Simon Zhornitsky

Oral versus Long-Acting Injectable Antipsychotics in the Treatment of Schizophrenia and Special Populations at Risk for Treatment Nonadherence: A Systematic Review.

Long-acting injectable antipsychotics (LAIs) should offer better efficacy and tolerability, compared to oral antipsychotics due to improved adherence and more stable pharmacokinetics. However, data on LAIs has been mixed, with some studies finding that they are more effective and tolerable than oral antipsychotics, and others finding the contrary. One possibility for the disparate results may be that some studies administered different antipsychotics in the oral and injectable form. The present systematic review examined the efficacy and tolerability of LAIs versus their oral equivalents in randomized and naturalistic studies. In addition, it examined the impact of LAIs on special populations such as patients with first-episode psychosis, substance use disorders, and a history of violence or on involuntary outpatient commitment. Randomized studies suggest that not all LAIs are the same; for example, long-acting risperidone may be associated with equal or less side effects than oral risperidone, whereas fluphenazine decanoate and enanthate may be associated with equal or more side effects than oral fluphenazine. They also suggest that LAIs reduce risk of relapse versus oral antipsychotics in schizophrenia outpatients when combined with quality psychosocial interventions. For their part, naturalistic studies point to a larger magnitude of benefit for LAIs, relative to their oral equivalents particularly among first-episode patients.

Cannabidiol in humans-the quest for therapeutic targets.

Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in the electronic databases PubMed and EMBASE using the key word “cannabidiol”. Both monotherapy and combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies), schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies), neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington’s disease (one study), insomnia (one study), and epilepsy (one study). Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical trials suggest that high-dose oral CBD (150–600 mg/d) may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed.

Dose-response and comparative efficacy and tolerability of quetiapine across psychiatric disorders: a systematic review of the placebo-controlled monotherapy and add-on trials

The atypical antipsychotic, quetiapine, is frequently prescribed on-label and off-label for the treatment of a variety of psychiatric disorders. As quetiapine has variable affinity for dozens of receptors, its clinical effects should also show a large variation as a function of dose and diagnostic category. This study attempts to elucidate the dose-response and comparative efficacy and tolerability (metabolic data) of quetiapine across psychiatric disorders. A systematic search was carried out in the electronic databases, PubMed and EMBASE, using the keywords ‘quetiapine’ and ‘placebo’. Both monotherapy and add-on studies were included. A total of 41 studies were identified. In unipolar and bipolar depression, studies consistently found quetiapine to be effective versus placebo, at doses of approximately 150–300 and 300–600 mg per day, respectively. In bipolar mania, they consistently found quetiapine to be effective at doses of approximately 600 mg per day. In acute exacerbation of schizophrenia, the majority of studies found quetiapine to be effective at doses of approximately 600 mg per day; however, a few large studies found no difference versus placebo. In contrast, studies consistently found quetiapine to be more effective than placebo for stable schizophrenia. In obsessive-compulsive disorder, studies did not consistently find quetiapine to be effective at doses of approximately 300 mg per day. However, studies may have underestimated the efficacy of quetiapine for obsessive-compulsive disorder due to concomitant administration of antidepressants and the utilization of treatment-refractory patients. In generalized anxiety disorder, studies consistently found quetiapine to be effective at doses of approximately 150 mg per day. Finally, analysis of metabolic tolerability data suggests that even low doses of quetiapine may lead to increase in weight and triglycerides across psychiatric disorders. Interestingly, however, quetiapine-induced elevations in low-density lipoprotein and total cholesterol seem to be restricted to schizophrenia patients.

Sensation-seeking, social anhedonia, and impulsivity in substance use disorder patients with and without schizophrenia and in non-abusing schizophrenia patients

Substance use disorders (SUDs) are common in patients with schizophrenia and this comorbidity is associated with a poorer prognosis, relative to non-abusing patients. One hypothesis that has been advanced in the literature is that dual diagnosis (DD) patients may have a different personality profile than non-abusing schizophrenia patients. The present case-control study aimed to characterize levels of personality traits (sensation-seeking, social anhedonia, and impulsivity) in substance abuse/dependence patients with (DD group; n=31) and without schizophrenia (SUD group; n=39), relative to non-abusing schizophrenia patients (SCZ group; n=23), and healthy controls (n=25). Impulsivity was assessed using the Barratt Impulsivity Scale. Sensation-seeking was assessed using the Zuckerman Sensation Seeking Scale. Social anhedonia was assessed with the Chapman Social Anhedonia Scale. We found that sensation-seeking was significantly higher in DD and SUD, relative to SCZ patients. We found that social anhedonia was significantly elevated in DD and SCZ, relative to healthy controls. We found that impulsivity was significantly higher in DD, SCZ and SUD patients, compared to healthy controls. The results suggest that sensation-seeking is prominent in substance abuse/dependence (irrespective of schizophrenia), social anhedonia is prominent in schizophrenia (irrespective of substance abuse/dependence), and impulsivity is prominent in all three populations.

Antipsychotic agents for the treatment of substance use disorders in patients with and without comorbid psychosis.

Substance dependence has serious negative consequences upon society such as increased health care costs, loss of productivity, and rising crime rates. Although there is some preliminary evidence that atypical antipsychotic agents may be effective in treating substance dependence, results have been mixed, with some studies demonstrating positive and others negative or no effect. The present study was aimed at determining whether this disparity originates from that reviewers separately discussed trials in patients with (DD) and without (SD) comorbid psychosis. Using electronic databases, we screened the relevant literature, leaving only studies that used a randomized, double-blind, placebo-controlled or case-control design that had a duration of 4 weeks or longer. A total of 43 studies were identified; of these, 23 fell into the category of DD and 20 into the category of SD. Studies in the DD category suggest that atypical antipsychotic agents, especially clozapine, may decrease substance use in individuals with alcohol and drug (mostly cannabis) use disorders. Studies in the SD category suggest that atypical antipsychotic agents may be beneficial for the treatment of alcohol dependence, at least in some subpopulations of alcoholics. They also suggest that these agents are not effective at treating stimulant dependence and may aggravate the condition in some cases.

Extrapyramidal Symptoms in Substance Abusers with and Without Schizophrenia and in Nonabusing Patients with Schizophrenia

Extrapyramidal symptoms (EPS) such as parkinsonism, dystonia, dyskinesia, and akathisia are conditions of impaired motor function, which are associated with chronic antipsychotic treatment in schizophrenia. In addition, EPS is often exacerbated by psychoactive substance (PAS) abuse, which is frequently observed in this population. Few studies, however, have investigated the contribution of PAS abuse on EPS in PAS‐abusers without comorbid psychosis. This study compared the occurrence of EPS in outpatient schizophrenia patients with (DD group; n= 36) and without PAS abuse (SCZ group; n = 41) as well as in nonschizophrenia PAS abusers undergoing detoxification [substance use disorder (SUD) group; n = 38]. Psychiatric symptoms were measured using the Positive and Negative Syndrome Scale and the Calgary Depression Scale for schizophrenia. Extrapyramidal symptoms were evaluated with the Extrapyramidal Symptoms Rating Scale and the Barnes Akathisia Scale. SUD diagnoses were complemented with urine drug screenings. We found that DD patients exhibited significantly more parkinsonism than SCZ patients. Our subanalyses revealed that cocaine and alcohol abuse/dependence was responsible for the increase in parkinsonism in DD patients. Additionally, we found that SUD individuals exhibited significantly more akathisia than SCZ patients. In these latter individuals, subanalyses revealed that alcohol and cannabis abuse/dependence was responsible for the increase in akathisia. Our results suggest that PAS abuse is a contributor to EPS in individuals with and without schizophrenia.

Switching from conventional antipsychotics to ziprasidone: A randomized, open-label comparison of regimen strategies

In clinical psychopharmacology, the optimal method of switching from treatment A to treatment B with regard to efficacy and tolerability is an important area of study. We investigated the effects on efficacy and tolerability of switching patients from conventional antipsychotics to ziprasidone. This was a 6-week open-label, randomized study of 54 patients with persistent schizophrenia or schizoaffective disorder. Patients received ziprasidone 40 mg BID for 2 days, with titration up to 80 mg BID thereafter. The switch from conventional antipsychotics to ziprasidone was achieved using one of three discrete schedules: (1) abrupt discontinuation of conventional antipsychotics on day 1; (2) fast taper-50% of conventional antipsychotic dosage on days 1 through 7, followed by discontinuation and (3) slow taper-100% of conventional antipsychotic dosage on days 1 and 2, followed by 50% on days 3 through 7, then discontinuation. We found some evidence that the slow-taper strategy was associated with greater reductions in BPRS total scores early in the study compared to the other two strategies. However, these differences did not remain significant at endpoint, suggesting that there was no overall difference between the strategies.

Comparing tolerability of olanzapine in schizophrenia and affective disorders: a meta-analysis

BACKGROUND Olanzapine is prescribed for a number of psychiatric disorders, including schizophrenia, bipolar mania, and unipolar and bipolar depression. Olanzapine treatment is associated with tolerability issues such as metabolic adverse effects (e.g. weight gain, increase in blood glucose, triglycerides and total cholesterol levels), extrapyramidal symptoms [EPS] (e.g. parkinsonism, akathisia, tardive dyskinesia) and sedative adverse effects. Metabolic issues lead to some long-term consequences, which include cardiovascular diseases (CVD) and type 2 diabetes mellitus, and these complications cause high rates of mortality and morbidity among patients with severe mental illnesses. The expanded indications of olanzapine in psychiatry suggest a need to investigate whether there is a difference in the incidence and severity of adverse effects related to category diagnosis. Are the adverse effects expressed differently according to phenotype? Unfortunately, there are no reported studies that investigated these differences in adverse effects associated with olanzapine treatment in psychiatric patients with different phenotypes. OBJECTIVE The aim of the present meta-analysis is to separately examine olanzapine-induced cardiometabolic adverse effects and EPS in patients with schizophrenia and affective disorders. DATA SOURCES A search of computerized literature databases PsycINFO (1967-2010), PubMed (MEDLINE), EMBASE (1980-2010) and the clinicaltrials.gov website for randomized clinical trials was conducted. A manual search of reference lists of published review articles was carried out to gather further data. STUDY SELECTION Randomized controlled trials were included in our study if (i) they assessed olanzapine adverse effects (metabolic or extrapyramidal) in adult patients with schizophrenia or affective disorders; and (ii) they administered oral olanzapine as monotherapy during study. DATA EXTRACTION Two reviewers independently screened abstracts for choosing articles and one reviewer extracted relevant data on the basis of predetermined exclusion and inclusion criteria. It should be mentioned that for the affective disorders group we could only find articles related to bipolar disorder. DATA SYNTHESIS Thirty-three studies (4831 patients) that address olanzapine monotherapy treatment of adults with schizophrenia or bipolar disorder were included in the analysis. The primary outcomes were metabolic adverse effects (changes in weight, blood glucose, low-density lipoprotein, total cholesterol and triglyceride levels). The secondary outcomes of our study were assessing the incidence of some EPS (parkinsonism, akathisia and use of antiparkinson medication). The tolerability outcomes were calculated separately for the schizophrenia and bipolar disorder groups and were combined in a meta-analysis. Tolerability outcomes show that olanzapine contributes to weight gain and elevates blood triglycerides, glucose and total cholesterol levels in both schizophrenia and bipolar disorder patients. However, olanzapine treatment produced significantly more weight gain in schizophrenia patients than in bipolar disorder patients. In addition, increases in blood glucose, total cholesterol and triglyceride levels were higher in the schizophrenia group compared with the bipolar disorder group, even though these differences were not statistically significant. Based on our results, the incidence of parkinsonism was significantly higher in the schizophrenia group than in the bipolar disorder group. Subgroup analysis and logistic regression were used to assess the influence of treatment duration, dose, industry sponsorship, age and sex ratio on tolerability outcome. CONCLUSIONS Our results suggest that schizophrenia patients may be more vulnerable to olanzapine-induced weight gain. The findings may be explained by considering the fact that in addition to genetic disposition for metabolic syndrome in schizophrenia patients, they have an especially high incidence of lifestyle risk factors for CVD, such as poor diet, lack of exercise, stress and smoking. It might be that an antipsychotic induces severity of adverse effect according to the phenotype.

Comparing Tolerability of Olanzapine in Schizophrenia and Affective Disorders

AbstractBackground: Olanzapine is prescribed for a number of psychiatric disorders, including schizophrenia, bipolar mania, and unipolar and bipolar depression. Olanzapine treatment is associated with tolerability issues such as metabolic adverse effects (e.g. weight gain, increase in blood glucose, triglycerides and total cholesterol levels), extrapyramidal symptoms [EPS] (e.g. parkinsonism, akathisia, tardive dyskinesia) and sedative adverse effects. Metabolic issues lead to some long-term consequences, which include cardiovascular diseases (CVD) and type 2 diabetes mellitus, and these complications cause high rates of mortality and morbidity among patients with severe mental illnesses. The expanded indications of olanzapine in psychiatry suggest a need to investigate whether there is a difference in the incidence and severity of adverse effects related to category diagnosis. Are the adverse effects expressed differently according to phenotype? Unfortunately, there are no reported studies that investigated these differences in adverse effects associated with olanzapine treatment in psychiatric patients with different phenotypes. Objective: The aim of the present meta-analysis is to separately examine olanzapine-induced cardiometabolic adverse effects and EPS in patients with schizophrenia and affective disorders. Data Sources: A search of computerized literature databases PsycINFO (1967–2010), PubMed (MEDLINE), EMBASE (1980–2010) and the clinicaltrials.gov website for randomized clinical trials was conducted. A manual search of reference lists of published review articles was carried out to gather further data. Study Selection: Randomized controlled trials were included in our study if (i) they assessed olanzapine adverse effects (metabolic or extrapyramidal) in adult patients with schizophrenia or affective disorders; and (ii) they administered oral olanzapine as monotherapy during study. Data Extraction: Two reviewers independently screened abstracts for choosing articles and one reviewer extracted relevant data on the basis of predetermined exclusion and inclusion criteria. It should be mentioned that for the affective disorders group we could only find articles related to bipolar disorder. Data Synthesis: Thirty-three studies (4831 patients) that address olanzapine monotherapy treatment of adults with schizophrenia or bipolar disorder were included in the analysis. The primary outcomes were metabolic adverse effects (changes in weight, blood glucose, low-density lipoprotein, total cholesterol and triglyceride levels). The secondary outcomes of our study were assessing the incidence of some EPS (parkinsonism, akathisia and use of antiparkinson medication). The tolerability outcomes were calculated separately for the schizophrenia and bipolar disorder groups and were combined in a meta-analysis. Tolerability outcomes show that olanzapine contributes to weight gain and elevates blood triglycerides, glucose and total cholesterol levels in both schizophrenia and bipolar disorder patients. However, olanzapine treatment produced significantly more weight gain in schizophrenia patients than in bipolar disorder patients. In addition, increases in blood glucose, total cholesterol and triglyceride levels were higher in the schizophrenia group compared with the bipolar disorder group, even though these differences were not statistically significant. Based on our results, the incidence of parkinsonism was significantly higher in the schizophrenia group than in the bipolar disorder group. Subgroup analysis and logistic regression were used to assess the influence of treatment duration, dose, industry sponsorship, age and sex ratio on tolerability outcome. Conclusions: Our results suggest that schizophrenia patients may be more vulnerable to olanzapine-induced weight gain. The findings may be explained by considering the fact that in addition to genetic disposition for metabolic syndrome in schizophrenia patients, they have an especially high incidence of lifestyle risk factors for CVD, such as poor diet, lack of exercise, stress and smoking. It might be that an antipsychotic induces severity of adverse effect according to the phenotype.

Evolution of Substance use, Neurological and Psychiatric Symptoms in Schizophrenia and Substance use Disorder Patients: A 12-Week, Pilot, Case–Control Trial with Quetiapine

Neurological and psychiatric symptoms are consequences of substance abuse in schizophrenia and non-schizophrenia patients. The present case–control study examined changes in substance abuse/dependence, and neurological and psychiatric symptoms in substance abusers with [dual diagnosis (DD) group, n = 26] and without schizophrenia [substance use disorder (SUD) group, n = 24] and in non-abusing schizophrenia patients (SCZ group, n = 23) undergoing 12-week treatment with the atypical antipsychotic, quetiapine. Neurological and psychiatric symptoms were evaluated with the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, the Extrapyramidal Symptoms Rating Scale, and the Barnes Akathisia Rating Scale. At endpoint, DD and SCZ patients were receiving significantly higher doses of quetiapine (mean = 554 and 478 mg/day, respectively), relative to SUD patients (mean = 150 mg/day). We found that SUD patients showed greater improvement in weekly dollars spent on alcohol and drugs and SUD severity, compared to DD patients. At endpoint, there was no significant difference in dollars spent, but DD patients still had a higher mean SUD severity. Interestingly, DD patients had significantly higher parkinsonism and depression than SCZ patients at baseline and endpoint. On the other hand, we found that SUD patients had significantly more akathisia at baseline, improved more than SCZ patients, and this was related to cannabis abuse/dependence. Finally, SUD patients improved more in Positive and Negative Syndrome Scale positive scores than DD and SCZ patients. Taken together, our results provide evidence for increased vulnerability to the adverse effects of alcohol and drugs in schizophrenia patients. They also suggest that substance abuse/withdrawal may mimic some symptoms of schizophrenia. Future studies will need to determine the role quetiapine played in these improvements.