Clozapine for Parkinson's Psychosis, Bipolar Disorder, and Other Off-Label Uses

Clozapine has two FDA-approved uses. The label states that it "is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment" and "for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state."¹ Any other use is off-label, meaning a doctor prescribes it for something the label doesn't cover.

The off-label uses differ widely in how much evidence sits behind them. For Parkinson's disease psychosis, the two placebo-controlled trials cited here had 60 patients each. A randomized trial in borderline personality disorder aimed for 222 participants and recruited 29.^{2, 3, 4}

I've written separately about the labeled uses, on the pages about when to start clozapine and clozapine and suicide risk.

Clozapine for Parkinson's disease psychosis: two small trials at low doses

The Parkinson Study Group randomized 60 patients, mean age 72, with drug-induced psychosis to clozapine at 6.25 to 50 mg per day or placebo for four weeks, with weekly blood counts. The mean dose was 24.7 mg per day. Clinical Global Impression scores improved by 1.6 points on clozapine and 0.5 on placebo. Tremor improved, parkinsonism didn't worsen, and one patient stopped clozapine because of leukopenia.²

A second trial of 60 patients used a four-week double-blind comparison, with a mean dose of 35.8 mg at the end of that period. Scores on the same scale improved by 1.8 on clozapine and 0.6 on placebo, and motor scores didn't change significantly. After a 12-week open period, 25 patients had completely recovered from delusions and hallucinations, and 19 relapsed within one month of stopping. Somnolence was more frequent with clozapine.³

Those are the doses the trials tested. The label's target dose in schizophrenia is 300 to 450 mg per day.¹

The International Parkinson and Movement Disorder Society's evidence review, updated through December 31, 2016, rated clozapine "Efficacious", with "Acceptable risk with specialized monitoring", and "Clinically useful". The same review rated pimavanserin efficacious and wrote that low-dose quetiapine "can be considered a pragmatic first choice because of its improved safety profile when compared with clozapine".⁵ The label states that clozapine "is not approved for use in patients with dementia-related psychosis".¹

Clozapine for treatment-resistant bipolar disorder: no pooled estimate

A 2015 systematic review covered 15 studies with 1,044 patients, a mix of randomized, open-label, and retrospective designs, and its abstract gives no pooled efficacy estimate. It concluded that clozapine "may be both an effective and a relatively safe medication" for treatment-resistant bipolar disorder.⁶

In manic episodes, a 2020 meta-analysis of 3 studies, with 100 patients on clozapine and 102 on other antipsychotics, found similar efficacy (p = 0.59). Two studies in that review enrolled patients with treatment-resistant bipolar disorder and favored clozapine.⁷ A 1999 randomized, open study assigned 38 patients with treatment-resistant schizoaffective or bipolar disorder to add-on clozapine or treatment as usual for 1 year. It found significant differences on all rating scales except the Hamilton depression scale.⁸

In a register study of 326 patients with bipolar disorder, the mean number of bed-days was 177.8 before clozapine and 34.6 during it. This was a mirror-image design, which compares the same patients before and after starting a drug.⁹

Clozapine for borderline personality disorder: the trial could not test it

In a register study, 1,107 of 25,916 patients with borderline personality disorder had redeemed at least one clozapine prescription. In a two-year mirror-image comparison of all of these patients, psychiatric admissions went from 2.52 to 2.00 and psychiatric bed-days from 190.08 to 65.95. The number of patients with intentional self-harm or overdose went from 189 to 114.¹⁰ A before-and-after design can't establish that the drug caused the change.

The CALMED trial aimed to recruit 222 inpatients with severe borderline personality disorder who had failed to respond to other antipsychotics. It closed early with 29 participants. The adjusted difference in symptom score at 6 months was -3.86, with a 95% confidence interval from -10.04 to 2.32, which includes no difference. The authors wrote, "We recruited insufficient participants to test the primary hypothesis."⁴

Clozapine and tardive dyskinesia: a slight reduction after switching

The label lists tardive dyskinesia as a risk of antipsychotic drugs, including clozapine.¹

A 2018 meta-analysis pooled 16 studies of people with schizophrenia or a related disorder who switched to clozapine alone. Across 1,060 patients the overall effect was d = -0.40, which the authors described as "a slight reduction" in tardive dyskinesia. The effect was larger (d = -2.56) in the 4 studies, with 48 patients, that examined tardive dyskinesia severity as a primary outcome.¹¹ A 2019 systematic review noted that clozapine carries a liability for tardive dyskinesia and that prospective randomized controlled trials are necessary.¹²

In a 505,474-person cohort, clozapine was associated with less hospitalization in every diagnosis except one

A 2025 study used nationwide registers in Finland and Sweden covering 505,474 people with psychotic, affective, and personality disorders, of whom 19,910 used clozapine. Each patient served as their own control. Clozapine use was associated with a lower risk of psychiatric hospitalization than other oral antipsychotics in all disorders except borderline personality disorder. The adjusted hazard ratio was 0.77 (95% CI 0.69 to 0.87) in bipolar disorder and 0.76 (0.61 to 0.96) in psychotic depression.¹³

The borderline personality disorder group had 36 clozapine users, with data available only in Sweden. Clozapine was used by 0.5% to 0.6% of people with bipolar disorder, so the off-label groups are small.¹³

Limitations of the evidence

This evidence has limitations. First, outside Parkinson's disease psychosis the data are mostly register studies and before-and-after comparisons, which can't establish that clozapine caused the change. Second, the Parkinson's trials lasted four weeks with 60 patients each. Nevertheless, the two labeled indications are clear, and any use outside them is a case-by-case decision made with a prescriber who can explain the evidence and its gaps.

In a crisis: call or text 988, or go to the nearest emergency department. A first episode of psychosis belongs in a hospital-based or coordinated specialty care program.

I start and manage clozapine in an outpatient practice in Chelsea, Manhattan. Details are on the schizophrenia care in NYC page. Clozapine should not be stopped, skipped, or restarted without the prescriber. This page is general information and does not replace an evaluation.

Related: Schizophrenia and psychosis treatment guide · When to start clozapine · Clozapine blood tests after the REMS ended · Clozapine side effects · Missed clozapine doses · Clozapine and suicide risk · Cannabis and psychosis · Schizoaffective vs schizophrenia · Cobenfy vs clozapine · Postpartum psychosis · Injections vs pills · Stimulants and psychosis · Drug-induced psychosis · Clozapine levels · CBT for psychosis · Clozapine myocarditis · Cannabis after psychosis · Clozapine constipation · Work and school · Clozapine drooling · Early signs in teens · Clozapine weight gain · Genetic and family risk · Who can prescribe clozapine · Schizophrenia and violence · Clozapine in teenagers · Sleepiness, bedwetting, heart rate · When clozapine isn't enough · Clozapine interactions · Benign ethnic neutropenia · Starting clozapine · Clozapine and pneumonia · Clozapine seizures · Clozapine in pregnancy · Clozapine rechallenge · Relative refuses treatment · Late-onset schizophrenia · Negative symptoms · First-episode psychosis · Tardive dyskinesia · Stopping antipsychotics · Schizophrenia life expectancy · Key clozapine studies