Insomnia and related mental health conditions: Essential neurobiological underpinnings towards reduced polypharmacy utilization rates.

Insomnia represents a significant public health burden, with a 10% prevalence in the general population. Reduced sleep affects social and working functioning, productivity, and patient's quality of life, leading to a total of $100 billion per year in direct and indirect healthcare costs. Primary insomnia is unrelated to any other mental or medical illness; secondary insomnia co-occurs with other underlying medical, iatrogenic, or mental conditions. Epidemiological studies found a 40-50% comorbidity prevalence between insomnia and psychiatric disorders, suggesting a high relevance of mental health in insomniacs. Sleep disturbances also worsen the outcomes of several psychiatric disorders, leading to more severe psychopathology and incomplete remission, plausibly contributing to treatment-resistant conditions. Insomnia and psychiatric disorder coexistence can lead to polypharmacy, namely, the concurrent use of two or more medications in the same patient, regardless of their purpose or rationale. Polypharmacy increases the risk of using unnecessary drugs, the likelihood of drug interactions and adverse events, and reduces the patient's compliance due to regimen complexity. The workup of insomnia must consider the patient's sleep habits and inquire about any medical and mental concurrent conditions that must be handled to allow insomnia to be remitted adequately. Monotherapy or limited polypharmacy should be preferred, especially in case of multiple comorbidities, promoting multipurpose molecules with sedative properties and with bedtime administration. Also, non-pharmacological interventions for insomnia, such as sleep hygiene, relaxation training and Cognitive Behavioral Therapy may be useful in secondary insomnia to confront behaviors and thoughts contributing to insomnia and help optimizing the pharmacotherapy. However, insomnia therapy should always be patient-tailored, considering drug indications, contraindications, and pharmacokinetics, besides insomnia phenotype, clinical picture, patient preferences, and side effect profile.

Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations.

Selegiline is an irreversible, selective type-B monoamine oxidase inhibitor (MAOI) approved for Parkison's disease-oral and major depressive disorder-transdermal formulation) resulting in non-selective MAOI activity at oral doses≥20 mg/day. The present systematic review and meta-analysis appraises the evidence of different formulations/dosages of selegiline across different psychiatric conditions. We inquired PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience and the Chinese-Electronic-Journal Database from inception to 10/26/2022 for selegiline trials involving psychiatric patients. Random-effects meta-analyses assessed heterogeneity, publication/risk biases, and confidence in the evidence, followed by sensitivity, subgroup, and meta-regression analyses. Co-primary outcomes were: changes in symptom score (standardized mean difference=SMD) and author-defined response (risk ratios=RRs). RRs of adverse events and all-cause discontinuation were secondary and acceptability outcomes, respectively. Systematic-review included 42 studies; meta-analysis, 23. Selegiline outperformed placebo in depressive symptom reduction (SMD=-0.96, 95%C.I.=-1.78, -0.14, k = 10, n = 1,308), depression (RR=1.61, 95%C.I.=1.20, 2.15, k = 9, n = 1,238) and atypical-depression response (RR=2.23, 95%C.I.=1.35, 3.68, k = 3, n = 136). Selegiline failed to outperform the placebo in negative (k = 4) or positive symptoms of schizophrenia (k = 4), attention-deficit-hyperactivity disorder (ADHD) symptoms reduction (k = 2), and smoking abstinence rate (k = 4). Selegiline did not differ from methylphenidate and ADHD scores (k = 2). No significant difference emerged in acceptability, incident diarrhea, headache, dizziness, and nausea RRs, in contrast to xerostomia (RR=1.58, 95%C.I. =1.03, 2.43, k = 6, n = 1,134), insomnia (RR=1.61, 95%C.I.=1.19, 2.17, k = 10, n = 1,768), and application-site reaction for transdermal formulation (RR=1.81, 95%C.I.=1.40, 2.33, k = 6, n = 1,662). Confidence in findings was low/very-low for most outcomes; moderate for depressive symptoms reduction (transdermal). Selegiline proved effective, safe, and well-tolerated for depressive disorders, yet further evidence is warranted about specific psychiatric disorders.

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics.

Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical-subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30-40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics' effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules.

The prevalence, odds, predictors, and management of tobacco use disorder or nicotine dependence among people with severe mental illness: Systematic review and meta-analysis.

The prevalence, correlates, and management of tobacco use disorder (TUD) or nicotine dependence (ND) among people with severe mental illness (SMI), namely schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), remain unclear. Therefore, a systematic review and meta-analysis was conducted. Electronic databases were systematically searched from inception to July 12, 2020, for observational studies documenting the prevalence, odds, and correlates of TUD/ND among people with SMI; randomized controlled trials (RCTs) informing the management of TUD/ND in people with SMI were also included. Random-effects meta-analyses were conducted. Sources of heterogeneity were explored. Nineteen observational studies, including 7527 participants with SMI met inclusion criteria. TUD/ND co-occurred in 33.4-65% of people with SMI. Rates were higher among males. While bupropion and varenicline represent promising treatment opportunities for schizophrenia with TUD/ND, non-pharmacological interventions require further research, mainly for people with primary mood disorders. TUD/ND represent prevalent co-occurring conditions among people with SMI. Further well-designed RCTs are warranted to inform their management.

Prominent autistic traits and subthreshold bipolar/mixed features of depression in severe anorexia nervosa

Objective: Autistic traits are associated with a burdensome clinical presentation of anorexia nervosa (AN), as is AN with concurrent depression. The aim of the present study was to explore the intertwined association between complex psychopathology combining autistic traits, subthreshold bipolarity, and mixed depression among people with AN. Method: Sixty patients with AN and concurrent major depressive episode (mean age, 22.2±7 years) were cross-sectionally assessed using the Autism-Spectrum Quotient test (AQ-test), the Hamilton depression scales for depression and anxiety, the Young Mania Rating Scale (YMRS), the Hypomania-Checklist-32 (HCL-32), second revision (for subthreshold bipolarity), the Brown Assessment and Beliefs Scale (BABS), the Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS), and the Eating Disorder Examination Questionnaire (EDE-Q). Cases were split into two groups depending on body mass index (BMI): severe AN (AN+) if BMI < 16, not severe (AN-) if BMI ≥ 16. Results: The "subthreshold bipolarity with prominent autistic traits" pattern correctly classified 83.6% of AN patients (AN+ = 78.1%; AN- = 91.3%, Exp(B) = 1.391). AN+ cases showed higher rates of positive scores for YMRS items 2 (increased motor activity-energy) and 5 (irritability) compared to AN- cases. Conclusions: In our sample, depressed patients with severe AN had more pronounced autistic traits and subtly mixed bipolarity. Further studies with larger samples and prospective follow-up of treatment outcomes are warranted to replicate these findings.

Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia. METHODS: We undertook a systematic review, searching PubMed/Scopus/Clinicaltrials.gov for double-blind, randomized, placebo-controlled studies of psychostimulants or atomoxetine in schizophrenia published up to 1 January 2017. A meta-analysis of outcomes reported in two or more studies is presented. RESULTS: We included 22 studies investigating therapeutic effects of stimulants (k=14) or measuring symptomatic worsening/relapse prediction after stimulant challenge (k=6). Six studies of these two groups plus one additional study investigated biological effects of psychostimulants or atomoxetine. No effect resulted from interventional studies on weight loss (k=1), smoking cessation (k=1), and positive symptoms (k=12), and no improvement was reported with atomoxetine (k=3) for negative symptoms, with equivocal findings for negative (k=6) and mood symptoms (k=2) with amphetamines. Attention, processing speed, working memory, problem solving, and executive functions, among others, showed from no to some improvement with atomoxetine (k=3) or amphetamines (k=6). Meta-analysis did not confirm any effect of stimulants in any symptom domain, including negative symptoms, apart from atomoxetine improving problem solving (k=2, standardized mean difference (SMD)=0.73, 95% CI=0.10-1.36, p=0.02, I2=0%), and trending toward significant improvement in executive functions with amphetamines (k=2, SMD=0.80, 95% CI=-1.68 to +0.08, p=0.08, I2=66%). In challenge studies, amphetamines (k=1) did not worsen symptoms, and methylphenidate (k=5) consistently worsened or predicted relapse. Biological effects of atomoxetine (k=1) and amphetamines (k=1) were cortical activation, without change in ß-endorphin (k=1), improved response to antipsychotics after amphetamine challenge (k=2), and an increase of growth hormone-mediated psychosis with methylphenidate (k=2). No major side effects were reported (k=6). CONCLUSIONS: No efficacy for stimulants or atomoxetine on negative symptoms is proven. Atomoxetine or amphetamines may improve cognitive symptoms, while methylphenidate should be avoided in patients with schizophrenia. Insufficient evidence is available to draw firm conclusions.

Aripiprazole-induced atrial fibrillation in a patient with concomitant risk factors.

Aripiprazole is an atypical antipsychotic drug with a polypharmacological mechanism of action and a favorable tolerability profile. Its major indications are schizophrenia and mania in adults and adolescents. Here we present the case of a 43-year-old Caucasian man with schizophrenia who developed atrial fibrillation (AF) after starting aripiprazole treatment. Prior to this treatment, he had never received any antipsychotic drugs. On admission to our inpatient unit, he showed severe psychotic symptoms and was started on aripiprazole with a rapid titration regimen (15 mg on the first day and then 15 mg twice daily thereafter) in combination with lorazepam (2.5 mg thrice a day). On the third day, the patient exhibited vomiting and an irregular pulse. An electrocardiogram (ECG) revealed new-onset AF with rapid ventricular response. Aripiprazole was discontinued and cardioversion was obtained with intravenous amiodarone. A different antipsychotic treatment was thus started (perphenazine 12 mg/d), which led to symptom remission without any relevant adverse effects. During the 2-year follow-up observation, neither psychotic symptoms nor ECG abnormalities were detected. Besides aripiprazole, other co-occurring factors might have contributed to the onset of AF in our patient, namely hypertension, low-grade diastolic dysfunction, chronic inflammatory disease, CYP2D6 polymorphism, corticosteroid and antiulcer treatment, and a family loading for myocardial infarction. In conclusion, our case study suggests that although aripiprazole has fewer cardiovascular effects than other antipsychotic drugs, in the presence of concomitant risk factors, high dose, and rapid titration regimen, regular monitoring of clinical parameters and ECG is highly recommended. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Nicotine and caffeine modulate haloperidol-induced changes in postsynaptic density transcripts expression: Translational insights in psychosis therapy and treatment resistance.

Caffeine and nicotine are widely used by schizophrenia patients and may worsen psychosis and affect antipsychotic therapies. However, they have also been accounted as augmentation strategies in treatment-resistant schizophrenia. Despite both substances are known to modulate dopamine and glutamate transmission, little is known about the molecular changes induced by these compounds in association to antipsychotics, mostly at the level of the postsynaptic density (PSD), a site of dopamine-glutamate interplay. Here we investigated whether caffeine and nicotine, alone or combined with haloperidol, elicited significant changes in the levels of both transcripts and proteins of the PSD members Homer1 and Arc, which have been implicated in synaptic plasticity, schizophrenia pathophysiology, and antipsychotics molecular action. Homer1a mRNA expression was significantly reduced by caffeine and nicotine, alone or combined with haloperidol, compared to haloperidol. Haloperidol induced significantly higher Arc mRNA levels than both caffeine and caffeine plus haloperidol in the striatum. Arc mRNA expression was significantly higher by nicotine plus haloperidol vs. haloperidol in the cortex, while in striatum gene expression by nicotine was significantly lower than that by both haloperidol and nicotine plus haloperidol. Both Homer1a and Arc protein levels were significantly increased by caffeine, nicotine, and nicotine plus haloperidol. Homer1b mRNA expression was significantly increased by nicotine and nicotine plus haloperidol, while protein levels were unaffected. Locomotor activity was not significantly affected by caffeine, while it was reduced by nicotine. These data indicate that both caffeine and nicotine trigger relevant molecular changes in PSD sites when given in association with haloperidol.

Effect of agomelatine treatment on C-reactive protein levels in patients with major depressive disorder: an exploratory study in "real-world," everyday clinical practice.

OBJECTIVE: Agomelatine is a newer antidepressant but, to date, no studies have been carried out investigating its effects on C-reactive protein (CRP) levels in major depressive disorder (MDD) before and after treatment. The present study aimed (i) to investigate the effects of agomelatine treatment on CRP levels in a sample of patients with MDD and (ii) to investigate if CRP variations were correlated with clinical improvement in such patients. METHODS: 30 adult outpatients (12 males, 18 females) with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of MDD were recruited in "real-world," everyday clinical practice and treated with a flexible dose of agomelatine for 12 weeks. The Hamilton Rating Scale for Depression (HAM-D) and the Snaith-Hamilton Pleasure Scale (SHAPS) were used to evaluate depressive symptoms and anhedonia, respectively. Moreover, serum CRP was measured at baseline and after 12 weeks of treatment. RESULTS: Agomelatine was effective in the treatment of MDD, with a significant reduction in HAM-D and SHAPS scores from baseline to endpoint. CRP levels were reduced in the whole sample, with remitters showing a significant difference in CRP levels after 12 weeks of agomelatine. A multivariate stepwise linear regression analysis showed that higher CRP level variation was associated with higher baseline HAM-D scores, controlling for age, gender, smoking, BMI, and agomelatine dose. CONCLUSIONS: Agomelatine's antidepressant properties were associated with a reduction in circulating CRP levels in MDD patients who achieved remission after 12 weeks of treatment. Moreover, more prominent CRP level variation was associated with more severe depressive symptoms at baseline.

D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice.

D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. D-Asp also restored the levels of extracellular D-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike D-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that D-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice.

A comprehensive review on the efficacy of S-Adenosyl-L-methionine in Major Depressive Disorder.

OBJECTIVE: To review the antidepressant efficacy of S-Adenosyl-L-Methionine (SAMe) both in monotherapy and/or in augmentation with antidepressants to better understand its potential role in the treatment of patients with Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD). DATA SOURCES: A MEDLINE/PubMed search was carried out by using the following set of keywords: ((SAMe OR SAdenosyl- L-Methionine) AND (major depressive disorder OR depression)). Data Selection and Data Extraction: No language or time restrictions were placed on the electronic searches. Randomized controlled trials and open trials involving humans were here included and analyzed. The references of published articles identified in the initial search process were also examined for any additional studies appropriate for the review. DATA SYNTHESIS: SAMe is an important physiologic compound, playing a central role as precursor molecule in several biochemical reactions. Numerous studies have shown that SAMe may affect the regulation of various critical components of monoaminergic neurotransmission involved in the pathophysiology of MDD. Some findings have suggested its antidepressant efficacy in treating MDD. Several randomized controlled trials have supported that the antidepressant efficacy of SAMe in monotherapy is superior to placebo and tricyclic antidepressants. Recent findings have also demonstrated its efficacy in patients nonresponsive to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. CONCLUSION: Overall, SAMe is a well-tolerated medication, which may offer considerable advantages as an alternative to antidepressant drugs or as an add-on therapy in the treatment of MDD and TRD. More large-scale controlled trials are needed to gain a better understanding of the relative efficacy of this drug.

Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a.

Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several non-pharmacological treatments of depression upregulate adenosine concentration and/or adenosine A1 receptors (A1R) in the brain. To test whether enhanced A1R signaling mediates antidepressant effects, we generated a transgenic mouse with enhanced doxycycline-regulated A1R expression, specifically in forebrain neurons. Upregulating A1R led to pronounced acute and chronic resilience toward depressive-like behavior in various tests. Conversely, A1R knockout mice displayed an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation (SD). Various antidepressant treatments increase homer1a expression in medial prefrontal cortex (mPFC). Specific siRNA knockdown of homer1a in mPFC enhanced depressive-like behavior and prevented the antidepressant effects of A1R upregulation, SD, imipramine, and ketamine treatment. In contrast, viral overexpression of homer1a in the mPFC had antidepressant effects. Thus, increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments.

Progressive recruitment of cortical and striatal regions by inducible postsynaptic density transcripts after increasing doses of antipsychotics with different receptor profiles: insights for psychosis treatment.

Antipsychotics may modulate the transcription of multiple gene programs, including those belonging to postsynaptic density (PSD) network, within cortical and subcortical brain regions. Understanding which brain region is activated progressively by increasing doses of antipsychotics and how their different receptor profiles may impact such an activation could be relevant to better correlate the mechanism of action of antipsychotics both with their efficacy and side effects. We analyzed the differential topography of PSD transcripts by incremental doses of two antipsychotics: haloperidol, the prototypical first generation antipsychotic with prevalent dopamine D2 receptors antagonism, and asenapine, a second generation antipsychotic characterized by multiple receptors occupancy. We investigated the expression of PSD genes involved in synaptic plasticity and previously demonstrated to be modulated by antipsychotics: Homer1a, and its related interacting constitutive genes Homer1b/c and PSD95, as well as Arc, C-fos and Zif-268, also known to be induced by antipsychotics administration. We found that increasing acute doses of haloperidol induced immediate-early genes (IEGs) expression in different striatal areas, which were progressively recruited by incremental doses with a dorsal-to-ventral gradient of expression. Conversely, increasing acute asenapine doses progressively de-recruited IEGs expression in cortical areas and increased striatal genes signal intensity. These effects were mirrored by a progressive reduction in locomotor animal activity by haloperidol, and an opposite increase by asenapine. Thus, we demonstrated for the first time that antipsychotics may progressively recruit PSD-related IEGs expression in cortical and subcortical areas when administered at incremental doses and these effects may reflect a fine-tuned dose-dependent modulation of the PSD.

Agomelatine beyond borders: current evidences of its efficacy in disorders other than major depression.

Agomelatine, a melatonergic antidepressant with a rapid onset of action, is one of the most recent drugs in the antidepressant category. Agomelatine's antidepressant actions are attributed to its sleep-promoting and chronobiotic actions mediated by MT1 and MT2 receptors present in the suprachiasmatic nucleus, as well as to its effects on the blockade of 5-HT2c receptors. Blockade of 5-HT2c receptors causes release of both noradrenaline and dopamine at the fronto-cortical dopaminergic and noradrenergic pathways. The combined actions of agomelatine on MT1/MT2 and 5-HT2c receptors facilitate the resynchronization of altered circadian rhythms and abnormal sleep patterns. Agomelatine appeared to be effective in treating major depression. Moreover, evidence exists that points out a possible efficacy of such drug in the treatment of bipolar depression, anxiety disorders, alcohol dependence, migraines etc. Thus, the aim of this narrative review was to elucidate current evidences on the role of agomelatine in disorders other than major depression.

Dandy-Walker syndrome with psychotic symptoms: a case report.

Here we report the case of a patient with psychotic symptoms apparently resistant to antipsychotic treatments. Since the last admission in a psychiatric division the patient was diagnosed with Bipolar Disorder type I and then referred to our Outpatients Unit of Treatment Resistant Psychosis, where she was subsequently re-diagnosed with Dandy-Walker Syndrome. The Dandy Walker Complex is a congenital brain malformation involving the fourth ventricle and the cerebellum. We investigated the cognitive impairment of the patient and found deficits prominently in executive functions. This report may add further evidence on the importance of a correct diagnosis prior to defining a patient as treatment resistant and highlights cerebellar dysfunctions that may contribute to neuropsychiatric symptoms and cognitive impairment.

Efficacy and clinical determinants of antipsychotic polypharmacy in psychotic patients experiencing an acute relapse and admitted to hospital stay: results from a cross-sectional and a subsequent longitudinal pilot study.

Background. Antipsychotic polypharmacy is used in several psychiatric disorders, despite poor evidence existing to support this practice. Aim. We evaluated whether psychotic patients in acute relapse exposed to antipsychotic polypharmacy (AP + AP) showed different demographic, clinical, or psychopathological features compared to those exposed to one antipsychotic (AP) and whether AP + AP patients showed significantly higher improvement compared to AP patients after a 4-week treatment. Methods. Inpatients were subdivided into AP + AP and AP ones. In the cross-sectional step, patients were compared according to demographics, clinical variables, and scores on rating scales. In the longitudinal step, patients remained for 4 weeks under admission medications and were compared for clinical improvement. Results. AP + AP patients were more frequently diagnosed with schizophrenia and mental retardation as a comorbid illness. AP + AP patients were more frequently under first-generation antipsychotics and had worse clinical presentation. After 4 weeks of treatment, both AP + AP and AP patients improved compared to the baseline. However, AP patients scored significantly less than AP + AP patients at the Clinical Global Impression Scale at the 4-week time point but not at the baseline, indicating a treatment-specific improvement. Conclusions. Antipsychotic polypharmacy may be offered to specific types of psychotic patients. However, efficacy of this strategy is limited at best.

Tobacco smoking in treatment-resistant schizophrenia patients is associated with impaired cognitive functioning, more severe negative symptoms, and poorer social adjustment.

Tobacco smoking is common in schizophrenia patients. It has been reported that schizophrenia patients who are tobacco smokers have better cognitive performances compared to those who are nonsmokers. However, little is known on the effects of tobacco smoking in treatment-resistant schizophrenia (TRS) patients. The aim of this study was to compare cognitive performances, psychotic symptoms, and social adjustment in tobacco smoker TRS patients compared to nonsmoker TRS patients. Smoker and nonsmoker TRS patients did not differ in demographics and in mean daily antipsychotic dose. Smoker TRS patients had significantly higher scores than nonsmoker patients on the positive and negative syndrome scale (PANSS) and on the negative symptoms subscale. These patients also performed worse than nonsmoker patients on problem-solving cognitive domain. Social adjustment was not significantly different between the two groups. In both groups of patients, worse cognitive performances were mostly predicted by higher severity of negative symptoms. Worse performances on the verbal memory and problem-solving cognitive domains were correlated with social-functioning impairment in tobacco smoker TRS patients but not in nonsmoker ones. The results showed that tobacco smoking was not significantly associated with better cognitive performances in TRS patients, while it was significantly associated with higher negative symptoms. Even if a direct causative mechanism cannot be inferred and despite the fact that these patients may use tobacco to self-medicate, it could be speculated that these associations may, at least partially, be related to a tobacco-smoking-induced worsening of abnormal dopamine dysfunction, which has been suggested to occur in TRS patients.

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.

Selective regulation of presynaptic calcium/calmodulin-dependent protein kinase II by psychotropic drugs.

BACKGROUND: Changes in neuroplasticity have been involved in the pathogenesis of psychiatric disorders as well as in psychotropic drug action. Calcium/calmodulin-dependent protein kinase II (CaM kinase II), an enzyme with a pivotal role in synaptic plasticity and cognitive functions, has been implicated in the action of anticonvulsants, benzodiazepines, and antidepressants, but little is known as to its role in the action of different drugs employed for treatment of psychiatric disorders. METHODS: We studied the function and expression of CaM kinase II following chronic treatment of rats with two antidepressants, fluvoxamine and desipramine, a typical antipsychotic drug, haloperidol, and the typical medication for manic-depressive disorder, lithium. RESULTS: Antidepressants significantly increased the kinase activity in presynaptic vesicles of frontal/prefrontal cortex. Haloperidol induced no change, whereas lithium significantly decreased the activity. Kinase activation by antidepressants was further demonstrated by increased phosphorylation of exogenously added recombinant synaptotagmin. Immunoreactivity of vesicular kinase (alpha-isoform) was significantly increased by reuptake blockers but not by the two other drugs. Kinetic analysis showed that limiting value of enzymatic velocity (Vmax) of the kinase for substrate was also increased by reuptake blockers and decreased by lithium; however, neither messenger ribonucleic acid nor protein expression level of the kinase was increased in frontal/prefrontal cortex homogenates of antidepressant-treated rats, suggesting the involvement of local synaptic mechanisms. CONCLUSIONS: These findings show that functional regulation of presynaptic CaM kinase II is selectively affected by different psychotropic drugs, and suggest local synaptic mechanisms for pharmacological regulation of the kinase.