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Developing therapeutics for schizophrenia and other psychotic disorders.

ABSTRACT: Although the second-generation or atypical antipsychotic drugs have been breakthrough medicines for the treatment of schizophrenia and other psychotic conditions, cognitive dysfunction and to some extent negative symptoms of the disease continue to be the main cause of poor vocational status of the patients. Thus, the majority of investigational drug development efforts today target these unmet medical needs. This review postulates that the field of schizophrenia research has advanced sufficiently to develop biochemical hypotheses of the etiopathology of the disease and target the same for revolutionary disease modifying therapy. This postulate is based on recent studies that have begun to provide a testable etiopathology model that integrates interactions between genetic vulnerability factors, neurodevelopmental anomalies, and neurotransmitter systems. This review begins with a brief overview of the nosology and etiopathology of schizophrenia and related psychotic disorders to establish a context for subsequent detailed discussions on drug discovery and development for psychotic disorders. Particular emphasis is placed on recent advances in genetic association studies of schizophrenia and how this can be integrated with evidence supporting neurodevelopmental abnormalities associated with the disease to generate a testable model of the disease etiopathology. An in-depth review of the plethora of new targets and approaches targeting the unmet medical need in the treatment of schizophrenia exemplify the challenges and opportunities in this area. We end the review by offering an approach based on emerging genetic, clinical, and neurobiological studies to discover and validate novel drug targets that could be classified as disease modifying approaches.

SUBMITTER: Marek G

PROVIDER: S-EPMC1201317 | biostudies-literature | 2005 Oct

REPOSITORIES: biostudies-literature

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Developing therapeutics for schizophrenia and other psychotic disorders.

Marek Gerard G Merchant Kalpana K

NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics 20051001 4

Although the second-generation or atypical antipsychotic drugs have been breakthrough medicines for the treatment of schizophrenia and other psychotic conditions, cognitive dysfunction and to some extent negative symptoms of the disease continue to be the main cause of poor vocational status of the patients. Thus, the majority of investigational drug development efforts today target these unmet medical needs. This review postulates that the field of schizophrenia research has advanced sufficient ...[more]

PMID: 16489367

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Project description:Emotion dysfunction has long been considered a cardinal feature across psychotic disorders, including schizophrenia and affective psychosis. However, few studies have used objective markers of emotional function to compare psychotic disorders to one another, and fewer studies have examined such markers within a longitudinal framework. Here, we examine one objective marker of emotional responsivity, the late positive potential (LPP), which is a centro-parietal event-related potential (ERP) that tracks the dynamic allocation of attention to emotional vs. neutral stimuli. We used the LPP to characterize abnormal emotional responsivity by relating it to negative, depressive, and psychotic symptoms among two clinical groups: individuals diagnosed with affective psychosis and individuals with schizophrenia. We also used a long-term longitudinal framework, examining concurrent associations between LPP amplitude and symptom severity, as well as prospective associations with symptoms 4 years later. Participants were 74 individuals with psychotic illness: 37 with schizophrenia spectrum disorders and 37 with a primary affective disorder (psychotic bipolar disorder, psychotic depression). There were no mean-level differences in LPP amplitude between the schizophrenia spectrum and primary affective psychosis group. In the primary affective psychosis group, reduced LPP amplitude was associated with greater depressive, negative, and psychotic symptom severity, both concurrently and at follow-up; associations between LPP and symptoms were not observed within the schizophrenia spectrum group. This pattern of results suggests that the neural correlates of emotion dysfunction may differ across psychotic disorders. One possibility is that schizophrenia is characterized by a decoupling of symptom severity and emotional processing. Such findings underscore the importance of analyzing transdiagnostic samples to determine common or specific symptom relationships across various patient populations.

Project description:BACKGROUND: Persons with schizophrenia and other psychotic disorders have a high prevalence of obesity, impaired glucose tolerance, and lipid abnormalities, particularly hypertriglyceridemia and low high-density lipoprotein. More detailed molecular information on the metabolic abnormalities may reveal clues about the pathophysiology of these changes, as well as about disease specificity. METHODS: We applied comprehensive metabolomics in serum samples from a general population-based study in Finland. The study included all persons with DSM-IV primary psychotic disorder (schizophrenia, n = 45; other non-affective psychosis (ONAP), n = 57; affective psychosis, n = 37) and controls matched by age, sex, and region of residence. Two analytical platforms for metabolomics were applied to all serum samples: a global lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry, which covers molecular lipids such as phospholipids and neutral lipids; and a platform for small polar metabolites based on two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC × GC-TOFMS). RESULTS: Compared with their matched controls, persons with schizophrenia had significantly higher metabolite levels in six lipid clusters containing mainly saturated triglycerides, and in two small-molecule clusters containing, among other metabolites, (1) branched chain amino acids, phenylalanine and tyrosine, and (2) proline, glutamic, lactic and pyruvic acids. Among these, serum glutamic acid was elevated in all psychoses (P = 0.0020) compared to controls, while proline upregulation (P = 0.000023) was specific to schizophrenia. After adjusting for medication and metabolic comorbidity in linear mixed models, schizophrenia remained independently associated with higher levels in seven of these eight clusters (P < 0.05 in each cluster). The metabolic abnormalities were less pronounced in persons with ONAP or affective psychosis. CONCLUSIONS: Our findings suggest that specific metabolic abnormalities related to glucoregulatory processes and proline metabolism are specifically associated with schizophrenia and reflect two different disease-related pathways. Metabolomics, which is sensitive to both genetic and environmental variation, may become a powerful tool in psychiatric research to investigate disease susceptibility, clinical course, and treatment response.

Project description:BackgroundIn Chile, the clinical guidelines "for the treatment of people from first episode of schizophrenia" aim to support individuals with schizophrenia to live independently, establishment occupational goals, and gain an adequate quality of life and social interaction. This requires the implementation of a treatment model that integrates psychosocial and pharmacological dimensions. Community intervention strategies ensure the achievement of these goals.ObjectivesThis study compiles and synthesizes available scientific evidence from the last 14 years on the effectiveness of community intervention strategies for schizophrenia and related psychotic disorders.MethodologyAn electronic search was carried out using PUBMED, LILACS, and Science Direct as databases. Criteria of inclusion: (i) randomized clinical trials, (ii) Community-based interventions, (iii) diagnosis of schizophrenia or related psychotic disorder (section F2 of ICD-10).Exclusion criteria(i) treatments exclusively pharmacological, (ii) interventions carried out in inpatient settings, (iii) bipolar affective disorder or substance-induced psychosis (greater than 50% of sample).ResultsSixty-six articles were reviewed. Community strategies for integrated treatment from the first outbreak of schizophrenia significantly reduced negative and psychotic symptoms, days of hospitalization, and comorbidity with substance abuse and improved global functioning and adherence to treatment. In other stages, there were improved outcomes in negative and positive symptoms and general psychopathology. Psychoeducation for patients and families reduced the levels of self-stigma and domestic abuse, as well as improved knowledge of the disease and treatment adherence. Training focused on cognitive, social, and labor skills has been shown to improve yields in social functioning and employment status.ConclusionCommunity-based intervention strategies are widely supported in the treatment of patients with schizophrenia.

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Developing therapeutics for schizophrenia and other psychotic disorders.

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Developing therapeutics for schizophrenia and other psychotic disorders.

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