clozapine and Depressive-Disorder--Major

Clozapine is superior to other antipsychotics as a therapy for treatment-resistant schizophrenia and schizoaffective disorder with increased risk of suicidal behavior. This drug has also been used in the off-label treatment of bipolar disorder, major depressive disorder (MDD), and Parkinson's disease (PD). Although usually reserved for severe and treatment-refractory cases, it is interesting that electroconvulsive therapy (ECT) has also been used in the treatment of these psychiatric disorders, suggesting some common or related mechanisms. A literature review on the applications of clozapine and electroconvulsive therapy (ECT) to the disorders mentioned above was undertaken, and this narrative review was prepared. Although both treatments have multiple actions, evidence to date suggests that the ability to elicit epileptiform activity and alter EEG activity, to increase neuroplasticity and elevate brain levels of neurotrophic factors, to affect imbalances in the relationship between glutamate and γ-aminobutyric acid (GABA), and to reduce inflammation through effects on neuron-glia interactions are common underlying mechanisms of these two treatments. This evidence may explain why clozapine is effective in a range of neuropsychiatric disorders. Future increased investigations into epigenetic and connectomic changes produced by clozapine and ECT should provide valuable information about these two treatments and the disorders they are used to treat.

Topics: Antipsychotic Agents; Bipolar Disorder; Clozapine; Depressive Disorder, Major; Electroconvulsive Therapy; Humans; Parkinson Disease; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Depressive Disorder, Major; Dose-Response Relationship, Drug; Female; Humans; Stuttering; Treatment Outcome

Studies have found that a large percentage of depressed patients may have limited response and remission rates when treated with traditional antidepressants. Options for augmenting antidepressant treatment include buspirone, lithium, and triiodothyronine. There are also increasing data concerning the use of atypical antipsychotics as augmenting agents in the treatment of unipolar, nonpsychotic, treatment-resistant depression. Aripiprazole has recently received an indication from the U.S. Food and Drug Administration (FDA) for adjunctive treatment in unipolar, nonpsychotic depression, the first indication of its kind, after two double-blind trials; doses were slightly lower than those recommended for monotherapy in schizophrenia or bipolar disorder. Olanzapine and risperidone have several controlled clinical trials indicating the efficacy of both of these agents, generally at low doses. One trial of quetiapine suggested that it may not be effective in the treatment of unipolar, nonpsychotic depression. One open-label trial of ziprasidone indicated some efficacy. According to these results, aripiprazole, olanzapine, and risperidone are reasonable choices as augmentation agents, with only aripiprazole currently having an FDA indication for this use. Given the preliminary results, double-blind, placebo-controlled trials with quetiapine and ziprasidone are needed, as well as studies comparing atypical antipsychotic agents with traditional augmentation agents in the treatment of depression.

Topics: Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Depressive Disorder, Major; Dibenzothiazepines; Drug Synergism; Drug Therapy, Combination; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Risperidone; Thiazoles

Cumulative data indicate that atypical antipsychotics can serve as adjunctive as well as alternative agents in the treatment of drug-resistant mood disorders. Olanzapine and risperidone add-on treatment was found to be effective for major depression with psychotic features and good results were achieved with currently available atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine and ziprasidone) in reducing symptoms of acute mania, especially when added to mood stabilizers. The role of atypical antipsychotics in maintenance and prophylactic treatment is not yet clear. Although there are differences in the side effect profiles of the various atypical antipsychotics, their use is limited by adverse effects such as extrapyramidal symptoms, weight gain, somnolence and sexual dysfunction.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clinical Trials as Topic; Clozapine; Depressive Disorder, Major; Dibenzothiazepines; Humans; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Risperidone; Thiazoles

The comparative antidepressant effects of clozapine and other atypical antipsychotics for schizophrenia remain elusive, leading us to examine this question using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness phase 2E.. Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone because of inadequate efficacy were randomly assigned to open-label treatment with clozapine (n=49) or double-blind treatment with another atypical antipsychotic not previously received in the trial (olanzapine [n=19], quetiapine [n=15], or risperidone [n=16]). The primary outcome was the Calgary Depression Scale for Schizophrenia (CDSS) total score. Antidepressant effects of clozapine and the other atypical antipsychotics were compared in patients with chronic schizophrenia and those with a major depressive episode (MDE) at baseline (i.e. ≥6 on the CDSS), using mixed models.. No differences in the baseline CDSS total scores were found between the treatment groups regardless of presence of an MDE. Clozapine was more effective than quetiapine in antidepressant effects for chronic schizophrenia (p<.01 for the whole sample and p=.01 for those with an MDE), and comparable to olanzapine and risperidone.. The present findings suggest that clozapine demonstrates superior antidepressant effects to quetiapine and comparable effects to olanzapine and risperidone in chronic schizophrenia regardless of presence of MDE. Given the indication of clozapine for treatment-resistant schizophrenia (TRS) and the negative impacts of depressive symptoms on clinical outcomes in schizophrenia, further research is warranted to investigate antidepressant effects of clozapine in TRS with an MDE.

Topics: Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Depressive Disorder, Major; Double-Blind Method; Olanzapine; Piperazines; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome

Emerging evidence indicates that inflammation plays an important role as a mechanism underlying mental disorders. However, most of the research on inflammatory mechanisms focuses on serum levels of interleukins and very few studies have investigated molecules that initiate and expand innate immune pathways such as damage-associated molecular patterns (DAMPs).. This study investigated the levels of DAMPs among patients diagnosed with major depressive disorder (MDD), bipolar disorder (BD) I and II, schizophrenia (SCZ), and generalized anxiety disorder (GAD). We quantified serum levels of heat shock proteins (HSPs) 70 and 60 and of S100 calcium-binding protein B (S100B).. Serum levels of HSP70, HSP60, and S100B were assessed in a sample of participants with psychiatric disorders (n = 191) and a control group (CT) (n = 59) using enzyme-linked immunosorbent assay (ELISA).. Serum HSP70 concentrations were significantly higher in the MDD group compared to the CT, SCZ, and BD groups. The GAD group had higher concentrations of HSP70 than the SCZ group. Exploring associations with medications, lithium (p = 0.003) and clozapine (p = 0.028) were associated with lower HSP70 levels. Approximately 64% of the sample had DAMPs levels below the limits of detection indicated by the respective ELISA kit.. This was the first study to assess DAMPs levels in a transdiagnostic sample. Our preliminary findings suggest that HSP70 may be associated with MDD pathophysiology. Medications such as lithium and clozapine were associated with lower HSP70 levels in BD and SCZ groups, respectively. Therefore, it is worth mentioning that all participants were medicated and many psychotropic drugs exert an anti-inflammatory effect, possibly reducing the signs of inflammation.

Topics: Bipolar Disorder; Clozapine; Depressive Disorder, Major; HSP70 Heat-Shock Proteins; Humans; Inflammation; Lithium

Locked pediatric inpatient psychiatric units are vulnerable to the emergence and spread of infections, and nosocomial infection, especially respiratory tract infection is potentially a major problem. This study aimed to explore the risk factors for lower respiratory tract infection (LRI), in particular, pneumonia.. We conducted a retrospective study comprising 4643 patients with schizophrenia (SZ) and 1826 patients with major depressive disorder (MDD), and the chi-square test was performed to analyze the categorical variables.. The risk ratio for LRI, including pneumonia, in intensive care unit (ICU) was higher than in the general ward, and electroconvulsive therapy (ECT) increased the patients' susceptibility to LRI and pneumonia. Our data have revealed that patients treated with restraint or clozapine showed a higher prevalence of LRI and pneumonia, and the results indicated that the increased risk of LRI, not pneumonia, was dose-dependently observed in patients with clozapine treatment.. Our study shows that ICU and ECT treatment were risk factors for LRI and pneumonia in patients with SZ or MDD, and patients with SZ has a prevalence of hospital-acquired infection because of restraint and clozapine treatments.

Topics: Child; Clozapine; Cross Infection; Depressive Disorder, Major; Hospitals, Psychiatric; Humans; Respiratory Tract Infections; Retrospective Studies; Risk Factors

Non-suicidal self-injury (NSSI) is a challenging issue in clinical settings. In the present case series, we report two female adolescents with recurrent depression and NSSI. Numerous approaches, such as anti-depressants, anti-psychotics, and even electroconvulsive therapy, were not effective. Clozapine has been implemented in a broad spectrum of psychiatric disorders, particularly refractory depression, impulse control problems, suicidal ideation, and NSSI. With a low dose (12.5-25 mg) of clozapine, the depressive symptoms and NSSI remarkably improved, and the improvement was sustained over four months after discharge. Low-dose clozapine monotherapy may be a treatment option with refractory depression and NSSI.

Topics: Adolescent; Clozapine; Depressive Disorder, Major; Female; Humans; Risk Factors; Self-Injurious Behavior; Suicidal Ideation

The prevalence of major depressive disorder in patients with schizophrenia (SZ-MDD) has been reported to be about 32.6 %, but it varies considerably depending on the stage (early or chronic) and state (acute or post-psychotic) of schizophrenia. The exploration of ideal strategies for the treatment of major depressive disorder in the context of schizophrenia is urgently needed. Thus, the present study was conducted to investigate the treatment effects of clozapine, electrical stimulation (ECS; the mouse model equivalent of electroconvulsive therapy for humans), venlafaxine, and mirtazapine for SZ-MDD.. A mouse model of SZ-MDD was established with MK801 administration and chronic unpredictable mild stress exposure. Clozapine and ECS, alone and with mirtazapine and/or venlafaxine, were used as treatment strategies. In-vivo two-photon imaging was performed to visualize Ca. ECS + venlafaxine + mirtazapine performed significantly better than other treatments in alleviating major depressive disorder, as reflected by PFC Ca. In this mouse model of SZ-MDD, ECS + venlafaxine + mirtazapine improved brain Ca2+ activity, pre-pulse inhibition, and immobility time. These findings provide useful information for the further exploration of treatment methods for patients with SZ-MDD, although the mechanisms underlying this comorbidity needed to be investigated further.

Topics: Animals; Clozapine; Depressive Disorder, Major; Humans; Mice; Mirtazapine; Prefrontal Cortex; Schizophrenia; Venlafaxine Hydrochloride

The widespread prevalence of coronavirus disease 2019 (COVID-19) means that inpatient psychiatric units will necessarily manage patients who have COVID-19 that is comorbid with acute psychiatric symptoms. We report a case of recurrence of respiratory symptoms and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription-polymerase chain reaction (RT-PCR) testing in a patient on an inpatient psychiatric unit occurring 42 days after the initial positive SARS-CoV-2 RT-PCR test, 38 days after initial symptom resolution, and 30 days after the first of 3 negative SARS-CoV-2 RT-PCR tests. Over the course of the admission, the patient was safely initiated on clozapine. Recent literature on COVID-19's potential recurrence and neuropsychiatric effects is reviewed and implications for the management of COVID-19 on inpatient psychiatric units are discussed. In the era of COVID-19 and our still-developing understanding of this illness, psychiatrists' role as advocates and collaborators in our patients' physical health care has become even more critical.

Topics: Adult; Alcoholism; Antidepressive Agents; Antipsychotic Agents; Clozapine; COVID-19; COVID-19 Nucleic Acid Testing; Depressive Disorder, Major; Hospitals, Psychiatric; Humans; Inpatients; Male; Mirtazapine; Psychotic Disorders; Recurrence; SARS-CoV-2; Sertraline; Suicide, Attempted

Numerous human clinical studies have suggested that decreased locomotor activity is a common symptom of major depressive disorder (MDD), as well as other psychiatric diseases. In MDD, the midbrain ventral tegmental area (VTA) dopamine (DA) neurons are closely related to regulate the information processing of reward, motivation, cognition, and aversion. However, the neural circuit mechanism that underlie the relationship between VTA-DA neurons and MDD-related motor impairments, especially hypolocomotion, is still largely unknown. Herein, we investigate how the VTA-DA neurons contribute to the hypolocomotion performance in chronic social defeat stress (CSDS), a mouse model of depression-relevant neurobehavioral states. The results show that CSDS could affect the spontaneous locomotor activity of mice, but not the grip strength and forced locomotor ability. Chemogenetic activation of VTA-DA neurons alleviated CSDS-induced hypolocomotion. Subsequently, quantitative whole-brain mapping revealed decreased projections from VTA-DA neurons to substantia nigra pars reticulata (SNr) after CSDS treatment. Optogenetic activation of dopaminergic projection from VTA to SNr with the stimulation of phasic firing, but not tonic firing, could significantly increase the locomotor activity of mice. Moreover, chemogenetic activation of VTA-SNr dopaminergic circuit in CSDS mice could also rescued the decline of locomotor activity. Taken together, our data suggest that the VTA-SNr dopaminergic projection mediates CSDS-induced hypolocomotion, which provides a theoretical basis and potential therapeutic target for MDD.

Topics: Animals; Channelrhodopsins; Chronic Disease; Clozapine; Depressive Disorder, Major; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Genes, Reporter; Genetic Vectors; Hand Strength; Locomotion; Male; Mice; Mice, Inbred C57BL; Neural Pathways; Optogenetics; Pars Reticulata; Receptor, Muscarinic M3; Recombinant Proteins; Rotarod Performance Test; Social Defeat; Stress, Psychological; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

Antipsychotics produce electroencephalogram (EEG) modifications and increase the risk of epileptic seizure. These modifications remain sparsely studied specifically for atypical antipsychotics. In this context, our study focuses on EEG modifications associated with atypical strict antipsychotic monotherapies.. Electroencephalogram recordings of 84 psychiatric patients treated with atypical antipsychotics in strict monotherapy (clozapine, n = 22; aripiprazole, n = 22; olanzapine, n = 17; risperidone, n = 9; quetiapine, n = 8; risperidone long-acting injection, n = 4; and paliperidone long-acting injection, n = 2) were analyzed. The modifications were ranked according to both slowing and excitability scores.. Electroencephalogram modifications (in 51 subjects, 60.71%) were graded according to 4 stages combining general slowing and sharp slow waves and/or epileptiform activities. The presence of sharp or epileptiform activities was significantly greater for clozapine (90.9%) compared with other second-generation antipsychotics (aripiprazole, 50%; olanzapine, 58.8%; quetiapine, 37.5%; risperidone, 44.4%). Age, duration of disease progression, and diagnosis were not associated as risk factors. Electroencephalogram modifications were associated with lower doses for treatment with quetiapine but not for specific antipsychotics. Electroencephalogram modifications and severe excitability were associated with higher chlorpromazine equivalent doses.. Atypical antipsychotics (clozapine, aripiprazole, quetiapine, olanzapine, and risperidone) induce EEG modifications, and these are significantly greater for clozapine and appear dependent on chlorpromazine equivalent dose. No encephalopathy was observed in these antipsychotic monotherapies, whatever dose.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Cerebral Cortex; Clozapine; Depressive Disorder, Major; Electroencephalography; Female; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Young Adult

Little is known about the comparative effectiveness of long-term pharmacological treatments for severe unipolar depression. We aimed to study the effectiveness of pharmacological treatments in relapse prevention in a nationwide cohort of patients who had been admitted to hospital at least once as a result of unipolar depression.. Our nationwide cohort study investigated the risk of readmission to hospital in 1996-2012 in all patients in Finland who had been admitted to hospital at least once for unipolar depression (without a diagnosis of schizophrenia or bipolar disorder) in Finland between Jan 1, 1987, and Dec 31, 2012. We used nationwide databases to obtain data for hospital admission, mortality, and dispensed medications. Exposure and non-exposure periods for medications were established using the PRE2DUP method. The primary analysis was within-individual analysis of readmission to hospital in the total cohort, in which each individual was used as his or her own control to eliminate selection bias. Putative survival and protopathic biases were controlled in sensitivity analyses. Since 33 independent statistical comparisons were done for specific medications, the level of statistical significance was set at p<0·0015.. Data from 123 712 patients were included in the total cohort, with a mean follow-up time of 7·9 years (SD 5·3). Lithium use was associated with a lower risk of re-admission to hospital for mental illness than was no lithium use (hazard ratio [HR] 0·47 [95% CI 0·40-0·55]; p<0·0001), whereas the groups of antidepressants (HR 1·10 [1·06-1·13]; p<0·0001) and antipsychotics (HR 1·16 [1·12-1·20]; p<0·0001) were not associated with a reduced risk of readmission to hospital. Risk of hospital readmission was lower during lithium therapy alone (HR 0·31 [0·21-0·47]; p<0·0001) than during use of lithium with antidepressants (HR 0·50 [0·43-0·59]; p<0·0001). After lithium, clozapine (HR 0·65 [0·46-0·90]; p=0·010) and amitriptyline (HR 0·75 [0·70-0·81]; p<0·0001) were the specific agents associated with the next lowest risk of readmission. In the sensitivity analyses controlling for survival and protopathic biases, all drugs were associated with lower rates of readmission to hospital than they were in the primary analysis, showing the same rank order in comparative effectiveness. The lowest mortality was observed during antidepressant use (HR 0·56 [0·54-0·58]; p<0·0001).. Our results indicate that lithium, especially without concomitant antidepressant use, is the pharmacological treatment associated with the lowest risk of hospital readmission for mental illness in patients with severe unipolar depression, and the outcomes for this measure related to antidepressants and antipsychotics are poorer than lithium. Lithium treatment should be considered for a wider population of severely depressed patients than those currently considered, taking into account its potential risks and side-effects.. The Finnish Ministry of Health.

Topics: Adult; Aged; Amitriptyline; Antidepressive Agents; Antipsychotic Agents; Clozapine; Cohort Studies; Depressive Disorder; Depressive Disorder, Major; Female; Finland; Humans; Incidence; Lithium; Male; Middle Aged; Outcome Assessment, Health Care; Patient Readmission; Risk; Secondary Prevention; Severity of Illness Index

This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients treated with antipsychotics. The first column in this series began with the case of a 76-year-old man with major depressive disorder who developed orofacial dyskinesias while being treated with aripiprazole as an antidepressant augmentation strategy. It was alleged that a higher than intended dose of aripiprazole (ie, 20 mg/d for 2 wk followed by 10 mg/d for 4 wk instead of the intended dose of 2 mg/d) was the cause of the dyskinetic movements in this man, and the authors were asked to review the case and give their opinion. The principal basis for this theory of causation was the class warning about TD in the package insert for aripiprazole. The rationale for concluding aripiprazole caused TD in the 76-year-old man led to this series of columns about aripiprazole, its potential--if any--to cause TD, and the presence of a class warning about TD in its package insert. The central point is to illustrate why class warnings exist and their implications for practice. The first column in this series focused on the historical background, incidence, prevalence, risk factors, and clinical presentations of tardive and spontaneous dyskinesias and concluded with a discussion of diagnostic considerations explaining why clinicians should avoid making a diagnosis of TD until a thorough differential diagnosis has been considered. This second column in the series reviews the pharmacology of aripiprazole and the preclinical and phase I translational human studies that suggest aripiprazole should have a low to nonexistent risk of causing TD compared with other antipsychotics. The third column in the series will review the systematic clinical trial data and "real-world" data on TD and the use of aripiprazole as adjunctive treatment with antidepressants for major depressive disorder to see whether these data support the conclusion of a low to nonexistent relationship between aripiprazole treatment and the development of TD. The fourth and final column in the series will consider the type of study that would need to be performed to avoid a specific class warning, focusing on the TD class warning as an

Topics: Aged; Antipsychotic Agents; Aripiprazole; Clinical Trials as Topic; Clozapine; Depressive Disorder, Major; Dyskinesia, Drug-Induced; History, 20th Century; Humans; Male; United States; United States Food and Drug Administration

Relieving catatonia helps identify the underlying etiology and its treatment. However, catatonia may reemerge after some time, but there are few data on the relapses and recurrences of catatonia. We aimed to investigate the characteristics of patients with relapses or recurrences of catatonia as well as the efficacy of the lorazepam-diazepam protocol on them.. Patients with catatonia who had more than one episode of catatonia and were treated with the lorazepam-diazepam protocol were identified. Their medical charts were reviewed, and interview was conducted.. Thirty patients were identified. Nineteen (63.3%) were diagnosed with schizophrenia, five (16.7%) with major depressive disorder, two (6.7%) with bipolar disorder, and four (13.3%) with general medical conditions. In the 68 relapses and relapses the lorazepam-diazepam protocol was used, full response was reported in 54 (79.4%) of them. Twelve of 19 (63.2%) patients with schizophrenia were treated with clozapine. Twenty (66.7%) out of 30 patients were maintained on oral lorazepam by the time of discharge. Literature review showed similar prevalence of schizophrenia in patients with more than one episode of catatonia, and a wide variety of treatment options.. The lorazepam-diazepam protocol was mostly effective in managing relapses and recurrences of catatonia. Maintenance clozapine and oral lorazepam were beneficial in a significant number of patients.

Topics: Adolescent; Adult; Antipsychotic Agents; Bipolar Disorder; Catatonia; Clozapine; Depressive Disorder, Major; Diazepam; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Lorazepam; Male; Middle Aged; Recurrence; Schizophrenia, Catatonic; Young Adult

Rapid reduction of suicidal thoughts is critical for treating suicidal patients. Clinical trials evaluating these treatments require appropriate measurement. Key methodological issues include: 1) the use of single or multi-item assessments, and 2) evaluating whether suicidal ideation measures can track rapid change over time. The current study presents data from two randomized, placebo-controlled, crossover clinical trials evaluating ketamine in individuals with treatment-resistant depression (n = 60). Participants were assessed for suicidal thoughts using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Scale for Suicidal Ideation (SSI) at eight time points over three days. Assessments were compared using correlational analyses and effect sizes at 230 min and three days after ketamine infusion. Linear mixed models evaluated change in ideation across all time points. The HAM-D and MADRS suicide items demonstrated correlations of r > .80 with the first five items of the SSI (SSI5). On linear mixed models, an effect for ketamine was found for the HAM-D, MADRS, BDI items, and SSI5 (p < .001), but not for the full SSI (p = .88), which suggests a limited ability to assess change over time in patients with low levels of suicidal thoughts. Taken together, the results suggest that repeated suicidal assessments over minutes to days appear to detect improvement in suicidal thoughts after ketamine infusion compared to placebo. The MADRS suicide item, BDI suicide item, and SSI5 may be particularly sensitive to rapid changes in suicidal thoughts.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Bipolar Disorder; Clozapine; Cross-Over Studies; Depressive Disorder, Major; Female; Humans; Ketamine; Male; Middle Aged; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Statistics as Topic; Suicidal Ideation; Time Factors; Young Adult

Psychiatric hospital readmissions correlate with illness severity, drug selection, and compliance with treatment in the outpatient setting. The risk factors for psychiatric rehospitalization have been mainly assessed in databases lacking information regarding somatic comorbidity and anthropometric variables, such as body mass index (BMI), which are known to predict readmissions in nonpsychiatric settings.. To determine independent predictors of 1-year readmission occurring among unselected adults consecutively admitted for treatment of severe mental illness to an academic, freestanding psychiatric hospital in New York City from August 2010 through January 2011.. After identifying univariate correlates of readmission, we used logistic regression with backward elimination to identify independent predictors of readmissions within 1 year after the index psychiatric hospitalization.. Among 224 (23.7%) of 945 readmitted patients, psychiatric readmission was significantly associated with age (P = .0029), length of stay (P = .036), schizophrenia/schizoaffective disorder (P < . 0001), dementia (P = .027), major depressive disorder (P = .0006), treatment with atypical antipsychotic drugs (P = .0054), electroconvulsive therapy (P < .0001), and BMI (P = .0079), but not with physical comorbidities and routine laboratory data.The independent predictors of readmission were higher BMI (median = 28.5 kg/ m2; odds ratio [OR] = 3.6; Cl, 1.2-10.6), a diagnosis of schizophrenia/schizoaffective disorder (OR = 2.2; Cl, 1.5-3.4), clozapine treatment (OR = 2.8; CI, 1.1-6.9), no electroconvulsive therapy (OR = 0.13; Cl, 0.02-0.45), and shorter length of stay (median = 18 days; OR = 0.08; Cl, 0.01-0.42).. Body mass index was identified, for the first time, as an independent predictor of psychiatric rehospitalization. Enhanced outpatient treatment programs for overweight and obese psychiatric patients might influence readmission rates and should be explored in prospective studies.

Topics: Adult; Age Factors; Antipsychotic Agents; Body Mass Index; Clozapine; Combined Modality Therapy; Depressive Disorder, Major; Electroconvulsive Therapy; Female; Hospitals, Psychiatric; Humans; Length of Stay; Male; Mental Disorders; Middle Aged; Patient Readmission; Prognosis; Psychotherapy; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Young Adult

The first of the atypical antipsychotics introduced in the 1970s, clozapine remains the most efficacious neuroleptic to this day. However, serious and potentially fatal side effects have necessitated careful regular monitoring among prescribing clinicians. Some adverse effects (e.g. ischaemic bowel) remain under recognized, while newly identified adverse effects continue to be described in the literature.. In this report, we describe a healthy 43-year old Caucasian male who experienced onset of a full body deep burning pain several months after the onset of treatment with clozapine. The pain worsened over time, ceased with cessation of treatment, and returned soon after the patient was rechallenged.. We describe an unusual adverse effect from clozapine treatment that has not been described elsewhere to our knowledge. We present the time course of the pain symptom, relationship to dose, associated laboratory results, and ultimately how it was dealt with and how it improved for the benefit of clinicians who may encounter it in the future.

Topics: Adult; Antipsychotic Agents; Clozapine; Depressive Disorder, Major; Humans; Male; Pain; Psychotic Disorders

Negative affect is critical for conferring vulnerability to opiate addiction as reflected by the high comorbidity of opiate abuse with major depressive disorder (MDD). Rodent models implicate amygdala prodynorphin (Pdyn) as a mediator of negative affect; however, evidence of PDYN involvement in human negative affect is limited. Here, we found reduced PDYN mRNA expression in the postmortem human amygdala nucleus of the periamygdaloid cortex (PAC) in both heroin abusers and MDD subjects. Similar to humans, rats that chronically self-administered heroin had reduced Pdyn mRNA expression in the PAC at a time point associated with a negative affective state. Using the in vivo functional imaging technology DREAMM (DREADD-assisted metabolic mapping, where DREADD indicates designer receptors exclusively activated by designer drugs), we found that selective inhibition of Pdyn-expressing neurons in the rat PAC increased metabolic activity in the extended amygdala, which is a key substrate of the extrahypothalamic brain stress system. In parallel, PAC-specific Pdyn inhibition provoked negative affect-related physiological and behavioral changes. Altogether, our translational study supports a functional role for impaired Pdyn in the PAC in opiate abuse through activation of the stress and negative affect neurocircuitry implicated in addiction vulnerability.

Topics: Adult; Amygdala; Animals; Clozapine; Corticosterone; Depressive Disorder, Major; Designer Drugs; Enkephalins; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; GTP-Binding Protein alpha Subunits, Gi-Go; Heroin Dependence; Humans; Hungary; Limbic System; Male; Middle Aged; Neuroimaging; Neurons; Positron-Emission Tomography; Protein Precursors; Radiopharmaceuticals; Rats; Rats, Long-Evans; Recombinant Fusion Proteins; RNA, Messenger; United States

Although there are well-established psychiatric procedures available concerning switching of antipsychotic drugs, in practice we often face a situation where we have to consider not only the patient's demands, but also requests from relatives. In this article we describe a case where we encountered this situation. Our patient was a 48-year-old married man suffering from paranoid schizophrenia with extreme obesity. We had to consider the modification of the antipsychotic treatment because of the patient's persistent residual symptoms (significant lack of initiative, serious under-motivation, emotional plainessness, considerable passivity) his overweight and its consequences (metabolic syndrome). In our paper we describe the psychoeducational process and the clozapine/aripiprazol switch.

Topics: Ambulatory Care; Antipsychotic Agents; Aripiprazole; Clozapine; Depressive Disorder, Major; Drug Administration Schedule; Humans; Interpersonal Relations; Male; Middle Aged; Obesity; Patient Education as Topic; Patient Satisfaction; Piperazines; Quinolones; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Spouses

Altered glutamate transmission has been found in the medial temporal lobe in severe psychiatric illnesses, including major depressive disorder (MDD) and bipolar disorder (BD). The vesicular glutamate transporters (VGLUTs) have a pivotal role in presynaptic release of glutamate into the synaptic cleft. We investigated this presynaptic marker in major psychiatric illness by measuring transcript expression of the VGLUTs in the medial temporal lobe.. The study sample comprised four groups of 13 subjects with MDD, BD, or schizophrenia (SCZ), and a comparison group from the Stanley Foundation Neuropathology Consortium. In situ hybridization was performed to quantify messenger RNA (mRNA) expression of VGLUT 1, 2, and 3 in medial temporal lobe structures. We also examined the same areas of rats treated with antidepressants, a mood stabilizer, and antipsychotics to assess the effects of these medications on VGLUT mRNA expression.. We found decreased VGLUT1 mRNA expression in both MDD and BD in the entorhinal cortex (ERC), decreased VGLUT2 mRNA expression in MDD in the middle temporal gyrus, and increased VGLUT2 mRNA expression in SCZ in the inferior temporal gyrus (ITG). We also found a negative correlation between age and VGLUT1 mRNA expression in BD in the ERC and ITG. We did not find any changes in VGLUT mRNA expression in the hippocampus in any diagnostic group. We found decreased VGLUT1 mRNA expression in rats treated with haloperidol in the temporal cortex.. These data indicate region-specific alterations of presynaptic glutamate innervation in the medial temporal lobe in the mood disorders.

Topics: Adult; Aged; Analysis of Variance; Animals; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Bipolar Disorder; Clozapine; Depressive Disorder, Major; Female; Gene Expression Regulation; Haloperidol; Hippocampus; Humans; Imipramine; Male; Mesothelin; Middle Aged; Rats; Rats, Sprague-Dawley; RNA, Messenger; Schizophrenia; Statistics as Topic; Temporal Lobe; Vesicular Glutamate Transport Proteins

Topics: Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Anxiety Disorders; Asthma; Bronchodilator Agents; Buspirone; Clozapine; Comorbidity; Cooperative Behavior; Depressive Disorder, Major; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Humans; Long-Term Care; Patient Care Team; Piperazines; Referral and Consultation; Schizophrenia; Schizophrenic Psychology; Theophylline; Triazoles

The study of depressions in 183 schizophrenic patients after the management of acute psychosis included evaluation of depressive symptoms, their relation to other psychopathologic syndromes, and the efficiency of drug therapy. The Calgary scale (CDSS) was used to assess severity of depression in schizophrenia along with other standardized psychometric scales to characterize general psychopathologic, positive, and negative symptoms, locomotor disturbances, other concomitant disorders, and general clinical picture. The predominance of depressive conditions with adynamic symptoms was documented. The majority of depressions occurred after the first attack. Those developing in the early post-attack period differed from depressions within a few months after the reduction of psychosis. Syndromic nature of depressions was evident from the number of psychotic episodes experienced by the patients. Depressive symptoms that developed after the management of the acute psychotic state could be efficiently and safely relieved by additional differential treatment with antidepressants. Depressive symptoms in schizophrenia are not predictors of poor prognosis provided the patient receives adequate therapy. More attention is needed to identification and adequate treatment of depression in schizophrenia. Optimized therapy of affective disorders in schizophrenic patients permits to improve prognosis of the disease.

Topics: Acute Disease; Adult; Antipsychotic Agents; Clozapine; Depressive Disorder, Major; Drug Administration Schedule; Female; Humans; International Classification of Diseases; Male; Patient Compliance; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Time Factors

Massive elevations of serum creatine kinase (CK) can occur in a significant number of patients treated with neuroleptics in the absence of neuroleptic malignant syndrome (NMS). We report two cases of CK-elevations associated with quetiapine treatment, which disappeared after drug discontinuation. To our knowledge, case number one is the first case of quetiapine-induced CK elevation in a neuroleptic-naïve patient. We thus suggest CK assessment when myalgia occurs with neuroleptic treatment.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Creatine Kinase; Depressive Disorder, Major; Dibenzothiazepines; Humans; Male; Mianserin; Mirtazapine; Olanzapine; Pain; Psychotic Disorders; Quetiapine Fumarate

Topics: Atomoxetine Hydrochloride; Clozapine; Depressive Disorder, Major; Drug Therapy, Combination; Female; Humans; Middle Aged; Nortriptyline; Propylamines; Psychotic Disorders; Recurrence; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index

FGF-2 is important for stem cell proliferation, neocortical development and adult neuronal survival and growth. Reduced frontal cortical FGF-2 expression is described in major depression and is attenuated by antidepressants. We determined the distribution of hippocampal FGF-2 and its receptor (FGFR1) mRNA in post-mortem brains of people who suffered from major depression, bipolar disorder and schizophrenia and those of controls.. FGF-2 and FGFR1 mRNA were measured within hippocampal CA1, CA4 regions and the dentate gyrus (DG), using in situ hybridization. Within hippocampal regions, cellular staining was compared between diagnostic groups, using repeated measures analysis of variance.. The density of FGF-2 mRNA+ cells in CA4 was reduced in depression compared to controls. The percentage of FGFR1 mRNA+ cells was higher in depression (CA1 and CA4) and schizophrenia (CA4) than in controls. FGFR1 mRNA expression was higher in depression than in the other groups in CA1, CA4 and DG. Overall FGF-2 mRNA expression was higher in DG than in CA1 and CA4.. We found raised measures of FGFR1 mRNA+ in major depression and, less so, in schizophrenia, along with reduced FGF-2 mRNA density in depression. Perturbations of FGF regulation could be relevant to the pathogenesis of both disorders as FGF-2 and FGFR1 are implicated in normal hippocampal synaptology, stem cell recruitment, and connectivity, and are modulated by corticosteroids.

Topics: Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Clozapine; Depressive Disorder, Major; Female; Fibroblast Growth Factor 2; Gene Expression; Hippocampus; Humans; Image Processing, Computer-Assisted; In Situ Hybridization; Male; Middle Aged; Receptor, Fibroblast Growth Factor, Type 1; RNA, Messenger; Schizophrenia

In schizophrenia, elevations of serum and CSF S100B levels have been reported and related to state of the disease and negative symptoms. In elderly chronic schizophrenic inpatients with stable medication, S100B may be increased and correlated to psychopathology and neuropsychological deficits. We have measured serum levels of S100B in 41 elderly, chronic schizophrenic patients and 23 age- and gender-matched controls using an immunoluminometric assay. In patients, we assessed detailed psychopathology and neuropsychological performance and determined serum levels of haloperidol, clozapine and its two main metabolites desmethylclozapine and clozapine metabolite N-oxid by HPLC. S100B levels were increased in elderly chronic schizophrenic patients compared to healthy controls. In patients, levels were negatively correlated with deficit symptoms and positively with age. There were no significant differences of S100B between medication groups and no correlation with serum levels of antipsychotics or neuropsychological scores. Elevations of S100B in elderly chronic schizophrenic patients may be related to an active disease process lasting until old-age. Correlations point to the impact of S100B in neuroplasticity and ageing. Post-mortem studies should clarify the presence of altered S100B function in the brain and its relationship to neuroplastic or neurodegenerative processes.

Topics: Aged; Antipsychotic Agents; Chronic Disease; Clozapine; Cognition Disorders; Depressive Disorder, Major; Female; Haloperidol; Humans; Male; Middle Aged; Nerve Growth Factors; Neuropsychological Tests; Psychological Tests; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Depressive Disorder, Major; Dystonia; Female; Humans; Syndrome

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clozapine; Depressive Disorder, Major; Drug Therapy, Combination; Female; Humans; Maprotiline; Middle Aged; Psychotic Disorders

Converging evidence indicates that, in controlled drug trials, individuals receiving novel antipsychotic medications have fewer adverse effects than those receiving conventional antipsychotic medications. This in turn may lead to greater patient treatment satisfaction. This study examines patient satisfaction and burden of adverse effects in a county-wide epidemiologic study of first admission psychotic persons with psychosis who were receiving novel antipsychotic drugs (n = 42). Comparisons were made within this group, and between 25 of these persons and 25 others with the same diagnosis and sex, from the same epidemiologic study, who were receiving a comparable regimen of conventional antipsychotic drugs. Patients receiving novel antipsychotics were significantly more satisfied and were significantly less burdened by adverse effects than those receiving conventional antipsychotics. Among the group receiving novel antipsychotics, dosage was not related to satisfaction or burden of adverse effects. For those treated with risperidone (n = 27), there was a difference, approaching statistical significance, for greater satisfaction and less adverse effect burden among those persons with dosages less than 5 mg daily as compared to higher dosages.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Depressive Disorder, Major; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neurologic Examination; Olanzapine; Patient Satisfaction; Pirenzepine; Risperidone; Schizophrenia; Schizophrenic Psychology

[123I]Iodobenzamide (IBZM) is an iodine-labeled dopamine receptor ligand and can be used to visualize brain D2 receptors in humans with single photon emission computerized tomography (SPECT). The ratio of striatal IBZM uptake to uptake in frontal cortex (ST/FC ratio) represents a semiquantitative measure of D2 receptor binding in the striatum. Our study sample included six patients treated with haloperidol (3.0-8.0 mg/day orally; one patient with an average of 0.9 mg/day intramuscularly), five patients with benperidol (9.0-15.0 mg/day orally) and nine patients treated with clozapine (200.0-600.0 mg/day orally). Typical neuroleptics (TNs) and atypical neuroleptics (ANs) were significantly different in their ST/FC ratios. The ST/FC ratios indicated that patients treated with benperidol exhibited the lowest ST/FC ratios, with increasingly higher ratios in patients on haloperidol or clozapine. We found a curvilinear relationship between the ST/FC ratios and the dose/kg body wt. of TNs and ANs on the basis of a dose-normalization according to Ki-values of the neuroleptic at D2 receptors and a weaker, but also curvilinear relationship between ST/FC ratios and normalized dosages according to clinically defined chlorpromazine equivalents. The specific uptake of IBZM did not correlate with the plasma levels of the TN haloperidol at the present dose range (0-12.4 ng/ml). For clozapine, a meaningful negative correlation between plasma levels and ST/FC ratio could be established. There was a negative continuous correlation between uptake of IBZM and extrapyramidal side effects, which is different from the threshold-based relationship between extrapyramidal side effects and IBZM uptake reported previously.

Topics: Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Benperidol; Benzamides; Bipolar Disorder; Brain; Clozapine; Corpus Striatum; Depressive Disorder, Major; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Frontal Lobe; Haloperidol; Humans; Male; Middle Aged; Neurologic Examination; Psychiatric Status Rating Scales; Pyrrolidines; Receptors, Dopamine D2; Schizophrenia, Paranoid; Tomography, Emission-Computed, Single-Photon