Patients with poor response to antipsychotics have a more severe pattern of frontal atrophy: a voxel-based morphometry study of treatment resistance in schizophrenia.

Approximately 30% of schizophrenia patients do not respond adequately to the therapy. Previous MRI studies have suggested that drug treatment resistance is associated with brain morphological abnormalities, although region-of-interest analysis of MR studies from nonresponder and responder patients failed to demonstrate a statistically significant difference between these two schizophrenia subgroups. We have used a voxel-based analysis of segmented MR studies to assess structural cerebral differences in 20 nonresponder and 15 responder patients and 16 age-matched normal volunteers. Differences between the three groups emerged bilaterally mainly at the level of the superior and middle frontal gyri, primarily due to reduced grey matter volumes in nonresponders, as compared to both normal volunteers and responder patients. Post hoc direct comparison between the two schizophrenia subgroups demonstrated significantly reduced grey matter volumes in middle frontal gyrus bilaterally, in the dorsolateral aspects of left superior frontal gyrus extending into postcentral gyrus and in the right medial temporal cortex. Our results extend and integrate previous findings suggesting a more severe atrophy in nonresponder schizophrenia patients, compared to responder patients, mainly at the level of the superior and middle frontal gyri. Longitudinal studies in drug-naïve patients are needed to assess the role of these associations.

Discriminative hypomania checklist-32 factors in unipolar and bipolar major depressive patients.

BACKGROUND: Although manic or hypomanic episodes define bipolar disorder (BD), most patients show a predominance of depressive symptomatology, often associated with delayed or disregarded BD diagnosis. The Hypomania Checklist-32 (HCL-32) has therefore been developed and tested internationally to facilitate BD recognition. SAMPLING AND METHODS: Five hundred seventy-one (563 eligible) patients diagnosed with a major depressive episode according to DSM-IV criteria were consecutively enrolled in a cross-sectional, multicenter, observational study (Come To Me). Lifetime manic or hypomanic features were assessed by the HCL-32, and severity of depressive and anxious symptomatology was assessed using the Zung's self-report questionnaires for depression and anxiety. RESULTS: Among the patients diagnosed with BD (n = 119), either type I or type II, the occurrence of (hypo)manic symptoms was significantly higher compared to major depressive disorder (MDD) symptoms according to HCL-32 total and subscale scores obtained using a score of 14, which ensured an optimal discrimination between BD and MDD with a sensitivity of 0.85 and a specificity of 0.78. CONCLUSIONS: Although some false positives might occur, the HCL-32 was confirmed to be a useful instrument in the detection of past hypomania in MDD patients, finally contributing to proper therapeutic choices.

Brain-behavior relationship in a case of successful ECT for drug refractory catatonic OCD.

This case report describes the successful response to electroconvulsive therapy (ECT) in a patient with an unusual presentation of catatonia, whose onset occurred in the context of an extremely severe form of refractory obsessive-compulsive disorder (OCD). We correlated the clinical improvement in catatonic and OCD symptoms with specific changes in brain function as shown by regional cerebral blood flow scans, neurological soft signs examination, and neuropsychological testing. All assessments were conducted before and after the ECT course. The results strongly suggest that a right hemisphere dysfunction was the neural correlate of our patient's symptoms, and that ECT, by reverting this abnormality, may serve as an effective therapeutic approach for refractory catatonic OCD.

Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance.

Clinical and experimental evidence indicates that atypical antipsychotics impair glucose metabolism. We investigated whether clozapine may directly affect insulin action by analyzing insulin signaling in vitro and in vivo. Clozapine reduced insulin-stimulated glucose uptake in PC12 and in L6 cells, representative models of neuron and skeletal muscle, respectively. Consistently, clozapine reduced insulin effect on insulin receptor (IR) by 40% and on IR substrate-1 (IRS1) tyrosine phosphorylation by 60%. Insulin-stimulated Akt phosphorylation was also reduced by about 40%. Moreover, insulin-dependent phosphorylation of protein kinase C-ζ (PKC-ζ) was completely blunted in clozapine-treated cells. Interestingly, clozapine treatment was accompanied by an insulin-independent increase of Akt phosphorylation, with no change of IR, IRS1, and PKC-ζ basal phosphorylation. The cellular abundance of Ped/Pea-15, an Akt substrate and inducer of insulin resistance, was also increased following clozapine exposure, both in the absence and in the presence of cyclohexymide, a protein synthesis inhibitor. Similar as in cellular models, in the caudate-putamen and in the tibialis muscle of clozapine-treated C57/BL/KsJ mice, Akt phosphorylation and Ped/Pea-15 protein levels were increased and PKC-ζ phosphorylation was decreased. Thus, in these experimental models, clozapine deranged Akt function and up-regulated Ped/Pea-15, thereby inhibiting insulin stimulation of PKC-ζ and of glucose uptake.

Are "social drugs" (tobacco, coffee and chocolate) related to the bipolar spectrum?

BACKGROUND: Across all ages and cultures, mankind has always used substances in order to induce pleasurable sensations or desirable psychophysical states. These substances, notably caffeine, tobacco, alcohol and chocolate, can be labeled 'social drugs'. METHODS: We analyzed the social drug habits of 562 patients suffering from mood disorders, according to DSM-IV-R criteria (major depressive episode, recurrent depression, bipolar type I and II disorders and depression not otherwise specified). The sample was also divided into bipolar and non-bipolar according to Hypomania Check-list 32 (HCL-32), which proposes a broader concept of hypomania and soft bipolarity, comprising the spectrum of bipolar disorders proper, along with other, "softer" expressions of bipolarity intermediate between bipolar disorder and normality. RESULTS: Using HCL-32 criteria, but DSM-IV-R criteria, a link was confirmed between bipolar spectrum and substance use including social drugs such as tobacco and coffee. LIMITATION: Observational correlational study. CONCLUSION: This study is in support of earlier theoretical formulations within the framework of the Pisa-San Diego collaboration.

Prevalence and diagnostic distribution of medically unexplained painful somatic symptoms across 571 major depressed outpatients.

OBJECTIVE: To assess the prevalence and distribution of medically unexplained painful somatic symptoms (PSSs) versus nonpainful somatic symptoms (NPSSs) in patients diagnosed with major depressive episode (MDE). METHOD: A total of 571 outpatients diagnosed with MDE according to DSM-IV-TR criteria were consecutively enrolled into a cross-sectional, multicentric, observational study over a period of 7 months. Subjects were evaluated by means of the ad hoc validated 30-item Somatic Symptoms Checklist (SSCL-30) and Zung's questionnaires for depression and anxiety. The 32-item Hypomania Checklist (HCL-32) was also administered in order to explore any eventual association of PSSs or NPSSs with sub-threshold (DSM-IV-TR [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision] not recognized) bipolar disorder (BD). RESULTS: In our sample, just 183 patients (32%) did not report painful somatic symptoms (NPSSs). Of these, 90 patients (15.76%) had no somatic symptoms at all. The remaining 388 (68%) had at least one PSS being subdivided as follows: 248 (43%) had one or two PSSs, while 140 (25%) experienced two or more. Patients with at least one PSS also reported a greater number of nonpainful somatic symptoms than NPSS. Bipolar patients (associated with higher HCL-32 scores) were less represented across PSS cases than NPSS subjects. Conversely, females were more prone to having a higher number of total somatic symptoms (and bipolar features). CONCLUSION: PSSs are common in patients with MDE, especially among those patients reporting fewer somatic symptoms in general as opposed to those patients who exhibit more somatic symptoms (both PSSs and NPSSs) with lower relative number of PSSs. A major therapeutic implication is that antidepressant monotherapy could be used with more confidence in unexplained PSS patients than in NPSS patients because of the latter group's lower frequency of (sub)-threshold bipolar features.

Unexplained somatic symptoms during major depression: prevalence and clinical impact in a national sample of Italian psychiatric outpatients.

BACKGROUND: The aim of this study was to explore the prevalence and impact of unexplained somatic symptoms during major depression. SAMPLING AND METHODS: A total of 560 consecutive outpatients with a major depressive episode according to the DSM-IV (text revision) were evaluated in 30 psychiatric facilities throughout Italy. 'Unexplained' somatic symptoms were evaluated using the 30-item Somatic Symptoms Checklist (SSCL-30). Somatic symptoms were considered explained if they were best accounted for as coming from a concomitant physical illness or side effects. Patients evaluated their own mood symptomatology using the Zung questionnaires for depression and anxiety and the Hypomania Checklist-32. RESULTS: According to the SSCL-30, only 90 subjects (16.1%) had no unexplained somatic symptoms, while 231 (41.3%) had 1-5 unexplained symptoms and 239 (42.7%) had more than 5. Asthenia was the most commonly observed unexplained somatic symptom (53% of patients). Unexplained somatic symptoms were more common in females and among those suffering from major depression and depression not otherwise specified rather than in patients with recurrent major depression and bipolar disorders. No relationship between unexplained somatic symptoms and hypomanic features was observed. CONCLUSIONS: The presence of a large number of unexplained somatic symptoms is associated with more severe depression and higher rates of misdiagnosis and inappropriate treatment.

Pattern of acute induction of Homer1a gene is preserved after chronic treatment with first- and second-generation antipsychotics: effect of short-term drug discontinuation and comparison with Homer1a-interacting genes.

Homer1a is a glutamate-related gene whose expression is induced by antipsychotics acutely (i.e. 90 min after treatment). Acute Homer1a expression is preserved after prolonged antipsychotic treatments, while the effects of short-term discontinuation after chronic antipsychotic treatment have not yet been assessed. Here, we studied early and long-term effects on gene expression by antipsychotics for Homer1a and other components of glutamatergic synapses. In the first paradigm, we evaluated Homer1a acute expression by single administration of antipsychotics (haloperidol 0.8 mg/kg, ziprasidone 10 and 4 mg/kg, clozapine 15 mg/kg). Haloperidol and ziprasidone induced Homer1a in the striatum. Induction by ziprasidone was dose-dependent. These results suggest that acute Homer1a expression correlates with dopaminergic affinity and motor side effects of antipsychotics. In the second paradigm, we studied antipsychotic-mediated long-term changes in Homer1a and glutamate-related genes. Rats were treated (21 days) with haloperidol 0.8 mg/kg, ziprasidone 4 mg/kg, or vehicle, and then sacrificed at 90 min (early time-point) or 24 h (delayed time-point) after last injection. Gene expression at these two time-points was compared. Homer1a preserved its pattern of expression at the early but not at the delayed time-point. Significant changes were also observed for PSD-95. The results suggest that Homer1a preserves its expression profile after chronic antipsychotics.

Haloperidol induces higher Homer1a expression than risperidone, olanzapine and sulpiride in striatal sub-regions.

Homer1a and Yotiao are two post-synaptic density proteins at the crossroad of dopamine-glutamate neurotransmission. Homer1a has been implicated in the pathophysiology of schizophrenia and is differentially induced by typical and atypical antipsychotics, perhaps according to their dopaminergic profile. Yotiao has been involved in glutamate and dopamine post-synaptic signalling. Here, we seek to determine whether Homer1a and Yotiao might be implicated in post-synaptic response to antipsychotics with affinity to different dopamine D(2) receptors: haloperidol (0.8mg kg(-1)), risperidone (3mg kg(-1)), olanzapine (2.5mg kg(-1)) and (-)-sulpiride (50mg kg(-1)). Homer1a expression was significantly induced by haloperidol compared to vehicle and to atypical antipsychotics in almost all striatal sub-regions. Atypical antipsychotics induced the gene in the lateral putamen and in the core of the accumbens only. All antipsychotics, with the exclusion of sulpiride, elicited a dorsolateral-to-ventromedial distribution pattern of Homer1a expression. No significant induction was detected for Yotiao. These results suggest that the quantitative and topographical pattern of Homer1a expression may putatively be related to antipsychotics affinity and/or occupancy at dopamine D(2) receptors.

HOMER1 promoter analysis in Parkinson's disease: association study with psychotic symptoms.

AIMS: HOMER1 gene expression has been linked to abnormal movements in animals receiving chronic administration of antipsychotics. The continuing neurodegeneration of Parkinson's disease (PD) and the prolonged use of L-dopa are associated with motor complications, such as dyskinesia, and psychotic side effects, including hallucinations and paranoid delusions. Approximately 25-40% of patients with idiopathic PD experience hallucinations. Genetic variability within different candidate genes has been implicated in the clinical severity of sporadic PD in many populations. MATERIALS AND METHODS: We investigated 3 polymorphisms located in the 5' flanking region of the HOMER1 gene within a sample of 131 sporadic PD patients from southern Italy, using a 3-SNP genotype and haplotype combination (rs4704559, rs10942891, rs4704560). RESULTS: Our study implicates the effects of allele A of the rs4704559 marker in susceptibility to psychotic symptoms in PD (chi2 = 8.092, 1 d.f., p = 0.004). CONCLUSION: Even though our results are preliminary, this HOMER1 gene variant may represent a biomarker for side effect evaluation in PD patients.

Dopamine receptor subtypes contribution to Homer1a induction: insights into antipsychotic molecular action.

The inducible gene Homer1a has been considered a candidate gene for schizophrenia. Drugs efficacious in schizophrenia and acting as dopamine receptor antagonists induce Homer1a expression, although the specific role of the different dopamine receptors in its induction is not completely known. In this study, we explored Homer1a expression induced by selective antagonists at dopamine receptors (SCH-23390, D(1) receptor selective antagonist, 0.5 mg/kg; L-741,626, D(2) receptor selective antagonist, 2 mg/kg; U-99194, D(3) receptor selective antagonist, 5 mg/kg; L-745,870, D(4) receptor selective antagonist, 3 mg/kg), haloperidol (0.8 mg/kg), and terguride (0.5 mg/kg), a partial agonist at D(2) receptors. Moreover, we evaluated the expression of two Homer1a-related genes which play essential roles in synaptic plasticity: mGluR5 and Homer1b. Gene expression was analyzed in brain regions relevant for schizophrenia pathophysiology and therapy, namely the striatum, the cortex, and the hippocampus. In striatum, Homer1a was induced by D(2) receptor antagonists and, with a different distribution, by SCH-23390. In the cortex, Homer1a was differentially induced by D(1), D(2), and D(3) receptors antagonists, while haloperidol and terguride did not affect or reduced its expression. Homer1b expression was reduced by L-741,626, L-745,870, terguride, and haloperidol in the ventral caudate-putamen, in the nucleus accumbens and in the cortex, while SCH-23390 increased the expression in the core of the accumbens. mGluR5 expression was increased by SCH-23390 in the dorsomedial putamen, the core of the accumbens, and in some hippocampal subregions. A reduction of gene expression by terguride and an increase by L-745,870 was observed in the dorsomedial putamen. The changes in expression suggest that these gene transcripts are differentially regulated by antagonism at different dopamine receptors.

Association of antipsychotic induced weight gain and body mass index with GNB3 gene: a meta-analysis.

It has been reported that C825T variant in the gene encoding the G-protein subunit beta3 (GNB3) is associated with antipsychotic-induced weight gain and obesity. We investigated the association of the GNB3 and antipsychotic-induced weight gain as well as body mass index (BMI) using meta-analytical techniques. Our analysis of 402 schizophrenia subjects showed a trend (p=0.072) only under a fixed-model. As it was observed heterogeneity among the studies (p=0.007), we re-analyzed using a random-effects framework and no significance was found (p=0.339). No evidence for bias publication was reported (p=0.868). Our analysis of 18,903 subjects showed a trend (p=0.053) associating CC and lower BMI under a fixed model. Although no significant association was found, the same pattern (CC and lower antipsychotic-induced weight gain) was observed. Our meta-analysis indicates that firmly establishing the role of pharmacogenetics in clinical psychiatry requires much larger sample sizes that have been reported.

Differential expression of Homer 1 gene by acute and chronic administration of antipsychotics and dopamine transporter inhibitors in the rat forebrain.

Neuronal expression of immediate-early genes in response to a drug is a powerful screening tool for dissecting anatomical and functional brain circuitry affected by psychoactive compounds. We examined the effect of dopaminergic perturbation on two Homer 1 gene splice variants, Homer 1a and ania-3, in rat forebrain. Rats were treated with the "typical" antipsychotic haloperidol, the "atypical" quetiapine, or the selective dopamine transporter (DAT) inhibitor GBR 12909 in acute and chronic paradigms. Our results show that the high affinity dopamine D(2) receptor antagonist haloperidol strongly induces Homer 1 gene expression in the caudate-putamen, whereas quetiapine, a fast D2R dissociating antagonist, does not. This confirms that Homer 1 may be considered a predictor of "atypicality" of antipsychotic compounds in acute and also chronic regimens. Chronic treatment with GBR 12909 showed a strong induction in the parietal cortex, resembling the activation of "sensitization" circuitry by stimulants. Finally, we describe a differential spatial induction pattern of Homer 1 gene within the caudate-putamen by typical antipsychotics and DAT blockers, and propose a novel method to quantitate it.

Ketamine-related expression of glutamatergic postsynaptic density genes: possible implications in psychosis.

Systemic administration of ketamine, a non-competitive antagonist of the N-methyl-d-aspartate receptor (NMDA-R), produces a condition of NMDA-R hypofunction, which is considered one of the putative molecular mechanisms involved in psychosis. In this study, we evaluated the effect of ketamine on glutamatergic markers of the postsynaptic density (PSD), a pivotal site for dopamine-glutamate interaction. We assessed gene expression of Homer1a, alpha and betaCaMKII, and dopamine transporter (DAT) by two different doses of ketamine. These genes were chosen because of their impact on signal transduction and dopamine-glutamate interplay in postsynaptic density. Moreover, Homer1a is modulated by antipsychotics and represents a candidate gene for schizophrenia. Male Sprague-Dawley rats were injected with saline, 12mg/kg ketamine or 50mg/kg ketamine, and sacrificed 90 minutes after injections. In situ hybridization histochemistry was used to quantitate the rate of gene expression in rat forebrain. Homer1a was induced by 50mg/kg ketamine in ventral striatum and by both 50 and 12mg/kg ketamine in nucleus accumbens, whereas gene expression was not affected in dorsal striatum. alphaCaMKII was increased by 12mg/kg ketamine against saline in almost all subregions assessed. betaCaMKII was not affected by ketamine. DAT was increased by both doses of ketamine in the ventro-tegmental area and substantia nigra pars compacta. We suggest that these changes may represent molecular adaptations to the perturbation in glutamatergic transmission induced by ketamine blockade of NMDA receptors and may be implicated in molecular alterations occurring in schizophrenia.

Increased dopaminergic activity in restricting-type anorexia nervosa.

Eye blink rate, a peripheral measure of central dopaminergic activity, has been investigated in 20 female anorexic "restricting-type" patients and 16 healthy female subjects. A significantly increased blink rate was found in the anorexic patients. A significant positive correlation between blink rate and duration of illness was also found.

Method for quantitative in situ hybridization histochemistry and image analysis applied for Homer1a gene expression in rat brain.

Here we describe the detailed method for quantitative in situ hybridization histochemistry adopted in our previously published short communication on differential gene expression of the postsynaptic density proteins Homer and PSD-95 in rat forebrain after acute treatment with antipsychotic drugs [de Bartolomeis et al., Mol. Brain Res. 98 (2002) 124-129]. Specific 35S radiolabeled oligodeoxyribonucleotides were used to hybridize rat forebrain sections and data analysis was carried out on digitalized images acquired by means of a CCD camera. Special emphasis has been posed on data preprocessing options applied to a dataset obtained using a transparency scanner as an alternative image capturing method.

Homer 1a gene expression modulation by antipsychotic drugs: involvement of the glutamate metabotropic system and effects of D-cycloserine.

N-methyl-D-aspartate receptor hypofunction has been suggested to play a role in the pathophysiology of schizophrenia. New glutamatergic mechanisms involving metabotropic receptors have been recently proposed to further expand this hypothesis. "Homer" is a family of postsynaptic density proteins functionally and physically attached to glutamate metabotropic receptors. We investigated the activation of the early gene form of Homer after acute treatment with typical or atypical antipsychotic drugs alone or with the adjunction of D-cycloserine. This activation was compared with that of c-fos, considered a putative molecular marker of brain regions activated by antipsychotics. Male Sprague-Dawley rats were treated intraperitoneally with haloperidol (0.8 mg/Kg) or clozapine (15 mg/Kg) alone or with the adjunction of D-cycloserine (20 mg/Kg). Rats were sacrificed ninety minutes after injection and the brains were processed for quantitative in situ hybridization histochemistry. Haloperidol induced a statistically significant increase of Homer both in caudate-putamen and nucleus accumbens compared with controls; clozapine induced Homer significantly only in the accumbens. The adjunction of D-cycloserine attenuated the haloperidol-induced increase of Homer expression in caudate-putamen and nucleus accumbens and attenuated the clozapine-induced increase in the accumbens. The c-fos gene expression was potently induced by haloperidol in caudate-putamen and nucleus accumbens, and by clozapine only in the accumbens. The adjunction of D-cycloserine enhanced c-fos expression only for clozapine in both regions of the forebrain. These results demonstrate a differential involvement of glutamatergic metabotropic system in gene expression modulation induced by typical or atypical antipsychotic drugs and may suggest new molecular basis for the augmentation strategy by a glycine site partial agonist.

Acute administration of antipsychotics modulates Homer striatal gene expression differentially.

Typical and atypical antipsychotics, the mainstay of schizophrenia pharmacotherapy, have been demonstrated to affect differently neuronal gene expression in several preclinical paradigms. Here we report the differential gene expression of the glutamatergic post-synaptic density proteins Homer and PSD-95 in rat forebrain following acute haloperidol or olanzapine treatment. Moreover, considering the extensive interactions between dopaminergic and opioidergic systems we also measured striatal preproenkephalin mRNA. Male Sprague-Dawley rats were treated with haloperidol 1 mg/kg or olanzapine 0.5 mg/kg or vehicle, i.p. and sacrificed 3 h after the injection. Homer gene expression was significantly increased in caudate putamen and nucleus accumbens of rats treated with haloperidol and in the core of accumbens of rats treated with olanzapine. No changes were detected for Homer in prefrontal and parietal cortex in any of the experimental groups. PSD-95 gene expression was not modulated in our paradigm by administration of either typical or atypical antipsychotics. These results (1) suggest a differential modulation of Homer by typical and atypical antipsychotics; (2) confirm that Homer can be induced as an early gene with putative direct effect on neuronal plasticity and (3) demonstrate different response to antipsychotics by different classes of postsynaptic density proteins at glutamatergic synapses.

Paroxetine versus amitriptyline in patients with recurrent major depression: A double-blind trial.

INTRODUCTION: Long-term exposure to antidepressants is required to prevent relapses and recurrences in patients with recurrent major depression. Furthermore, a good pharmacological compliance is the key to successful long-term treatment. Since the early phases of a treatment influence long-term compliance and compliance is adversely affected by poorly tolerated treatments, efficacy and tolerability of paroxetine and amitryptiline over 12 weeks were compared as an introduction to the issue of long-term compliance to these two agents. METHOD: A 12-week, randomized, double-blind, doubledummy, parallel-group trial which involved 129 patients with recurrent major depression. RESULTS: Both paroxetine and amitriptyline were effective in controlling the symptoms of depression, as shown by the reduction in HAMD total score and CGI severity-of-illness score at endpoint compared to baseline. There was no statistically or clinically significant difference between the two treatments in terms of efficacy. However, marked numerical differences were noted in tolerability: the percentage of patients who reported treatment-emergent adverse experiences was greater in the amitriptyline group (40.0% vs 28.1%). This difference was mainly due to anticholinergic adverse events, which were six times more frequent with amitriptyline than with paroxetine. CONCLUSION: When compared with amitriptyline, paroxetine should allow patients with recurrent major depression to receive an equally effective treatment with a relatively lower incidence of adverse experiences.