Conventional Antipsychotic Medications Research Articles

Discovery of novel protective agents for infection-related delirium through bispectral electroencephalography

Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

Optimization of Early Diagnosis of Glucose Metabolism Impairment for Patients Receiving Antipsychotic Medications at the Outpatient Psychiatric Clinic of the University Teaching Hospital, Lusaka, Zambia

Introduction: Patients using antipsychotic drugs are more likely than the general population to suffer glucose metabolism dysfunctions. Patients who take antipsychotic drugs, particularly second-generation antipsychotics, are four times more likely to develop overweight, obesity, and diabetes type 2. Failing to recognize these metabolic issues puts an individual at risk of developing cardio-metabolic and others disorders that potentially worsen psychiatric problems. For controlling and enhancing potential psychiatric treatment outcomes, early diagnosis and treatment of glucose metabolism dysfunction are crucial. Objective: To optimize the early diagnosis of glucose metabolism impairments in patients with psychiatric disorders treated with antipsychotic medications. Methodology: This is a descriptive cross-sectional study that was conducted at the outpatient psychiatric clinic of the University Teaching Hospital (Lusaka, Zambia). A systematic sampling method was applied to all patients who were receiving antipsychotic drugs. All participants were checked for their weight, height, Body Mass Index (BMI), waist circumference, random, and fasting blood glucose levels respectively. The results were analyzed by using SPSS software (version 20), while Fisher’s exact test was used to determine the relationship between categorical variables. Results: The proportion of individuals with impaired fasting blood glucose levels found in this study was 11.1% and that of individuals with diabetes was 10.0% respectively which is higher compared to the general population. Patients who were receiving second-generation antipsychotics showed a slightly higher proportion of impaired fasting blood glucose levels compared to those on conventional antipsychotic medications. Conclusion: The glucose metabolism deficit in patients with psychotic disorders was found to be high. Patients of both sexes had an equal chance of developing the problem, though females had a higher proportion as compared to males, and it is not time-dependent. Older patients showed a higher proportion of impaired fasting blood glucose levels compared to younger ones. It is recommended that basic screening measures of glucose metabolism parameters that are simple and cost-effective, like checking weight, BMI, waist circumferences, and regular checking of blood glucose levels, be routine practice in all psychiatric settings before starting antipsychotic medications.

Evaluation of Abnormal Movements among Senior Schizophrenics: A Local Study with Reference to Tardive Dyskinesia

Introduction: Tardive dyskinesia (TD) includes involuntary choreiform or athetoid movements of the jaw, lower face, tongue, and extremities, developing in association with the use of an antipsychotic medication, and may develop in about 20 to 40 percent of patients who require long-lasting hospitalization. In the present study, the prevalence of this condition has been measured among an elderly group of schizophrenic patients. Methods: One hundred and one elderly schizophrenic patients, who were hospitalized in the chronic section of a community psychiatric hospital, were selected for the present cross-sectional study. Abnormal Involuntary Movement Scale (AIMS) was employed to screen for patients with schizophrenia who also had TD. Scale for Assessment of Positive Symptoms, Scale for Assessment of Negative Symptoms, Schedule for Assessment of Insight, and Clinical Global Impressions – Severity of illness, as well, had been used as ancillary scales for evaluation of severity of general psychopathology of schizophrenia, and comparing the TD patients with the group of patients without TD, for probing the intervening parameters. Results: While abnormal movements were clear in 38.61% (n=39) of elderly schizophrenic patients, only seven of them (6.93 %) could be diagnosed as TD, based on the above-mentioned criteria. All of them were using conventional antipsychotic medications, accompanied with anticholinergic medications. Among TD patients, three cases had only abnormal facial and oral movements, one patient had atypical facial and oral movements as well as anomalous extremity movements, one patient had irregular facial and oral movements in addition to unusual trunk movements, and lastly, two patients had nonstandard extremity movements. In addition, around 71% of patients with TD were aware of their unusual movements. Between-group analysis did not show any significant difference between patients with TD and patients without TD in age, duration of illness, positive symptoms, negative symptoms, insight, and general psychopathology. Conclusion: According to the findings of the present study, the prevalence of Tardive Dyskinesia among elderly schizophrenic patients, who were using typical antipsychotic medications, is very lower than what has been indicated thus far.

Variations immunologiques après traitement d’un épisode maniaque

Bipolar disorder is a chronic and disabling mental illness affecting approximately 1–2% of the general population, characterized by the occurrence of manic episodes alone or alternating with depressive episodes. Bipolar disorder is associated with significant morbidity, mortality and personal suffering. The mechanisms underlying the onset and progression of bipolar disease are still poorly understood. Recently, immunological dysfunctions have been suggested in the pathogenesis of bipolar disorder, and many studies have focused on the interaction between bipolar disorder and immunity. Immunological changes have been widely studied during depressive episodes but less explored during manic episodes. The objective of our study was to explore changes in serum proteins and autoantibodies after treatment for a manic episode of bipolar I disorder. This study was carried out over a 30-month period from January 2017 to June 2019, in collaboration between the psychiatry department B of the Hédi Chaker CHU and the immunology department of the Habib Bourguiba CHU, in Sfax, Tunisia. It focused on a sample of 45 bipolar patients with manic relapse, naïve to psychotropic treatment, or discontinuing treatment for a period of at least three months and without a history of autoimmune disease. The study was conducted in two stages : on admission and after treatment. The mean plasma levels of IgG and complement C3 fraction were significantly higher in bipolar patients with relapsing mania. Studies of variation in immunoglobulins and complement fractions during relapses of bipolar disorder have all objected to variations in these serum proteins, but their results were inconsistent regarding the direction of variation and the fractions affected. After treatment, there was a statistically significant increase in the mean plasma levels of IgG and IgA and a decrease in the mean plasma level of the C4 fraction of complement. No significant variation in autoantibodies was noted after treatment. The mean plasma IgM level was significantly lower with sodium valproate. On atypical antipsychotic medication, the mean plasma level of fraction C3 was statistically lower, whereas on conventional antipsychotic medication it was statistically higher. This is in line with the data in the literature which support the immunomodulatory role of thymoregulators and antipsychotics. Serum proteins have been more sensitive than autoantibodies to the effect of psychotropic therapy during manic relapse.

Adenosine and Kynurenic Acid Interactions: Possible Relevance for Schizophrenia Treatment?

Adenosine and Kynurenic Acid Interactions: Possible Relevance for Schizophrenia Treatment?

Cognitive performance in early, treatment-resistant psychosis patients: Could cognitive control play a role in persistent symptoms?

Approximately one third of psychosis patients fail to respond to conventional antipsychotic medication, which exerts its effect via striatal dopamine receptor antagonism. The present study aimed to investigate impaired cognitive control as a potential contributor to persistent positive symptoms in treatment resistant (TR) patients. 52 medicated First Episode Psychosis (FEP) patients (17 TR and 35 non-TR (NTR)) took part in a longitudinal study in which they performed a series of cognitive tasks and a clinical assessment at two timepoints, 12 months apart. Cognitive performance at baseline was compared to that of 39 healthy controls (HC). Across both timepoints, TR patients were significantly more impaired than NTR patients in a task of cognitive control, while performance on tasks of phonological and semantic fluency, working memory and general intelligence did not differ between patient groups. No significant associations were found between cognitive performance and psychotic symptomatology, and no significant performance changes were observed from the first to second timepoint in any of the cognitive tasks within patient groups. The results suggest that compared with NTR patients, TR patients have an exacerbated deficit specific to cognitive control, which is established early in psychotic illness and stabilises in the years following a first episode.

Identification and Quantification of Antipsychotics in Blood Samples by LC-MS-MS: Case Reports and Data from Three Years of Routine Analysis.

Antipsychotic drugs (AP) are widely prescribed for the treatment of schizophrenia and psychosis. The pharmacological treatment of schizophrenia is often performed with the simultaneous use of two or more antipsychotic agents to achieve the desired control of psychotic symptoms Available AP include both conventional (typical) and new (atypical) antipsychotic medications. Atypical AP, such as quetiapine, now account for the vast majority of AP prescriptions. In forensic toxicology, AP are of considerable interest because of their potential abuse and their involvement in intoxications and suicides. The authors retrospectively examined AP positive cases detected in samples collected during autopsies performed in the Forensic Clinical and Pathology Service of National Institute of Legal Medicine and Forensic Sciences Centre Branch or in other autopsies carried out in the central region of Portugal, between January 2016 and December 2018. A quantitative liquid chromatography-tandem mass spectrometry assay was developed for the simultaneous determination of 16 AP (amisulpride, aripiprazole, chlorpromazine, clozapine, cyamemazine, fluphenazine, haloperidol, levomepromazine, melperone, olanzapine, paliperidone, promethazine, quetiapine, risperidone, sulpiride and ziprasidone) in blood samples of postmortem cases. The Laboratory of Forensic Chemistry and Toxicology received 3,588 requests for toxicological analysis: 1,413 cases were positive for drugs from which 351 (24.8%) cases were positive for AP, 60.1% from male individuals and 39.9% from female. Quetiapine was the most prevalent AP (36.5%) followed by olanzapine (20.8%). During this period, there were 25 postmortem cases with AP blood concentrations above therapeutic range, in which 36% of those are in agreement with the information received (psychological history or acute intoxication suspicion) and the manner of death was suicide. Our results point that antipsychotics are an increasingly prevalent class of drugs. AP must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases; therefore, it is important to come up with a sensitive method to cover the low therapeutic range in which AP are usually present.

Hippocampal subfield transcriptome analysis in schizophrenia psychosis.

We have previously demonstrated functional and molecular changes in hippocampal subfields in individuals with schizophrenia (SZ) psychosis associated with hippocampal excitability. In this study, we use RNA-seq and assess global transcriptome changes in the hippocampal subfields, DG, CA3, and CA1 from individuals with SZ psychosis and controls to elucidate subfield-relevant molecular changes. We also examine changes in gene expression due to antipsychotic medication in the hippocampal subfields from our SZ ON- and OFF-antipsychotic medication cohort. We identify unique subfield-specific molecular profiles in schizophrenia postmortem samples compared with controls, implicating astrocytes in DG, immune mechanisms in CA3, and synaptic scaling in CA1. We show a unique pattern of subfield-specific effects by antipsychotic medication on gene expression levels with scant overlap of genes differentially expressed by SZ disease effect versus medication effect. These hippocampal subfield changes serve to confirm and extend our previous model of SZ and can explain the lack of full efficacy of conventional antipsychotic medication on SZ symptomatology. With future characterization using single-cell studies, the identified distinct molecular profiles of the DG, CA3, and CA1 in SZ psychosis may serve to identify further potential hippocampal-based therapeutic targets.

Clozapine-dependent inhibition of EGF/neuregulin receptor (ErbB) kinases

Clozapine is an antipsychotic agent prescribed to psychotic patients exhibiting tolerance and/or resistance to the conventional antipsychotic medications that mainly drive monoamine antagonism. As the pharmacological fundamentals of its unique antipsychotic profile have been unrevealed, here, we attempted to obtain hints at this question. Here, we found that clozapine directly acts on ErbB kinases to downregulate epidermal growth factor (EGF)/neuregulin signaling. In cultured cell lines and cortical neurons, EGF-triggered ErbB1 phosphorylation was diminished by 30 μM clozapine, but not haloperidol, risperidone, or olanzapine. The neuregulin-1-triggered ErbB4 phosphorylation was attenuated by 10 μM clozapine and 30 μM haloperidol. We assumed that clozapine may directly interact with the ErbB tyrosine kinases and affect their enzyme activity. To test this assumption, we performed in vitro kinase assays using recombinant truncated ErbB kinases. Clozapine (3–30 μM) significantly decreased the enzyme activity of the truncated ErbB1, B2, and B4 kinases. Acute in vivo administration of clozapine (20 mg/kg) to adult rats significantly suppressed the basal phosphorylation levels of ErbB4 in the brain, although we failed to detect effects on basal ErbB1 phosphorylation. Altogether with the previous findings that quinazoline inhibitors for ErbB kinases harbor antipsychotic potential in animal models for schizophrenia, our present observations suggest the possibility that the micromolar concentrations of clozapine can attenuate the activity of ErbB receptor kinases, which might illustrate a part of its unique antipsychotic psychopharmacology.

Prolactin and Thyroid Stimulating Hormone (TSH) Levels and Sexual Dysfunction in Patients with Schizophrenia Treated with Conventional Antipsychotic Medication: A Cross-Sectional Study.

BackgroundThis study aimed to investigate the relationship between serum profiles of prolactin and thyroid stimulating hormone (TSH) and sexual dysfunction in patients with schizophrenia treated with conventional antipsychotic medication.Material/MethodsA hospital-based cross-sectional study included 118 patients, age range 18–57 years (55 men, 63 women), with a confirmed diagnosis of schizophrenia. All patients were stable after antipsychotic treatment. Serum levels of hormones, including prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone, testosterone, thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3) and free thyroxine (FT4), were detected in venous blood. The Positive and Negative Syndrome Scale (PANSS) score was used to measure symptom severity of patients with schizophrenia. The Mandarin Chinese version of the Arizona Sexual Experience Scale (ASEX), a 5-item scale, was used to measure sexual function.ResultsThere were 66 patients (55.9%) who had hyperprolactinemia, the prevalence of hyperprolactinemia was markedly higher in the sexual dysfunction group than the non-sexual dysfunction group (91.8% vs. 17.5%) (P<0.001). Mean prolactin levels were significantly increased in patients with sexual dysfunction compared with the patients without sexual dysfunction (P<0.001), with a higher incidence in female patients. Subclinical hypothyroidism and hyperprolactinemia were found to be independently associated with sexual dysfunction, and an increased PANSS negative score was an independent risk factor for the development of sexual dysfunction.ConclusionsThe incidence of sexual dysfunction was significantly increased in patients with schizophrenia. Hyperprolactinemia and subclinical hypothyroidism were associated with sexual dysfunction, especially in female patients.

Cholinergic medication for antipsychotic-induced tardive dyskinesia.

Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat TD. To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating antipsychotic-induced TD in people with schizophrenia or other chronic mental illness. An electronic search of the Cochrane Schizophrenia Group's Study-Based Register of Trials (16 July 2015 and April 2017) was undertaken. This register is assembled by extensive searches for randomised controlled trials in many electronic databases, registers of trials, conference proceedings and dissertations. References of all identified studies were searched for further trial citations. We included reports identified by the search if they were of controlled trials involving people with antipsychotic-induced TD and chronic mental illness, who had been randomly allocated to either a cholinergic agent or to a placebo or no intervention. Two review authors independently assessed the methodological quality of the trials. Two review authors extracted data and, where possible, estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We analysed data on an intention-to-treat basis, with the assumption that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE. We included 14 studies investigating the use of cholinergic drugs compared with placebo published between 1976 and 2014. All studies involved small numbers of participants (five to 60 people). Three studies that investigated the new cholinergic Alzheimer drugs for the treatment of TD are new to this update. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, we are unsure if data are incomplete, and data were often poorly or selectively reported.We are uncertain about the effect of new or old cholinergic drugs on no clinically important improvement in TD symptoms when compared with placebo; the quality of evidence was very low (RR 0.89, 95% CI 0.65 to 1.23; 27 people, 4 RCTs). Eight trials found that cholinergic drugs may make little or no difference to deterioration of TD symptoms (low-quality evidence, RR 1.11, 95% CI 0.55 to 2.24; 147 people). Again, due to very low-quality evidence, we are uncertain about the effects on mental state (RR 0.50, 95% CI 0.10 to 2.61; 77 people, 5 RCTs), adverse events (RR 0.56, 95% CI 0.15 to 2.14; 106 people, 4 RCTs), and leaving the study early (RR 1.09,95% CI 0.56 to 2.10; 288 people 12 RCTs). No study reported on social confidence, social inclusion, social networks, or personalised quality of life. TD remains a major public health problem. The clinical effects of both older cholinergic drugs and new cholinergic agents, now used for treating Alzheimer's disease, are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with TD, their effects should be demonstrated in large well-designed, conducted and reported randomised trials.

Metyrosine treatment in a woman with chromosome 22q11.2 deletion syndrome and psychosis: a case study

Background: People with 22q11.2 deletion syndrome (DS) are assumed to be especially vulnerable to developing mental illness such as psychosis.Aim: The study was established to contribute to knowledge about metyrosine medication in patients with 22q11.2 DS and psychosis.Methods: A case study was established including a woman with intellectual disability, 22q11.2 DS, and psychosis. Metyrosine medication was implemented, as conventional anti-psychotic medication was unsuccessful.Results: Effect of metyrosine medication included both psychotic symptom relief with decreased aggressive behaviour. Adjunctive milieu therapy contributed to complience.Conclusion: For patients with 22q11.2 DS and psychosis, metyrosine medication may prove effective. However, there are significant ethical dilemmas related to metyrosine medication for psychotic symptoms.

Therapeutic effect of adjunctive N-acetyl cysteine (NAC) on symptoms of chronic schizophrenia: A double-blind, randomized clinical trial

BackgroundSchizophrenia is one of the most disabling psychiatric syndromes with the prevalence of 1% in the general population. Despite availability of various antipsychotics, negative symptoms and cognitive impairment are difficult to treat. In addition antipsychotic monotherapy is not effective in most of these patients. Current evidence indicates the roles of glutamatergic system in this disorder. N-acetyl cysteine (NAC) also increases extracellular glutamate. This study was conducted to evaluate the clinical effects of oral NAC as an add-on to maintenance medication for the treatment of chronic schizophrenia. Materials and methodsThis 12-week, double-blind, randomized, placebo-controlled, clinical trial was performed to determine the effectiveness of 1200mg N-acetyl cysteine as an adjunctive treatment with conventional antipsychotic medications in 84 patients with chronic schizophrenia. The subjects were evaluated with the Positive and Negative Syndrome Scale (PANSS), Mini-Mental State Examination (MMSE), and a standard neuropsychological screening test. Data were analyzed with SPSS-16 software. ResultsNAC-treated patients showed significantly improvement in the positive (F=5.47, P=0.02) and negative (F=0.20, df=1) PANSS subscale. Also the general and total PANSS score of NAC group declined over times whilst it was increased for placebo group. Regarding cognitive functions, improvement was observed in some explored areas, such as attention, short-term and working memory, executive functioning and speed of processing. There was no significant difference between the 2 groups in the frequency of adverse effects. ConclusionThe present study detected improvement in positive, negative, general and total psychopathology symptoms as well as cognitive performance with NAC treatment. It is also well-tolerated, safe and easy-to-use agent as an effective therapeutic strategy to improve outcome in schizophrenia treatment.

SA85. White Matter Connectivity as a Predictor of Response to Antipsychotic Treatment: A Diffusion Connectometry Study in Unmedicated Patients With Schizophrenia

Abstract A number of studies have reported decreased white matter integrity in patients with schizophrenia, but little is known the relationship between white matter alterations and response to antipsychotic treatment. We enrolled 30 unmedicated patients with schizophrenia in a 6-week longitudinal trial with risperidone, a commonly used antipsychotic medication. Symptom severity was assessed with the Brief Psychiatric Rating Scale (BPRS). We obtained diffusion-weighted images before treatment was started. Thirty diffusion sampling directions spanning the whole sphere were acquired twice and concatenated (in plane resolution 2.2 mm, slice thickness 2.2 mm, b-value 1000 s/mm, 5 b0 images). Motion and eddy current correction were performed with the FSL EDDY tool. Diffusion data were then reconstructed in MNI space using q-space diffeomorphic reconstruction to obtain the spin distribution function, with a sampling length ratio of 1.25. Group diffusion connectometry was performed to examine the relationship between connectivity and clinical response after 6 weeks of treatment (defined as [BPRS total baseline − BPRS total week 6]/ BPRS total at baseline × −100) with multiple regression analyses using age and sex as covariates. Local connectomes were tracked using a deterministic fiber-tracking algorithm, with seeding density of 100 seeds/ mm, t-threshold of 2.3, and length threshold of 50 mm; all tracks from bootstrap resampling were included. Track trimming was conducted with 5 iterations. A total of 2000 randomized permutations were applied to obtain the null distribution of the track length. Connectometry analysis indicated that greater connectivity in the corpus callosum, external capsule, and cerebellar peduncle at baseline is related to better treatment response after 6 weeks of treatment; no tracks with lower connectivity related to treatment response were found. Our results suggest a relationship between white matter integrity and response to antipsychotic medications. Future studies investigating the pathophysiological mechanisms underlying white matter alterations will be important for targeted drug development and ultimately improvement of outcomes in patients with poor response to conventional antipsychotic medications.

Haloperidol inactivates AMPK and reduces tau phosphorylation in a tau mouse model of Alzheimer's disease

IntroductionThe use of antipsychotic medications in Alzheimer's disease has been associated with an increased risk of mortality in clinical trials. However, an older postmortem literature suggests that those with schizophrenia treated in an era of exclusively conventional antipsychotic medications had a surprisingly low incidence of tau pathology. No previously published studies have investigated the impact of conventional antipsychotic exposure on tau outcomes in a tau mouse model of AD.MethodsIn two experiments, transgenic rTg (tauP301L) 4510 tau mice were treated with either haloperidol or vehicle and phosphotau epitopes were quantified using high-sensitivity tau ELISA.ResultsAfter treatments of 2 and 6 week's duration, mice treated with haloperidol evidenced a significant reduction in tau phosphorylation associated with an inactivation of the tau kinase AMPK.DiscussionThe data suggest that D2 receptor blockade reduces tau phosphorylation in vivo. Future studies are necessary to investigate the impact of this reduction on tau neuropathology.

Neuroleptic prescriptions sequences analysis in relation to cardiovascular medication and death occurrence in Poland

Introduction The potential role of antipsychotic treatment in increasing cardiovascular risk and in explaining the increased mortality due to somatic disorders is still debated. The aim of this study was to assess the sequences of atypical and atypical neuroleptic prescriptions in relation to cardiovascular medication and death occurrence. Methods We conducted a retrospective longitudinal analysis involving 84,881 patients who had drug insurance benefits in Pomeranian voivodship and who were receiving a typical or atypical antipsychotic medication between 2008 and 2012. Data on deaths have been collected from National Death Registry. The sequence creation was performed according to algorithm that iterates over neuroleptic prescriptions in chronological order and appends them to the end of patient's prescriptions sequence. Patients were also assigned to cardiovascular groups depending on the use of cardiovascular or diabetic medications before, simultaneously or after the treatment with neuroleptics. Results There were 1,095,518 neuroleptic prescriptions and 16,010 deaths among antipsychotic users in analyzed period. The most prevalent sequence was consisting of typical neuroleptics. Less frequent were sequenced with use of both typical and atypical drugs or only atypical medications. The least frequent were sequenced with clozapine or clozapine with other neuroleptics. The highest occurrence of death and occurrence of cardiovascular drug after introducing antipsychotic treatment was observed for clozapine. There was lower occurrence of death in atypical neuroleptic sequence compared to typical drug sequence but similar prevalence of cardiovascular drugs. Conclusion These results suggest that conventional antipsychotic medications are associated with increased risk of death compared to atypical drugs.

Mortality in Users of Conventional Vs. Atypical Antipsychotic Medications in Poland

Introduction The potential role of antipsychotic treatment in affecting suicide rates and in explaining the increased mortality due to somatic disorders is still debated. The aim of this study was to assess mortality in individuals who were prescribed typical and atypical neuroleptics in one voivodship in Poland. Methods We conducted a retrospective cohort study involving 84881 patients who had drug insurance benefits in Pomeranian voivodship and who began receiving a conventional or atypical antipsychotic medication between 2008 and 2012. Data on deaths in this population have been collected from National Death Registry. Age-standardized death rates were calculated in the adult population exposed population to any dose of atypical antipsychotic medication, in popualtion of users of atypical antipsychotics only, in population of users of conventional antipsychotic drugs only and in population of clozapine users. Results In individuals who were prescribed conventional antipsychotic medication age-standardized death rate was significantly higher than in ever users of atypical medicatioons and people using only atypical drugs: 69.6 per 1000, 95% confidence interval (95% CI) 67.64–71.56 compared with 53.24 per 1000, 95% CI 50.8–55.69 and 48,38 per 1000, 95% CI 44.78–51.98. Mortality rate in clozapine users was also higher than in users oaf atypical medications (65,11 per 1000, 95% CI 50.8–55.69). Conclusion These results suggest that conventional antipsychotic medications are associated with increased risk of death compared to atypical drugs. Analysis based on administrative record linkage is the major limitation of this study. No adjustment has been made for confounding factors that may modify mortality risk.

Long-term clinical course and outcome of schizophrenia in rural Ethiopia: 10-year follow-up of a population-based cohort

BackgroundAlthough the few available studies from LMICs report favorable outcome, the course of schizophrenia is more complex than has been indicated so far. MethodsA sample of 361 people with a standardized clinical diagnosis of schizophrenia were recruited from a predominantly rural community in Ethiopia and followed up regularly for an average of 10years. Psychiatrists used the Longitudinal Interval Follow-up Evaluation chart to carry out assessment of illness course. Duration of time in clinical remission was the primary outcome. ResultAbout 61.0% of the patients remained under active follow-up, while 18.1% (n=65) were deceased. The mean percentage of follow-up time in complete remission was 28.4% (SD=33.0). Female patients were significantly more likely to have episodic illness course with no inter-episode residual or negative symptoms (χ2=6.28, P=0.012). Nearly 14.0% had continuous psychotic symptoms for over 75% of their follow-up time. Only 18.1% achieved complete remission for over 75% of their follow-up time. Later onset of illness was the only significant predictor of achieving full remission for over 50% of follow-up time in a fully adjusted model. Conventional antipsychotic medications were fairly well tolerated in 80% of the patients and 4.2% (n=15) experienced tardive dyskinesia. ConclusionThis population-based study is one of the very few long-term outcome studies of schizophrenia in LMICs. The study demonstrated clearly a differential and more favorable course and outcome for female patients but overall course and outcome of schizophrenia appeared less favorable in this setting than has been reported from other LMICs.

New approaches to the management of schizophrenia: focus on aberrant hippocampal drive of dopamine pathways.

Schizophrenia is a disease affecting up to 1% of the population. Current therapies are based on the efficacy of chlorpromazine, discovered over 50 years ago. These drugs block dopamine D2-like receptors and are effective at primarily treating positive symptoms in a subset of patients. Unfortunately, current therapies are far from adequate, and novel treatments require a better understanding of disease pathophysiology. Here we review the dopamine, gamma-aminobutyric acid (GABA), and glutamate hypotheses of schizophrenia and describe a pathway whereby a loss of inhibitory signaling in ventral regions of the hippocampus actually drives a dopamine hyperfunction. Moreover, we discuss novel therapeutic approaches aimed at attenuating ventral hippocampal activity in a preclinical model of schizophrenia, namely the MAM GD17 rat. Specifically, pharmacological (allosteric modulators of the α5 GABAA receptor), neurosurgical (deep brain stimulation), and cell-based (GABAergic precursor transplants) therapies are discussed. By better understanding the underlying circuit level dysfunctions in schizophrenia, novel treatments can be advanced that may provide better efficacy and a superior side effect profile to conventional antipsychotic medications.

Challenges in Estimating Mortality Risk From Antipsychotics in People With Alzheimer’s Disease

Back to table of contents Previous article Next article Communications and UpdatesFull AccessChallenges in Estimating Mortality Risk From Antipsychotics in People With Alzheimer’s DiseaseRyan M. Carnahan, Pharm.D., M.S.Ryan M. CarnahanSearch for more papers by this author, Pharm.D., M.S.Published Online:1 Feb 2014https://doi.org/10.1176/appi.ajp.2013.13091231AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: I read with interest the article by Lopez et al. (1) in the September 2013 issue on the long-term effects of antipsychotics in people with Alzheimer’s disease, which suggested that after controlling for psychiatric symptoms, neither typical nor atypical antipsychotics were associated with time to death. I would like to expand on one of the limitations noted by the authors, as I believe it is critical to interpreting the results.Previous research suggests that the excess mortality associated with antipsychotics is greatest early in treatment, with the relative risk trending toward no mortality effect of drug as the duration of antipsychotic use increases (2). The Lopez et al. study assessed medications every 6 months, without tracking interim changes. Periodic assessments such as this create challenges when interpreting results that are related to adverse events for which the greatest excess risk occurs early in treatment. This is a particularly important issue in a dementia sample, where death is not a rare occurrence. That is, if someone both started an antipsychotic and died during the time between two assessments, there would be no record that the individual received an antipsychotic before they died, and only those who survived the early treatment period would be recorded as receiving an antipsychotic. Thus, data are lost from individuals who may be particularly vulnerable to the adverse event of interest, in this case death. This is termed “depletion of susceptibles” and may lead to bias in effect estimates, as those who survive treatment through an initial high-risk period are often less susceptible to an adverse effect. This is one reason that new-user designs are generally preferred in pharmacoepidemiology studies of adverse drug effects (3).Lopez et al. have presented a compelling case that psychotic symptoms are a prognostic marker for increased mortality in people with dementia and an influential unmeasured confounder in observational studies of antipsychotics and mortality. However, the design limitations make it difficult to fully discern the role of the psychiatric symptoms relative to that of antipsychotics that were received but not recorded. I admire the authors’ efforts to address this important question but do not place higher weight on these results than on those of randomized controlled trials that identify an increased risk of mortality associated with antipsychotic use in dementia. Randomized trials have their own limitations, such as highly selected samples, shorter follow-up, and small numbers of events in any given trial. Yet Schneider et al.’s meta-analysis of these trials (4) showing greater mortality with antipsychotics compared with placebo included more than 10 times as many antipsychotic users as were in the Lopez et al. study. I hope the null mortality result in this study is not interpreted as an indication that caution and restraint are not necessary when considering the use of antipsychotics in this vulnerable patient population.From The University of Iowa College of Public Health, Department of Epidemiology, Iowa City, Iowa.Dr. Carnahan reports no financial relationships with commercial interests. He has received funding for research and education related to antipsychotic use in dementia from the Agency for Healthcare Research and Quality, the Health Resources and Services Administration, and the Patient Centered Outcomes Research Institute.References1 Lopez OL, Becker JT, Chang YF, Sweet RA, Aizenstein H, Snitz B, Saxton J, McDade E, Kamboh MI, DeKosky ST, Reynolds CF, Klunk WE: The long-term effects of conventional and atypical antipsychotics in patients with probable Alzheimer’s disease. Am J Psychiatry 2013; 170:1051–1058Link, Google Scholar2 Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH, Brookhart MA: Risk of death in elderly users of conventional vs atypical antipsychotic medications. N Engl J Med 2005; 353:2335–2341Crossref, Medline, Google Scholar3 Ray WA: Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 2003; 158:915–920Crossref, Medline, Google Scholar4 Schneider LS, Dagerman KS, Insel P: Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294:1934–1943Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 171Issue 2 February 2014Pages 227-227 Metrics PDF download History Accepted 1 December 2013 Published online 1 February 2014 Published in print 1 February 2014