David D. Kim

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 drugs 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.

Exercise-associated extrapyramidal symptoms during treatment with long-acting injectable antipsychotic medications: A case report

Antipsychotic medications can effectively treat psychotic symptoms in individuals with schizophrenia. However, side effects including cardiovascular and extrapyramidal symptoms are often inevitable. Exercise has proven effective in ameliorating cardiometabolic abnormalities in individuals with schizophrenia. In addition, exercise has consistently been an effective intervention for improving the symptoms associated with schizophrenia. We report here two cases in which individuals with schizoaffective disorder treated with a long-acting injectable antipsychotic medication displayed worsening of extrapyramidal symptoms over the course of a 12-week exercise program. This can be attributed to an increase in blood flow to the depot site during exercise, accelerating the rate of absorption and bioavailability of the antipsychotic medication and subsequently increasing dopamine D2 blockade. Clinicians need to be vigilant when patients receiving long-acting injectable antipsychotic medications engage in exercise.

Exercise-induced hippocampal neurogenesis: 5-HT 3 receptor antagonism by antipsychotics as a potential limiting factor in Schizophrenia

Aerobic exercise is a well-understood stimulus to hippocampal plasticity [1]. Exercise for individuals with Schizophrenia is especially promising as smaller hippocampal volume (HV) is a core feature, and volume increases are associated with improved clinical and cognitive outcomes [2]. One major component of hippocampal plasticity is adult neurogenesis. Evidence has demonstrated significant deficits in hippocampal cell proliferation or neurogenesis in post-mortem brain tissue of patients with Schizophrenia [3], suggesting that restoration of hippocampal neurogenesis (e.g., by exercise) may have therapeutic implications. Over the past decade, several studies have investigated the effects of exercise on brain structures, including HV, in individuals with Schizophrenia. However, results have not been consistent. Pajonk and colleagues (2010) demonstrated that following 3-month aerobic training, relative HV significantly increased by 12 and 16% in patients and healthy participants, respectively, but not in patients who played table football (−1%) [1]. The study design was replicated with larger samples using the identical protocol; however, significant increases in HV were not observed in patients or healthy participants [4]. This is in line with another study that utilized 6 months of combined aerobic and resistance training [5]. Conflicting results as to the effects of aerobic exercise on HV are also present among individuals in the early stages of illness [6, 7]. Therefore, factors that are responsible for such inconsistent results need to be identified. Although variations in exercise protocols and image analysis strategies between the existing studies may be responsible, the recent study by Kondo and colleagues (2015) led us to consider 5-HT3 receptor antagonism by antipsychotics as a potential key factor that impedes exercise-induced HV expansion in individuals with Schizophrenia [8]. The study demonstrated that the 5-HT3 receptor, a ligand-gated ion channel, is required for exercise-induced hippocampal neurogenesis and antidepressant effects, as shown using a 5-HT3A receptor subunit-deficient (htr3a) mouse model [8]. In this study, with no difference at baseline, hippocampal cell proliferation and neurogenesis were enhanced by exercise in the wild-type, but not in the htr3a mice [8]. Furthermore, stimulation of 5-HT3 receptors using a selective 5-HT3 receptor agonist promoted neurogenesis in the wild-type, but not in the htr3a mice [8]. Given this evidence that 5-HT3 receptors are essential for exercise-induced hippocampal neurogenesis, the fact that some antipsychotics antagonize 5-HT3 receptors deserves attention. To this point, the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP) demonstrated via radioligand binding assays that antipsychotics, such as aripiprazole (Ki= 628 nM), clozapine (Ki= 241 nM), loxapine (Ki= 190 nM), and olanzapine (Ki= 202 nM), have moderate affinities for 5-HT3 (cloned human) receptors. Rammes and colleagues (2004) demonstrated, using the patch clamp technique, that apart from risperidone, various antipsychotics at therapeutic concentrations (i.e., clozapine, flupentixol, fluphenazine, haloperidol, levomepromazine, and thioridazine) antagonized 5-HT-evoked Na-inward and Ca-inward currents through 5-HT3 receptors stably expressed in human embryonic kidney 293 cells in a competitive (for clozapine) and noncompetitive (for all the other antipsychotics) manner [9]. Aside from their inhibitory effects on Na currents, most of these antipsychotics showed a higher potency against 5-HT3A receptor-mediated Ca 2+ currents (e.g., IC50 * Ric M. Procyshyn rprocyshyn@bcmhs.bc.ca

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 clozapines 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.

A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment in children and adolescents

The second generation antipsychotic drug risperidone is widely used in the field of child and adolescent psychiatry to treat conditions associated with disruptive behavior, aggression and irritability, such as autism spectrum disorders. While risperidone can provide symptomatic relief for many patients, there is considerable individual variability in the therapeutic response and side-effect profile of the medication. One well established biological factor that contributes to these individual differences is genetic variation in the cytochrome P450 enzyme 2D6. The 2D6 enzyme metabolizes risperidone and therefore affects drug levels and dosing. In the present review, we summarize the current literature on 2D6 variants and their effects on risperidone responses, specifically in children and adolescents. Relevant articles were identified through systematic review, and after irrelevant articles were discarded, ten studies were included in the review. Most prospective studies were well controlled, but often did not have a large enough sample size to make robust statements about rarer variants, including those categorized as ultra-rapid and poor metabolizers. Individual studies demonstrated a role for different genetic variants in risperidone drug efficacy, pharmacokinetics, hyperprolactinemia, weight gain, extrapyramidal symptoms and drug–drug interactions. Where studies overlapped in measurements, there was typically a consensus between results. These findings indicate that the value of 2D6 genotyping in the youth population treated with risperidone requires further study, in particular with the less common variants.