The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response.

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.

Schizophrenia and depression: challenging the paradigm of two separate diseases--a controlled study of schizophrenia, depression and healthy controls.

BACKGROUND: We studied descriptive and causal associations between schizophrenia, depressive symptoms and episodes of depression. METHODS: Untreated psychotic, depressive and negative symptoms were assessed retrospectively from onset until first admission using the IRAOS in a population-based sample of 232 first episodes of schizophrenia. A representative subsample of 130 patients, studied retrospectively until onset and followed up prospectively over 6 months after first admission, were compared with 130 age- and sex-matched healthy population controls and with 130 equally matched first admissions for unipolar depressive episodes. RESULTS: The lifetime prevalence of depressive mood (>or=2 weeks) at first admission for schizophrenia was 83%. The most frequent initial symptom of schizophrenia was depressive mood, appearing more than 4 years before first admission and followed by negative symptoms and functional impairment. Showing considerable overlap in symptoms and functional impairment at their initial stages, schizophrenia and unipolar depression became clearly distinguishable with the emergence of psychotic symptoms. In the first psychotic episode 71% presented clinically relevant depressive symptoms, 23% fulfilled the ICD-10 criteria for a depressive episode. With remitting psychosis the prevalence of depression, too, decreased. The high frequency of depressive symptoms at the prepsychotic prodromal stage and their increase and decrease with the psychotic episode suggests that depression in schizophrenia might be expression of an early, mild stage of the same neurobiological process that causes psychosis. CONCLUSIONS: The high prevalence of depression in the population and the diversity of its causes prompted us to speculate about a hierarchical model of preformed dimensional patterns of psychopathology.

Khat use as risk factor for psychotic disorders: a cross-sectional and case-control study in Somalia.

BACKGROUND: Little is known about the prevalence of khat-induced psychotic disorders in East African countries, where the chewing of khat leaves is common. Its main psycho-active component cathinone produces effects similar to those of amphetamine. We aimed to explore the prevalence of psychotic disorders among the general population and the association between khat use and psychotic symptoms. METHODS: In an epidemiological household assessment in the city of Hargeisa, North-West Somalia, trained local interviewers screened 4,854 randomly selected persons from among the general population for disability due to severe mental problems. The identified cases were interviewed based on a structured interview and compared to healthy matched controls. Psychotic symptoms were assessed using the items of the WHO Composite International Diagnostic Interview and quantified with the Positive and Negative Symptoms Scale. Statistical testing included Student's t-test and ANOVA. RESULTS: Local interviewers found that rates of severe disability due to mental disorders were 8.4% among males (above the age of 12) and differed according to war experiences (no war experience: 3.2%; civilian war survivors: 8.0%; ex-combatants: 15.9%). The clinical interview verified that in 83% of positive screening cases psychotic symptoms were the most prominent manifestations of psychiatric illness. On average, cases with psychotic symptoms had started to use khat earlier in life than matched controls and had been using khat 8.6 years before positive symptoms emerged. In most cases with psychotic symptoms, a pattern of binge use (> two 'bundles' per day) preceded the onset of psychotic symptoms, in contrast to controls of the same age. We found significant correlations between variables of khat consumption and clinical scales (0.35 to 0.50; p < 0.05), and between the age of onset of khat chewing and symptom onset (0.70; p <0.001). CONCLUSION: Evidence indicates a relationship between the consumption of khat and the onset of psychotic symptoms among the male population, whereby not the khat intake per se but rather early onset and excessive khat chewing seemed to be related to psychotic symptoms. The khat problem must be addressed by means other than prohibition, given the widespread use and its role in Somali culture.