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We aimed to characterize mortality among people with HIV (PWH) and psychotic disorders (PWH/psychosis+) vs. PWH alone (PWH/psychosis-).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.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 value0.0001). 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.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+.

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.

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 (

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 cloza­pine 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.

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.

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.

Background Schizophrenia is associated with poor cognitive function and elevated cardiometabolic disease risk. These health concerns may exacerbate neurocognitive dysfunction associated with hippocampal abnormalities, particularly hippocampal volume reductions. Regular exercise is thought to improve symptom severity, reduce depression, and improve cognition in schizophrenia, and may trigger exercise-mediated hippocampal growth. The potential for the benefits of exercise for treatment-resistant schizophrenia patients has not been clearly assessed. This study aims to assess the effect of exercise on hippocampal plasticity and clinical outcomes in chronic schizophrenia. Methods Seventeen DSM-IV criteria schizophrenia or schizoaffective disorder patients completed a customized moderate intensity 12-week aerobic or weight-bearing exercise program. Adherence rates were 83% ± 9.4%) with 70% of participants completing the entire exercise program. Concomitant neuroimaging, clinical and cognitive assessments were obtained at baseline and 12-weeks. Results At follow-up, symptom severity scores (t(16) = −16.8, p. ≤ 0.0001) and social functioning (t(16) = 4.4, p. = 0.0004) improved. A trend for improved depression scores (t(16) = −2.0, p. = 0.06) with no change in anxiety, or extrapyramidal symptoms were seen. Hippocampal volume increased (t(16) = −2.54, p. = 0.02), specifically in the left CA-1 field (F(16) = −2.33, p. = 0.03). Hippocampal vascular volume was unchanged. Change in hippocampal volume and vascular volume was not significantly correlated with change in symptom severity or affect scores. Conclusions Adjunct exercise may accelerate symptom improvement in treatment-resistant psychosis patients. While the underlying mechanism remains unclear, these results indicate that chronic schizophrenia patients experience hippocampal plasticity in response to exercise. Study registration Clinical Trials.gov NCT01392885 .

Although antipsychotics are used to treat Tourette syndrome, there have been reports of paradoxical induction of tics by first- and second-generation antipsychotics. The objective of this systematic review was to better characterize tics as the potential adverse effect of antipsychotics. 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. 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

Purpose To explore the relationship between antipsychotic-associated antagonism of alpha2-adrenergic receptors and resting heart rate in individuals with schizophrenia.

Objective: Prior research has suggested that treatment-resistant psychosis (TRP) may be a categorically distinct subtype from treatment-responsive psychotic disorders. However, relatively f...

A 35-year-old man with treatment-resistant schizophrenia was prescribed clozapine. Three weeks later, at a dose of 400 mg/d, his psychosis improved substantially, but contamination obsessions and cleaning compulsions developed, occupying a lot of his time. His family history was positive for

A 45-year-old man with treatment-resistant schizophrenia was treated with 400 mg/d of clozapine. A routine electrocardiographic (ECG) assessment upon admission to our facility revealed a measured QT interval of 440 ms, a resting heart rate of 80 beats/min, and a corrected QT (QTc) interval of 508 ms

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 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.

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.

To explore the relationship between antipsychotic-associated antagonism of alphaThirty-one inpatients treated with antipsychotics were included in this exploratory analysis. Antipsychotic doses were converted to haloperidol equivalents for alphaAfter controlling for confounding variables, the relationship between alphaThe observed inverted-U relationship between alphaNCT01392885.

Background: Smaller orbitofrontal and superior frontal cortical volumes have been associated with impaired executive function in patients with schizophrenia. In contrast, exercise interventions have been shown to reduce symptom severity and are thought to increase production of neurotrophic factors, induce neurogenesis, and alter gene expression to promote neuroplasticity in schizophrenia. We examined the efficacy of aerobic and resistance exercise to increase orbitofrontal cortex (OFC) and superior frontal cortex (SFC) volumes and executive functioning in chronic refractory schizophrenia patients.

Background: The neurotoxic and/or neuroprotective effects of individual antipsychotics remain controversial, with equivocal reports emerging from the animal and human literature, particularly in cognitively critical fronto-temporal areas. We investigated the relationship between antipsychotic dose and frontal white matter fractional anisotropy (FA) to determine potential neurotoxicity of atypical antipsychotics and the relationships between white matter FA, symptom severity and cognition.

A 59-year-old woman was admitted to a tertiary care refractory psychosis unit with a referral diagnosis of schizoaffective disorder. She was maintained on 400 mg of clozapine once daily as part of her pre-existing treatment for auditory hallucinations. The steady state plasma concentrations of clozapine and norclozapine were 2542 and 1465 nmol/L, respectively (metabolic ratio: 1.74). Seven weeks later, the plasma concentrations of clozapine and norclozapine increased to 3272 and 2025 nmol/L, respectively (metabolic ratio: 1.62), despite no changes in medications (including doses), smoking status, or adherence (based on previous clozapine levels). Although no adverse effects were observed in association with the elevated plasma concentrations, the daily dose was reduced to 200 mg as a precautionary measure. Upon investigation, a urinary tract infection (UTI) was diagnosed, for which nitrofurantoin and cotrimoxazole were initiated. After 1 week of antibiotic therapy, clozapine and norclozapine plasma concentrations decreased to 1406 and 639 nmol/L, respectively (metabolic ratio: 2.20). Similar increases in the plasma concentrations of clozapine and norclozapine have been described in other case reports involving concurrent UTIs.1–5 Adverse effects attributed to elevated plasma concentrations of clozapine include somnolence, confusion, disorientation, dizziness, aphasia and extrapyramidal symptoms.1–5 Apart from UTIs, this phenomenon has also been reported in association with other infectious processes and with tissue injury,1,6–9 sometimes without clozapine-associated adverse effects.10 The mechanism implicated in increasing plasma concentrations of clozapine and norclozapine is not believed to be related to the exposure to the pathogen or the damage to the tissue, but rather the effects of cytokines released in response to proinflammatory events, such as those mentioned above.11 Several cytokines involved in the acute inflammatory response have been identified as having an inhibitory effect on the expression of certain drug metabolizing enzymes. For instance, a downregulation of cytochrome P450 (CYP) 1A2 and CYP3A messenger RNA has been reported following the incubation of human hepatocytes with tumour necrosis factor, interleukin (IL)-1β, and IL-6. Furthermore, the activity of these enzymes were also reduced by the same cytokines.12 Since clozapine is primarily metabolized by CYP1A2, with contributions from CYP3A4,13 reductions in their expression and activity offer an explanation to the noted increase in its plasma concentration. However, this mechanism may not be in operation in our patient since the clozapine/norclozapine metabolic ratios did not increase from baseline to the time of UTI diagnosis. Typically, the ratio would increase to a value greater than 2:1 in response to inhibition of CYP1A2. Interestingly, there was a modest increase in the clozapine/norclozapine metabolic ratio after treatment for the UTI, which is consistent with the inhibitory effect of cotrimoxazole on CYP2C9, an enzyme involved in the demethylation of clozapine to norclozapine.14 A second mechanism that has been proposed to explain the UTI-associated elevations in the plasma concentrations of clozapine and norclozapine is related to an increase in α1-acid glycoprotein,10 an acute-phase protein whose synthesis is upregulated by cytokines such as IL-6.15 An increase in α1-acid glycoprotein will increase the binding capacity of both clozapine and norclozapine. The outcome will be an increase in the total (bound and unbound) plasma concentrations of clozapine and norclozapine; however, the unbound (free and active moiety) concentrations will remain unchanged. Since clinical laboratories report only total (bound and unbound) plasma concentrations, confirmation that the free levels have remained unchanged is not possible. The fact that the patient did not exhibit any clozapine-associated adverse effects supports the supposition that the free concentrations did not increase despite the increase in total concentration. Measuring plasma concentrations of α1-acid glycoprotein (if available) would have helped to confirm this proposed mechanism. UTI-associated increases in the plasma concentrations of clozapine and norclozapine are most readily explained by the actions of cytokines on drug metabolism and/or protein binding. Since we could not readily order plasma concentrations of unbound clozapine or α1-acid glycoprotein, confirmation of the underlying mechanism( s) was not possible. As such, clinicians should monitor for clozapine-associated adverse effects and adjust the dosage accordingly.

Brain derived neurotrophic factor (BDNF) is a molecular trophic factor that plays a key role in neuronal survival and plasticity. Single nucleotide polymorphisms (SNPs) of the BDNF gene have been associated with specific phenotypic traits in a large number of neuropsychiatric disorders and the response to psychotherapeutic medications in patient populations. Nevertheless, due to study differences and occasionally contrasting findings, substantial further research is required to understand in better detail the association between specific BDNF SNPs and these psychiatric disorders. While considerable progress has been made recently in developing advanced genotyping platforms of SNPs, many high-throughput probe- or array-based detection methods currently available are limited by high costs, slow processing times or access to advanced instrumentation. The polymerase chain reaction (PCR)-based, tetra-primer amplification refractory mutation system (T-ARMS) method is a potential alternative technique for detecting SNP genotypes efficiently, quickly, easily, and cheaply. As a tool in psychopathology research, T-ARMS was shown to be capable of detecting five common SNPs in the BDNF gene (rs6265, rs988748, rs11030104, 11757G/C and rs7103411), which are all SNPs with previously demonstrated clinical relevance to schizophrenia and depression. The present technique therefore represents a suitable protocol for many research laboratories to study the genetic correlates of BDNF in psychiatric disorders. Copyright Copyright © 2015 John Wiley & Sons, Ltd.

Basal body temperature (BBT) readings are handicapped as fertility predictors by exogenous influences on women's temperatures, many of which could be adjusted for by the presence of a non-cycling control. We, a married, cohabiting couple, tracked our BBTs for two months. We found substantial temperature covariability. When there were difficult-to-explain changes in the female partner's temperature, similar changes in the male partner's temperature suggested that these fluctuations were not attributable to ovulation. Additionally, a clear mid-cycle widening of our temperature gap suggested that ovulation had occurred. This is a limited trial of a new method. However, the potential for substantially improving the accuracy and usefulness of a globally utilized method, coupled with its inexpensiveness, ease, and painlessness, call for a larger study.