Studies on the biology of the neuroactive amines; a morphologic and pharmacologic approach

[From the Introduction] The discoveries that histamine is found in the mast cells of a myriad of species, that 5-hydroxytryptamine is found in the mast cells of the rat and mouse, and that these amines are largely bound in granules made this cell of great interest to the student of amine biology. It meant that the mast cell, along with the cells of the adrenal medulla and the blood platelets could serve as a model system for the amine biology of the vertebrate nervous system whose complexity makes a direct experimental approach extremely difficult. Thus, information about amine synthesis, destruction, binding, release, regulation, and the influence of hormones and rugs is much more easily obtained from the mast cell than from the vertebrate nervous system. And with the economy of mechanism that nature practices, it seems reasonable to hope that the information obtained from the mast cells would be of value in understanding many of the features of amines in the nervous system. This has indeed proven true. Investigators, throughout the world have explored the mast cells with particular attention to their amines. It need not be stressed that the mast cell has great intrinsic interest in its own right

Schizophrenia risk loci from xMHC region were associated with antipsychotic response in chronic schizophrenic patients with persistent positive symptom

We examined whether common variants from the extended major histocompatibility complex (xMHC) region contribute to the response to antipsychotic drugs (APDs) in patients with schizophrenia with persistent psychosis. Subjects participated in a prospective longitudinal study of the effect of APDs on psychopathology were temporally split into discovery (n = 88) and replication (n = 42) cohorts. The primary endpoint was a change in Brief Psychiatric Rating Scale at 6-week or 6-month after treatment. rs204991 (β = 3.917, p = 3.72 × 10−6), the strongest signal associated with response at 6-week was located near C4A/C4B after a linear regression adjusted for covariates. xMHC SNP imputation disclosed much stronger signals (rs9268469, β = 5.140, p = 1.57 × 10−7) and other weaker signals (p \u3c 1 × 10−5) spanning the entire xMHC region. All the variants were previously identified schizophrenia risk loci. Conditional fine-mapping revealed three subgroups of SNPs which were the eQTLs (p \u3c 1 × 10−7) for C4A, HLA-C, and BTN3A2 in disease-relevant tissue. Epistasis between HLA-C and C4A was observed (p = 0.019). Minor allele (G) carriers of rs204991, eQTL for C4A, having decreased risk for schizophrenia and lower imputed expression of C4A, had a better response to APDs. Some imputed HLA alleles associated with a decreased risk for schizophrenia had a positive association with improvement in psychotic symptoms. An independent cohort validated the association of change in psychosis with C4A. We provide evidence that genetic risk factors for schizophrenia from the xMHC region are associated with response to APDs and those variants significantly alter the imputed expression of C4A, HLA-C, and BTN3A2. The minor alleles predicting higher C4A level are associated with diminished improvement in psychotic symptoms after APD treatment

Association of Serotonin2c Receptor Polymorphisms With Antipsychotic Drug Response in Schizophrenia

There is conflicting evidence for the association between genetic polymorphisms in the serotonin (5-HT)2C receptor (HTR2C) and response to antipsychotic drugs (APD) in schizophrenic patients. We tested the association between the HTR2C polymorphisms, Cys23Ser, −759C/T, and −697G/C, and response to APDs (mainly clozapine) in a 6 month prospective study in 171 patients with schizophrenia. Ser23 was significantly associated with treatment response (positive symptoms, X2 = 7.540, p = 0.01; negative symptoms, X2 = 4.796, p = 0.03) in male patients only. A −759C-Ser23 haplotype was similar associated with positive (X2 = 6.648, p = 0.01) and negative (X2 = 6.702, p = 0.01) symptom improvement. Logistic regression, after controlling for covariates, also showed significant haplotypic associations. A meta-analysis of six studies for Ser23 and treatment response showed an overall odds ratio of 2.00 (95%CI, 1.38–2.91, p = 0.0003) or 1.94 (95%CI, 1.27–2.99, p = 0.0024) under fixed or random effect models. These results provide additional evidence that HTR2C polymorphisms are associated with treatment response to APD with HTR2C antagonism or inverse agonism, in male schizophrenic patients

Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo

Amisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia, a mild form of depression, in Italy. Amisulpride has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials. In part because of the selective D2/D3 receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties

Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors

The authors examined the affinities of 36 typical and atypical antipsychotic agents for the cloned rat 5-hydroxytryptamine-6 (5-HT6) and rat 5-hydroxytryptamine-7 (5-HT7) receptors in transiently expressed COS-7 cells (5-HT7) or stably transfected HEK-293 cells (5-HT6 receptors). Clozapine and several related atypical antipsychotic agents (rilapine, olanzepine, tiospirone, fluperlapine, clorotepine and zotepine) had high affinities for the newly discovered 5-HT6 receptor (Kis less than 20 nM). The 5-HT7 receptor bound clozapine, rilapine, fluperlapine, clorotepine, zotepine and risperidone but not tiospirone and olanzepine, with affinities less than 15 nM. In addition, several typical antipsychotic agents (chloroprothixene, chlorpromazine, clothiapine and fluphenazine) had high affinities for both the 5-HT6 and 5-HT7 receptors. Pimozide, a diphenylbutylpiperidine, had the highest affinity of all the typical antipsychotic agents tested for the 5-HT7 receptor (Ki = 0.5 nM). Three putative atypical antipsychotic agents melperone, amperozide and MDL 100907 did not bind with high affinities to either the 5-HT6 or 5-HT7 receptors (Kis > 50 nM). Several dopamine-selective antipsychotic agents (raclopride, rimcazole and penfluridol) had essentially no affinity for either the 5-HT6 or 5-HT7 receptors (Ki values > 5000 nM)

HL-Histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs

As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT2A and 5-HT2Cserotonin receptors, H1-histamine receptors, α1- and α2-adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H1-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman ρ=−0.72; p less than 0.01), as were affinities for α1A adrenergic (ρ=−0.54; p less than 0.05), 5-HT2C (ρ=−0.49; p less than 0.05) and 5-HT6 receptors (ρ=−0.54; p less than 0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H1, α2A, α2B, 5-HT2A, 5-HT2C, and 5-HT6 receptors were most highly correlated with the first principal component, and affinities for the D2, 5-HT1A, and 5-HT7 receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H1 and α1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H1-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H1-histamine receptor antagonists are known to induce weight gain with chronic use, and because H1-histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H1-histamine receptors

Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study

OBJECTIVE: To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD). METHODS: One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change. RESULTS: For the primary endpoint, deutetrabenazine significantly reduced AIMS scores from baseline to week 12 vs placebo (least-squares mean [standard error] -3.0 [0.45] vs -1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs 40.4%) favored deutetrabenazine but was not significant. Deutetrabenazine and placebo groups showed low rates of psychiatric adverse events: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs 1.7%), and suicidal ideation (0% vs 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the Unified Parkinson's Disease Rating Scale motor subscale, was noted from baseline to week 12 in either group. CONCLUSIONS: In patients with TD, deutetrabenazine was well tolerated and significantly reduced abnormal movements. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with TD, deutetrabenazine reduces AIMS scores

Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression

Background: This report provides histopathological evidence to support prior neuroimaging findings of decreased volume and altered metabolism in the frontal cortex in major depressive disorder. Methods: Computer-assisted three-dimensional cell counting was used to reveal abnormal cytoarchitecture in left rostral and caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects with major depression as compared to psychiatrically normal controls. Results: Depressed subjects had decreases in cortical thickness, neuronal sizes, and neuronal and glial densities in the upper (II–IV) cortical layers of the rostral orbitofrontal region. In the caudal orbitofrontal cortex in depressed subjects, there were prominent reductions in glial densities in the lower (V–VI) cortical layers that were accompanied by small but significant decreases in neuronal sizes. In the dorsolateral prefrontal cortex of depressed subjects marked reductions in the density and size of neurons and glial cells were found in both supra- and infragranular layers. Conclusions: These results reveal that major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex. Our data will contribute to the interpretation of neuroimaging findings and identification of dysfunctional neuronal circuits in major depression