Impact of patient-specific factors on clozapine metabolism in individuals with treatment-resistant schizophrenia or schizoaffective disorder.

BACKGROUND: There is high inter-individual variability in clozapine metabolism due to genetic and non-genetic differences. Patient-specific factors such as smoking, inflammation indicated by elevated C-reactive protein (CRP), and certain concurrent medications have a significant influence on clozapine metabolism. AIM: To assess which patient-specific factors best explain variability in clozapine metabolism estimated by clozapine concentration to dose (C/D) ratios. METHODS: A retrospective cohort analysis using electronic medical data was conducted on 172 inpatients at the BC Psychosis Program. Patients with normal renal and liver function were included if they were on clozapine and had at least one steady-state plasma concentration. The degree of influence of each factor on the variability of clozapine metabolism in the entire cohort and subgroups stratified by fluvoxamine use was evaluated using multiple linear regression analysis of C/D ratios. RESULTS: Model fit testing showed that the entire cohort model accounts for 52.7% of C/D ratio variability, while the no fluvoxamine and fluvoxamine models accounted for 40.8% and 43.8%. In the entire cohort (n = 172), fluvoxamine use explained the highest variance, and C/D ratios were higher by 30.6% on average. The second strongest predictor was elevated CRP > 10 mg/L, and C/D ratios were higher by 22.9% on average. Subsequently, obesity, nonsmoker status, and female sex explained a significant but modest proportion of variance. Among participants on fluvoxamine (n = 58), only fluvoxamine dose was associated with an increase, and for every 25 mg increase in dose, C/D ratios increased by 5% on average. CONCLUSION: In a clinical population, this study replicated the relationship between reduced rate of clozapine metabolism and the use of fluvoxamine, elevated CRP, obesity, nonsmoking status, and female sex; and the magnitude of the effects were large enough to be clinically relevant.

SETD1A variant-associated psychosis: A systematic review of the clinical literature and description of two new cases.

OBJECTIVE: SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding variants in SETD1A and schizophrenia has achieved genome-wide significance by rare variant burden testing, only a few studies have described the psychiatric phenomenology of such individuals in detail. This systematic review and case report aims to characterize the neurodevelopmental and psychiatric phenotypes of SETD1A variant-associated schizophrenia. METHODS: A PubMed search was completed in July 2022 and updated in May 2023. Only studies that reported individuals with a SETD1A variant as well as a primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases of SETD1A variant-associated psychosis from our own sequencing cohort are described. RESULTS: The search yielded 32 articles. While 15 articles met inclusion criteria, only five provided case descriptions. In total, phenotypic information was available for 11 individuals, in addition to our own two unpublished cases. Our findings suggest that although individuals with SETD1A variant-associated schizophrenia may share a number of common features, phenotypic variability nonetheless exists. Moreover, although such individuals may exhibit numerous other neurodevelopmental features suggestive of the syndrome, their psychiatric presentations appear to be similar to those of general schizophrenia populations. CONCLUSIONS: Loss-of-function SETD1A variants may underlie the development of psychosis in a small percentage of individuals with schizophrenia. Identifying such individuals may become increasingly important, given the potential for advances in precision medicine treatment approaches.

Developing prediction models for symptom severity around the time of discharge from a tertiary-care program for treatment-resistant psychosis.

Antipsychotics are the only therapeutic class indicated in the symptomatic management of psychotic disorders. However, individuals diagnosed with schizophrenia or schizoaffective disorder may not always benefit from these first-line agents. This refractoriness to conventional treatment can be difficult to address in most clinical settings. Therefore, a referral to a tertiary-care program that is better able to deliver specialized care in excess of the needs of most individuals may be necessary. The average outcome following a period of treatment at these programs tends to be one of improvement. Nonetheless, accurate prognostication of individual-level responses may be useful in identifying those who are unlikely to improve despite receiving specialized care. Thus, the main objective of this study was to predict symptom severity around the time of discharge from the Refractory Psychosis Program in British Columbia, Canada using only clinicodemographic information and prescription drug data available at the time of admission. To this end, a different boosted beta regression model was trained to predict the total score on each of the five factors of the Positive and Negative Syndrome Scale (PANSS) using a data set composed of 320 hospital admissions. Internal validation of these prediction models was then accomplished by nested cross-validation. Insofar as it is possible to make comparisons of model performance across different outcomes, the correlation between predictions and observations tended to be higher for the negative and disorganized factors than the positive, excited, and depressed factors on internal validation. Past scores had the greatest effect on the prediction of future scores across all 5 factors. The results of this study serve as a proof of concept for the prediction of symptom severity using this specific approach.

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis.

BACKGROUND: Antipsychotic medications are the mainstay of treatment for schizophrenia and are associated with a reduction in psychiatric hospitalization and overall mortality. Some evidence suggest that antipsychotic medications might have a varying effect on the improvement of comorbid substance use disorders (SUDs), with clozapine showing more favorable outcomes. AIM: We systematically reviewed all available evidence on effects of clozapine on the improvement of SUDs other than nicotine. METHODS: Electronic searches of MEDLINE, Embase, PsycINFO, and CINHAL were conducted up to March 1, 2022. Studies of any methodological design involving two concepts: (1) clozapine and (2) SUD terms (excluding nicotine) were included. For SUD outcomes with three or more comparative studies with available raw data meta-analysis was performed. SUD outcomes not meeting criteria for meta-analysis were described qualitatively. Risk of bias was examined using "Downs and Black," and "Q-Coh" instruments. RESULTS: The majority of individuals in the included 31 studies were male and of European ancestry. Abstinence was the most common outcome. Most of the studies were of low-to-moderate quality, and none of the studies met all the quality criteria. Pooled findings from four observational studies in samples of patients with predominantly comorbid alcohol use disorder showed that clozapine treatment is associated with significantly higher odds of remaining abstinent. In addition clozapine was associated with decreased odds of psychiatric hospitalization in all but one observational study. CONCLUSIONS: Our systematic review and meta-analysis builds upon previous reviews, and it suggests the association of clozapine treatment with significantly higher odds of remaining abstinent from substance use and decreased likelihood of psychiatric hospitalization, compared with continuing treatment with other antipsychotic medications. Still, the validity of this association needs greater exploration and providing recommendations for the utility of clozapine in individuals without treatment-resistant psychosis and comorbid SUDs would be premature.

A 1p31.3 deletion encompassing the nuclear factor 1A gene presenting as possible temporal lobe epilepsy in association with schizoaffective disorder.

Chromosome 1p32-p31 deletion syndrome, which is characterized by a variety of neurodevelopmental abnormalities, is thought to occur as a result of nuclear factor 1A (NFIA) haploinsufficiency. We present a case of a right-handed 40-year-old female with a 1p31.3 deletion, who exhibited numerous common features of this syndrome, in addition to treatment resistant schizoaffective disorder and possible temporal lobe epilepsy, making her presentation unique. While neither psychosis nor temporal lobe epilepsy has been described in this syndrome previously, these conditions likely occurred in our patient as a result of NFIA haploinsufficiency.

Impact of medications, mood state, and electrode placement on ECT outcomes in treatment-refractory psychosis.

BACKGROUND: Treatment-refractory psychosis (TRP) is a significant clinical challenge. While clozapine is frequently effective, alternate or augmentation strategies are often necessary. Evidence supports effectiveness of electroconvulsive therapy (ECT), but questions remain about optimal treatment parameters and impacts of concomitant pharmacotherapy. OBJECTIVE: /Hypothesis: To analyze the impact of clozapine, anticonvulsant medication, mood state, and ECT electrode placement on outcomes in TRP. We hypothesized that ECT would lead to greater reduction in positive symptoms, particularly in patients receiving clozapine. METHODS: Retrospective study in a tertiary TRP program. The Positive and Negative Syndrome Scale (PANSS) was used for clinical outcomes, with positive subscore as primary outcome. Clinical and ECT data were analyzed using a linear modelling approach, controlling for relevant covariates. RESULTS: A total of 309 patients were included. ECT plus clozapine associated with greater improvement in positive, general, and total symptoms than ECT alone. ECT associated with greater improvement in negative symptoms in depressed patients. Bifrontal placement was mostly equivalent to bitemporal, with greater reduction of positive symptoms in patients receiving clozapine, and associated with lower electrical dose in patients on anticonvulsants. Clozapine increased seizure duration, while anticonvulsants decreased it. Anticonvulsant use in ECT patients associated with equivalent to slightly improved symptom reduction. CONCLUSIONS: ECT's benefit in TRP may be greatest in patients receiving clozapine. ECT can improve negative symptoms in depressed TRP patients. Bifrontal placement is effective in TRP. Clozapine and anticonvulsants have opposite effects on seizure duration, but anticonvulsants may not adversely affect clinical outcomes of ECT for TRP.

A 20-year population-based study of all-cause and cause-specific mortality among people with concurrent HIV and psychotic disorders.

OBJECTIVE: We aimed to characterize mortality among people with HIV (PWH) and psychotic disorders (PWH/psychosis+) vs. PWH alone (PWH/psychosis-). METHOD: A population-based analysis of mortality in PWH (age ≥19) in British Columbia (BC) from April 1996 to March 2017 was conducted using data from the Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) study. Deaths were identified from the Vital Statistics Data (classified as HIV vs. non-HIV causes). Mortality trends across all fiscal years were examined. Cox models assessed the hazard of psychotic disorders on mortality; possible differences between schizophrenia and nonschizophrenia types of psychotic disorders were also evaluated. RESULTS: Among 13 410 PWH included in the analysis, 1572 (11.7%) met the case definition for at least one psychotic disorder. Over the study period, 3274 deaths (PWH/psychosis-: n  = 2785, PWH/psychosis+: n  = 489) occurred. A decline over time in all-cause mortality and HIV-related mortality was observed in both PWH/psychosis+ and PWH/psychosis- ( P value <0.0001). A decline in non-HIV mortality was observed among PWH/psychosis- ( P value = 0.003), but not PWH/psychosis+ ( P value = 0.3). Nonschizophrenia psychotic disorders were associated with increased risk of mortality; adjusted hazard ratios with (95% confidence intervals): all-cause 1.75 (1.46-2.09), HIV-related 2.08 (1.60-2.69), non-HIV-related 1.45 (1.11-1.90). Similar associations between schizophrenia and mortality were not observed. CONCLUSION: People with co-occurring HIV and nonschizophrenia psychotic disorders experienced a significantly higher risk of mortality vs. PWH without any psychotic disorder. Implementing care according to syndemic models considering interactions between HIV and particularly episodic psychotic disorders could help manage mortality risk more effectively among PWH/psychosis+.

Exercise and Worsening of Extrapyramidal Symptoms during Treatment with Long-Acting Injectable Antipsychotics.

Second-generation antipsychotic medications are used to treat schizophrenia and a range of other psychotic disorders, although adverse effects, including cardiovascular and metabolic abnormalities and extrapyramidal symptoms, are often inevitable. Studies have shown that exercise, as an adjunct therapy, can be effective in reducing the core symptoms of schizophrenia as well as ameliorating intrinsic and antipsychotic-induced cardiometabolic abnormalities. However, it is noteworthy that exercise may need to be implemented with caution in some individuals receiving certain antipsychotic treatment regimens. We report here two cases of exercise-associated worsening of extrapyramidal symptoms in two individuals with schizoaffective disorder treated with a long-acting injectable antipsychotic medication over the course of a 12-week exercise program. This worsening of extrapyramidal symptoms can be attributed to an increase in blood flow to the site of injection during exercise, accelerating the rate of absorption and bioavailability of the antipsychotic medication and subsequently increasing dopamine D2 receptor blockade. When monitoring drug therapy for patients receiving long-acting injectable antipsychotic medications, pharmacists and other healthcare professionals need to consider exercise as a contributing factor for the emergence of extrapyramidal symptoms.

High-Dose Fluvoxamine Augmentation to Clozapine in Treatment-Resistant Psychosis.

BACKGROUND: Although clozapine is the gold standard for treatment-resistant schizophrenia, more than 30% of patients remain unresponsive to clozapine monotherapy and may benefit from augmentation strategies. Fluvoxamine augmentation of clozapine may be beneficial in treatment resistance because of pharmacokinetic interactions, allowing for lower clozapine dosages with higher clozapine serum levels and an increased clozapine-to-norclozapine ratio, which can modify adverse effects. An augmentation strategy using higher fluvoxamine doses may also improve persistent negative, anxiety, and obsessive-compulsive symptoms through fluvoxamine's serotonergic activity. METHODS: Through chart review, we identified 4 cases of patients with treatment-resistant psychosis who underwent high-dose fluvoxamine augmentation of clozapine to target residual negative symptoms, refractory psychosis, anxiety, and obsessive-compulsive symptoms. FINDINGS: This augmentation strategy continued in 2 patients after discharge who showed clinical improvement without significant adverse effects. Two patients experienced adverse effects that led to the fluvoxamine discontinuation. Despite the fact that fluvoxamine augmentation led to symptom improvement in only 2 patients, all patients achieved high serum clozapine levels. Hematologic parameters were monitored in all patients, and no abnormalities were observed. No severe adverse effects of clozapine were experienced. CONCLUSIONS: Although high variability of responses and adverse effects were observed during fluvoxamine augmentation to clozapine, this strategy was successful in increasing clozapine serum levels. Through fluvoxamine's serotonergic effects, this strategy may confer benefit to residual negative, obsessive, and anxiety symptoms. Limitations of this case series include the retrospective nature, absence of controls, diversity of diagnoses, multiple interventions in each patient, and lack of masked raters.

Relationship between clozapine dose and severity of obsessive-compulsive symptoms.

Evidence supports the fact that clozapine can induce stressful obsessive-compulsive symptoms (OCS). Although clozapine's robust inhibition of serotonergic neurotransmission is believed to be a key mechanism underlying clozapine-induced OCS, the exact mechanism(s) are not fully understood. Intuitively, it is reasonable to believe that the dose of clozapine is likely related to emergent OCS severity. However, there is conflicting evidence where both positive and inverse relationships have been demonstrated between clozapine dose and emergent OCS severity. Upon examination of clozapine's receptor profile, in particular its affinity for 5-HT2A and D2 receptors, we hypothesize that there is a biphasic relationship between clozapine dose and emergent OCS severity. We present here a preliminary analysis of published cases in the literature to support our hypothesis.

Clozapine-Associated Obsessive-Compulsive Symptoms and Their Management: A Systematic Review and Analysis of 107 Reported Cases.

BACKGROUND: It is not uncommon to find obsessive-compulsive symptoms (OCS) in patients treated with clozapine. These symptoms are attributed to anti-serotonergic effects of clozapine. The objective of this study was to conduct a systematic review of reported cases of clozapine-associated OCS to better understand the nature and management of these symptoms. METHODS: MEDLINE, Embase, and PsycINFO databases were searched with no publication year or language restrictions. Studies reporting cases of clozapine-associated OCS, either de novo or exacerbation of preexisting OCS, were included. The final search date was July 11, 2019. RESULTS: Fifty-seven studies, involving 107 cases (75 de novo, 32 exacerbated OCS), were included. Clozapine triggered moderate-severe OCS at varying doses (100-900 mg/day) and treatment durations (median 6 months, interquartile range 2-24 months). Higher severity was significantly associated with preexisting OCS, poorer insight into OCS, and active psychosis at the time of OCS. Common strategies to treat clozapine-associated OCS included adding selective serotonin reuptake inhibitors, clomipramine, or aripiprazole, often accompanied by clozapine dose reduction. The rate of response to antidepressants was 49% (29/59), where younger age, shorter duration of underlying illness, shorter cloza-pine treatment duration, better insight into OCS, and presence of taboo thoughts were significantly associated with antidepressant response. Subsequent clozapine dose reduction was effective in many non-responders, where aripiprazole was simultaneously added in 50% (8/16). CONCLUSIONS: Clozapine can trigger severe OCS. Adding aripiprazole with/without clozapine dose reduction may be a good alternative to antidepressants for managing clozapine-associated OCS. Clinicians should be more vigilant about these adverse effects and administer appropriate treatments.

Preliminary examination of the validity of the NIH toolbox cognition battery in treatment-resistant psychosis.

Objective: Prior research has suggested that treatment-resistant psychosis (TRP) may be a categorically distinct subtype from treatment-responsive psychotic disorders. However, relatively few studies have investigated the cognitive profile of individuals with TRP. Moreover, no prior studies have investigated the effectiveness of using the NIH Toolbox Cognition Battery (NTCB) for assessing cognition among psychiatric inpatients despite its promising efficiency and practicality in such settings. The current study aimed to investigate the validity of the NTCB and the associated cognitive profile of inpatients with TRP.Methods: Participants (N = 38) were administered the NTCB and a neuropsychological test battery. The Positive and Negative Syndrome Scale and the Routine Assessment of Patient Progress measured psychosis symptomatology and daily functioning, respectively.Results: Results showed deficits relative to normative values in fluid cognitive abilities using the NTCB, as predicted. There was strong convergent validity and adequate divergent validity between the NTCB subtests and corresponding neuropsychological measures, though no NTCB subtest correlated with performance on the Wisconsin Card Sorting Task. NTCB performance correlated with positive and disorganized symptoms of psychosis as well as daily functioning.Conclusions: Taken together, the NTCB appears to be a relatively strong tool for cognitive screening among psychiatric inpatients and may be used to identify which patients might benefit from further neuropsychological evaluation.

Antipsychotic prescribing patterns on admission to and at discharge from a tertiary care program for treatment-resistant psychosis.

Retrospective data were collected from 330 individuals who were treated at a tertiary care program for treatment-resistant psychosis between 1994 and 2010. The main objectives were to compare the use of antipsychotic monotherapy to polypharmacy and to characterize within-individual changes in treatment and symptomatology between admission and discharge. At admission, individuals who were prescribed only one antipsychotic were comparable to those who were prescribed at least two antipsychotics with regard to demographics and symptom severity. The use of psychotropic medications other than antipsychotics was also similar between the two groups. However, the magnitude of antipsychotic utilization was greater in individuals who were receiving antipsychotic polypharmacy. In addition, a greater proportion received excessive doses at admission. Similar findings were observed when the two antipsychotic prescribing practices were compared at discharge. Three important patterns were identified when investigating within-individual changes. First, fewer individuals were prescribed more than one antipsychotic at discharge. This was accompanied by a general decrease in the magnitude of antipsychotic utilization. Second, the number of individuals who were prescribed clozapine had increased by discharge. Most who were already prescribed clozapine at admission had their doses increased. Third, improvements in symptomatology were observed across all of the subscales included in the Positive and Negative Symptom Scale (PANSS); 57.9% of individuals experienced a relative reduction in total PANSS scores exceeding 20%. Based on these findings, it is possible to alleviate symptom severity while reducing antipsychotic utilization when patients are treated at a tertiary care program for treatment-resistant psychosis.

Antipsychotic-Associated Symptoms of Tourette Syndrome: A Systematic Review.

BACKGROUND: Although antipsychotics are used to treat Tourette syndrome, there have been reports of paradoxical induction of tics by first- and second-generation antipsychotics. OBJECTIVE: The objective of this systematic review was to better characterize tics as the potential adverse effect of antipsychotics. METHODS: A literature search was performed, with no language restriction, using the MEDLINE, EMBASE, and PsycINFO databases for all publications up to January 2018. To be included, studies utilizing any study design had to meet the following criteria: (1) a temporal association of tics with antipsychotic use where tics emerged during treatment or after discontinuation and (2) no diagnosis of Tourette syndrome before tic emergence. More stringent criteria were used for individuals under 18 years of age that included (1) no personal or family history of primary tic disorder and either (2) tics occurring during antipsychotic treatment improved significantly upon discontinuation or dose reduction or (3) tics emerged after discontinuation of at least 3 months of antipsychotic treatment. Data were extracted according to: age, sex, diagnosis, personal history of motor symptoms or family history of tics, antipsychotic type and dose, treatment duration, types of symptoms emerged, treatment strategies, and follow-up. A Fisher's exact test was used to compare the occurrence of symptoms between first- and second-generation antipsychotic users. RESULTS: The search identified 1290 articles, of which 92 full-text articles were assessed leading to the inclusion of 50 articles. Most of the included articles were case reports or series, involving a total of 60 cases. Thirty cases were associated with treatment with first-generation antipsychotics, 27 with second-generation antipsychotics, and three with a combination of first- and second-generation antipsychotics. Antipsychotics were being used to treat schizophrenia in 60% of the cases and other indications included developmental, behavioral, and mood or anxiety disorders. Tics occurred during treatment (n = 44) or following treatment discontinuation (n = 16). The occurrence of vocal tics with or without motor tics was significantly higher in the first- vs. second-generation antipsychotic users (p < 0.0001). Significantly higher occurrences were also noted in the first- vs. second-generation antipsychotic users for specific types of vocal tics (i.e., barking and coprolalia) and other concurrent motor symptoms (i.e., tardive dyskinesia). In the cases identified, antipsychotic-associated tics were treated by (1) discontinuing the offending antipsychotic, reducing its dose, or switching to different antipsychotics for tics occurring during treatment, (2) reinitiating antipsychotic treatment for tics occurring following discontinuation, or (3) using non-antipsychotic agents. It should be noted that symptoms were not always fully reversible and recurred at times. CONCLUSION: Tics can be a disturbing adverse effect of antipsychotics. Clinicians need to be particularly vigilant when initiating and modifying antipsychotic regimens.

Clozapine-Induced Cardiovascular Side Effects and Autonomic Dysfunction: A Systematic Review.

Background: Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and has minimal risk for extrapyramidal symptoms. Therapeutic benefits, however, are accompanied by a myriad of cardiometabolic side-effects. The specific reasons for clozapine's high propensity to cause adverse cardiometabolic events remain unknown, but it is believed that autonomic dysfunction may play a role in many of these. Objective: This systematic review summarizes the literature on autonomic dysfunction and related cardiovascular side effects associated with clozapine treatment. Method: A search of the EMBASE, MEDLINE, and EBM Cochrane databases was conducted using the search terms antipsychotic agents, antipsychotic drug*, antipsychotic*, schizophrenia, schizophren*, psychos*, psychotic*, mental ill*, mental disorder*, neuroleptic*, cardiovascular*, cardiovascular diseases, clozapine*, clozaril*, autonomic*, sympathetic*, catecholamine*, norepinephrine, noradrenaline, epinephrine, adrenaline. Results: The search yielded 37 studies that were reviewed, of which only 16 studies have used interventions to manage cardiovascular side effects. Side effects reported in the studies include myocarditis, orthostatic hypotension and tachycardia. These were attributed to sympathetic hyperactivity, decreased vagal contribution, blockade of cholinergic and adrenergic receptors, reduced heart rate variability and elevated catecholamines with clozapine use. Autonomic neuropathy was identified by monitoring blood pressure and heart rate changes in response to stimuli and by spectral analysis of heart rate variability. Metoprolol, lorazepam, atenolol, propranolol, amlodipine, vasopressin and norepinephrine infusion were used to treat tachycardia and fluctuations in blood pressure, yet results were limited to case reports. Conclusion: The results indicate there is a lack of clinical studies investigating autonomic dysfunction and a limited use of interventions to manage cardiovascular side effects associated with clozapine. As there is often no alternative treatment for refractory schizophrenia, the current review highlights the need for better designed studies, use of autonomic tests for prevention of cardiovascular disease and development of novel interventions for clozapine-induced side effects.

Reduced cardiovascular fitness associated with exposure to clozapine in individuals with chronic schizophrenia.

Studies show that individuals with schizophrenia have impaired cardiovascular fitness (i.e., low peak aerobic power (VO2peak)). It is speculated that antipsychotics with adverse cardiovascular and metabolic profiles, in particular clozapine, have a significant impact on VO2peak. In this cross-sectional study, we examined whether exposure to clozapine was associated with further reduced VO2peak compared with non-clozapine antipsychotics. Thirty participants with chronic schizophrenia or schizoaffective disorder were divided into clozapine and non-clozapine groups. Mean daily doses of antipsychotics were standardized to chlorpromazine equivalents and haloperidol equivalents for antagonism of alpha1- and alpha2-adrenergic receptors. Participants completed an incremental-to-maximal symptom-limited exercise test on a cycle ergometer for the assessment of VO2peak. The clozapine group demonstrated significantly lower VO2peak than the non-clozapine group. Haloperidol equivalents for alpha-adrenergic receptor antagonism, but not chlorpromazine equivalents, demonstrated significant inverse associations with VO2peak. The clozapine group had a significantly higher amount of antagonistic activity at alpha-adrenergic receptors than the non-clozapine group. In conclusion, exposure to clozapine was associated with further reduced cardiovascular fitness, which may be explained by the drug's greater antagonistic activity at alpha-adrenergic receptors. Cardiovascular fitness needs to be promoted in individuals treated with antipsychotics, particularly clozapine, to prevent the risk of cardiovascular disease and mortality.