general population in Finland by 330-fold.
• The suicide rate remained high throughout the first week after discharge (3,884 per 100,000 person-years on days four to seven), but then fell steadily, dropping to 478 per 100,000 person-years after one year.
• Individuals who were admitted to the hospital due to a suicide attempt by firearm or hanging had the highest risk of death by suicide in the first three days after discharge. Other factors associated with immediate suicide risk included severe or psychotic depression, severe illness with impaired function, a history of attempted suicide, male sex, and age 40 and above.
• Some factors showed temporal trends. Having a higher household disposable income was associated with immediate suicide risk after discharge, but later it was associated with a lower risk compared with those with lower income. Individuals hospitalized with comorbid alcohol use disorder had a lower immediate suicide risk than those without, but then a higher risk over time.

“Although we found a decreasing trend over time, the high-risk post-discharge period still requires intensified attention,” the authors wrote. “Continuity of care and access to enhanced psychiatric outpatient care within days of discharge should be imperative.”

For related information, see the Psychiatric News article “Army STARRS Study Finds Risks to Progression From Suicidal Ideation to Attempts.”

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