Clozapine, Psychosis and Suicidality – Highlights from RCPsychIC 2019
This article is based on the talk by Prof Rachel Upthegrove at RCPsych IC 2019. Prof Upthegrove is a Reader in Psychiatry and Youth Mental Health at the University of Birmingham, and Consultant Psychiatrist in the Birmingham Early Intervention Services.
1.Suicidality is reported at around 24% of the population within clinical high-risk states, and in broader population-based studies the co-occurrence of positive symptoms and suicidal behaviour in the general population is quite high (HR, 1.6-3.0). [Yates K et al., 2019]. A recent systematic review and meta-analysis of population studies showed:
Individuals with psychotic experiences are at increased risk of suicidal ideation, suicide attempts, and suicide death. Psychotic experiences are important clinical markers of risk for future suicidal behavior.
2. Depression in the prodromal phase is the most significant predictor of future depression and acts of self‐harm. Depression occurred in 80% of patients at one or more phases of first-episode psychosis, and a combination of depression and suicidal thinking was present in 63%. [Upthegrove R et al., 2010]
3. There are three main hypotheses for depression in schizophrenia. [Upthegrove R et al., 2017]
- depression which is intrinsic to psychosis
- depression which is a psychological reaction to the diagnosis and its implications for social status and position
- depression as “smoking gun evidence” of historical childhood trauma
4. Overdose with prescribed medication is the most common form of suicidal behaviour in first-episode psychosis and care is needed regarding the number of pills issued in the first weeks of a new diagnosis or the case of relapse. [Upthegrove R et al., 2010]
5. Although suicidal risk in schizophrenia is highest in the first year after presentation, with the risk persisting even a decade after almost 4 times higher than in the general population. [Dutta R et al., 2010]
6. Regarding pharmacological therapies, antidepressants are effective in the treatment of depression in schizophrenia and treating comorbid depression is a significant factor in preventing suicidal behaviour.
7. Studies show a small benefit in augmenting antipsychotics with antidepressants without exacerbation of psychosis, but the results are mixed and limited by the small number of studies. [Gregory A et al., 2017], [Helfer B et al., 2016]
8. Depression must be recognised and treated appropriately to prevent suicide in schizophrenia.
9. Clozapine in schizophrenia is a useful suicide prevention measure. Clozapine demonstrated superiority to olanzapine in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide. [Meltzer H et al., 2003]
10. Two nationwide cohorts in Finland and Sweden showed Clozapine’s superiority in reducing the risk of attempted or completed suicide among patients with schizophrenia.
Compared with no use of antipsychotics, clozapine use was the only antipsychotic consistently associated with a decreased risk of suicidal outcomes. Hazard ratios (HRs) and 95% CIs for attempted or completed suicide were 0.64 (0.49–0.84) in the Finnish cohort and 0.66 (0.43–0.99) in the Swedish cohort. No other antipsychotic was associated with a reduced risk of attempted and/or completed suicide. Benzodiazepines and Z-drugs were associated with an increased risk of attempted or completed suicide (HRs: 1.29–1.30 for benzodiazepines and 1.33–1.62 for Z-drugs). [Taipale H et al., 2020]
10. More extensive population-based studies showed reduced mortality rates in patients prescribed with clozapine, and who remain on the medication. Individuals with treatment-resistant schizophrenia not treated with clozapine show a two-fold higher mortality rate compared to those treated with clozapine. [Wimberly T et al., 2017]. However, mortality rates increase again on withdrawal of clozapine and suggest clozapine as a longer-term measure for suicide prevention in schizophrenia.
11. A Systematic Review and Meta-analysis of studies lasting 1.1-12.5 yrs showed that continuous clozapine treatment in schizophrenia patients was associated with a significantly lower long-term all-cause mortality rate compared to other antipsychotic use. [Vermeulen J et al., 2019]
12. For the 1 in 5 early psychosis patients (based on 544 young people who presented with a first episode psychosis) who are eligible for clozapine treatment, there is a delay of up to 42 weeks or more in offering the drug.
Of those commenced on clozapine, 76.6% achieved remission of positive psychotic symptoms and 50% were in employment or education by the time of discharge or transfer to the adult mental health services. The rate of discontinuation of clozapine was 24.4% and 60.0% of discontinuations were due to cardiac complications and the remainder were due to non-compliance. [Thien K et al., 2018]
13. The mechanism of action of clozapine has a wide range of effects on muscarinic and serotonin receptors, and it is also known to have an effect on anxiety, agitation and distress, all of which may be relevant in reducing suicidal behaviour.
14. In other areas of research, clozapine is hypothesised to have some anti-inflammatory properties as demonstrated in rats exposed to an inflammatory challenge, with response measured through activated microglia. Clozapine administration reversed microglial activation and iNOS increase, but not the alterations of oxidative stress parameters. [Ribeiro B et al.,2013 ]