The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients with schizophrenia.

Bipolar disorders are prevalent, disabling, and costly diseases that often pursue an inexorable course. Underdetection, misdiagnosis, and diagnostic delay frequently and unnecessarily interfere with appropriate treatment of the disorder. Mortality studies in bipolar disorder underscore the relevance of both unnatural and natural causes of death, inviting the need for improved preventative and primary health care for bipolar patients. The treatment framework for bipolar disorder must recognize and anticipate the multidirnensionality and comorbidity of this illness. Pharmacotherapy is necessary, with multiple concomitant medications required for most patients, In addition, adjunctive psychosocial interventions offer enhanced compliance and may beneficially influence psychopathological and functional outcomes. This article emphasizes the public health concern of bipolr disorder, and provides tactics to enhance detection of cryptic bipolar states, underscore the clinical and pathophysiological relevance of comorbidity in bipolar disorder, and provide a framework for multimodality therapy for this condition.

It has long been considered that psychosocial stress plays a role in the expression of symptoms in schizophrenia (SZ), as it interacts with latent neural vulnerability that stems from genetic liability and early environmental insult. Advances in the understanding of the neurobiology of the stress cascade in both animal and human studies lead to a plausible model by which this interaction may occur: through neurotoxic effects on the hippocampus that may involve synaptic remodeling. Of late, the neurodevelopmental model of SZ etiology has been favored. But an elaboration of this schema that credits the impact of postnatal events and considers a role for neurodegenerative changes may be more plausible, given the evidence for gene-environment interaction in SZ expression and progressive structural changes observed with magnetic resonance imaging. Furthermore, new insights into nongliotic neurotoxic effects such as apoptosis, failure of neurogenesis, and changes in circuitry lead to an expansion of the time frame in which environmental effects may mediate expression of SZ symptoms.

The etiopathogenesis and treatment of major mood disorders have historically focused on modulation of monoaminergic (serotonin, norepinephrine, dopamine) and amino acid [γ-aminobutyric acid (GABA), glutamate] receptors at the plasma membrane. Although the activation and inhibition of these receptors acutely alter local neurotransmitter levels, their neuropsychiatric effects are not immediately observed. This time lag implicates intracellular neuroplasticity as primary in the mechanism of action of antidepressants and mood stabilizers. The modulation of intracellular second messenger/signal transduction cascades affects neurotrophic pathways that are both necessary and sufficient for monoaminergic and amino acid–based treatments. In this review, we will discuss the evidence in support of intracellular mediators in the pathophysiology and treatment of preclinical models of despair and major depressive disorder (MDD). More specifically, we will focus on the following pathways: cAMP/PKA/CREB, neurotrophin-mediated (MAPK and others), p11, Wnt/Fz/Dvl/GSK3β, and NFκB/ΔFosB. We will also discuss recent discoveries with rapidly acting antidepressants, which activate the mammalian target of rapamycin (mTOR) and release of inhibition on local translation via elongation factor stimulation. Throughout this discourse, we will highlight potential intracellular targets for therapeutic intervention. Finally, future clinical implications are discussed.

The risks of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage are not increased in the 9 months of gestation except for a high risk in the 2 days prior and 1 day postpartum. The remaining 6 weeks postpartum also have an increased risk of ischemic stroke and intracerebral hemorrhage, though less than the peripartum period. Although there are some rare causes of stroke specific to pregnancy and the postpartum period, eclampsia, cardiomyopathy, postpartum cerebral venous thrombosis, and, possibly, paradoxical embolism warrant special consideration. The diagnostic and therapeutic approaches to stroke during pregnancy and the postpartum period are similar to the approaches in the nonpregnant woman with some minor modifications based on consideration of the welfare of the fetus. There is a theoretical risk of magnetic resonance imaging exposure during the first and second trimester but the benefit to the mother of obtaining the information may outweigh the risk. Available evidence suggests that low-dose aspirin (<150 mg/day) during the second and third trimesters is safe for both mother and fetus. Postpartum use of low-dose aspirin by breast-feeding mother is also safe for infant. While proper counseling is imperative, a history of pregnancy-related stroke should not be a contraindication for subsequent pregnancy.

All three serotonin norepinephrine reuptake inhibitors (SNRIs) inhibit the reuptake of both serotonin and norepinephrine but they do so with differing affinity ratios. Venlafaxine has a 30-fold higher affinity for serotonin than for norepinephrine while duloxetine has a 10-fold selectivity for serotonin. Milnacipran has a balanced (1:1) ratio of potency for inhibition of reuptake of the two neurotransmitters. The most frequent adverse event with SNRIs is nausea. Not unexpectedly, adverse effects related to a noradrenergic stimulation, such as dry mouth, sweating, and constipation, are found more frequently with SNRIs than with selective serotonin reuptake inhibitors. At true SNRI doses, venlafaxine is associated with dose-dependent cardiovascular phenomena (principally increased blood pressure), an effect which is less frequent with duloxetine and rare with milnacipran. Serious and potentially fatal hepatotoxity has been reported with duloxetine. This problem appears to be unique to duloxetine and not a characteristic of the SNRI class. There are differences in overdose toxicity between venlafaxine and the other SNRIs, possibly related to its increased cardiotoxicity.

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy treatments for obsessive-compulsive disorder (OCD). Clomipramine is effective in OCD but associated with more adverse events. Typically, higher doses of antidepressants are required for OCD. Up to 50% of patients do not respond to initial treatment of OCD. Treatment options for nonresponders include augmentation of antidepressants with atypical antipsychotics, among other strategies. First-line treatments for anxiety disorders include SSRIs, serotonin norepinephrine reuptake inhibitors, and pregabalin. Tricyclic antidepressants are equally effective as SSRIs, but are less well tolerated. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of dependency and tolerance. Other treatment options include irreversible and reversible monoamine oxidase inhibitors, the atypical antipsychotic quetiapine, and other medications. Cognitive-behavioral therapy has been sufficiently investigated in controlled studies of OCD and anxiety disorders and is recommended alone or in combination with the above medications.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial was an effectiveness/”pragmatic” clinical trial designed to compare the efficacy, tolerability, and cost-effectiveness of four atypical antipsychotics (olanzapine, quetiapine, risperidone and ziprasidone) and a conventional antipsychotic (perphenazine) for an 18-month period in patients with schizophrenia. The study randomized 1,460 patients with fewer exclusion criteria than in most trials in hopes that this would allow for a more representative sample of outpatients in “real world” practice. Olanzapine demonstrated significant superiority in time to discontinuation for all cause and for lack of efficacy, as well as likelihood of hospitalization for relapse; however, it was associated with a significantly higher rate of metabolic side effects. Perphenazine exhibited comparable effectiveness with quetiapine, risperidone, and ziprasidone, and appeared to be as well tolerated as the atypicals. However, it had the highest rate of drop out due to extrapyramidal symptoms and was restricted to patients who did not have tardive dyskinesia (TD). This article examines the phase 1 CATIE results to guide the clinician in understanding how to interpret the findings, which were intended to be a guide for clinical practice. The nature of the patient population, the doses of drugs relative to one another, inclusion of patients who were treatment resistant, and exclusion of patients with TD from randomization to perphenazine were potential sources of bias in the study. In particular, the use of a higher-than-usual peak dose of olanzapine may have led to the superior results achieved with it. Practical suggestions are given for choice of antipsychotic medication in patients with chronic schizophrenia.

Akathisia is a neurological side effect of antipsychotic medications, which are used to treat various psychiatric disorders. Akathisia is characterized by physical restlessness and a subjective urge to move. Although side effects such as akathisia, dystonia, and dyskinesia are common with the use of conventional antipsychotics, they occur in reduced frequency with the use of new-generation antipsychotics. Despite a lowered incidence profile, akathisia and similar conditions continue to affect patients. Neuroleptic-induced akathisia can present as fidgety movements while seated, rocking in place while standing, pacing, inability to sit or stand still for an extended period of time, and an overwhelming urge to move. These symptoms can cause severe distress and an increased risk of suicide for affected patients. First-line treatment of akathisia includes benzodiazepines or β-blockers for patients who do not have symptoms of Parkinson's disease and anticholinergic medications for patients with Parkinson's symptoms. Clinicians should ensure that an accurate diagnosis of akathisia is made and that target symptoms are decreasing due to treatment. At the same time, it must be ensured that the treatment used does not negatively affect the mental health of the patient. This expert roundtable supplement will address the diagnosis, pathophysiology, phenomenology, classification, and history of akathisiaas well as discuss screening tools and treatment options for the condition.

The clinical use of monoamine oxidase inhibitors (MAOIs) has declined due to concerns about food and drug interactions and waning physician experience. Evidence indicates that MAOIs are effective in depressive disorders, in particular depression with atypical features. Efforts to address safety issues have led to the development of more selective and reversible MAOIs, such as moclobemide. Selegiline, a selective monoamine oxidase B inhibitor, has been approved for the adjunctive treatment of Parkinson's disease at low doses. At higher doses, oral selegiline is also effective in major depressive disorder (MDD) but loses its selectivity and has the potential for tyramine interactions.To overcome these problems, a transdermal formulation of selegiline, the selegiline transdermal system (STS), was developed with novel pharmacokinetic and pharmacodynamic properties. Compared with oral administration, transdermal selegiline leads to sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production. In addition, STS allows targeted inhibition of central nervous system monoamine A (MAO-A) and monoamine B isoenzymes with minimal effects on MAO-A in the gastrointestinal and hepatic systems, thereby reducing the risk of interactions with tyramine-rich foods (the “cheese-reaction”). Clinical trials have found 6 mg/24 hours of STS to be effective in MDD without the need for dietary restrictions. The efficacy and safety profile of STS supports its use in MDD. It is possible that STS may demonstrate benefit in MDD with atypical features or MDD resistant to other antidepressants. However, more research is needed. Clinicians should familiarize themselves with the properties and indications for the new generation of MAOIs.

This study was conducted to show that catatonia is a predisposing factor for neuroleptic malignant syndrome (NMS) and to review the nosological relationship between catatonia and NMS. Seventeen consecutive cases of NMS were analyzed prospectively with reference to clinical and investigative findings before and after exposure to a neuroleptic. The series comprised eight males and nine females, ranging in age from 18 years to 65 years. Prior to neuroleptic exposure, all patients exhibited features compatible with criteria for catatonia (mutism/excitement) according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised, (DSM-III-R). Following neuroleptic administration (single dose in nine cases), patients deteriorated into a febrile, rigid, and obtunded state accompanied by autonomic dysfunction and raised creatine phosphokinase levels. These features were consistent with a diagnosis of NMS. Neuroleptics were discontinued and supportive medical treatment instituted. Benzodiazepines were beneficial in eight cases in relieving stupor, but bromocriptine and dantrolene were generally ineffective. In all patients diagnosed with NMS in the authors' series, catatonia was an invariable prodromal state. It appears that the administration of a neuroleptic intensified the preexisting catatonic state and precipitated a malignant variant of the disorder, which is currently recognized as NMS. The authors, therefore, challenge the separate nosological status of NMS and catatonia and suggest that these syndromes are part of a unitary pathophysiological disorder.

Our objective is to report a coincident reduction in headache pain in patients treated with repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD). Two patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD, non-responsive to prior antidepressant treatment who were enrolled in a sham-controlled, double-blind study of rTMS for MDD. After the study, it was revealed that both were in the active-treatment arm. Both patients suffered from near daily headaches and kept logs of headache frequency and severity before, during, and after the study. Headache pain was significantly reduced under double-blind conditions with rTMS treatment, but returned to baseline following cessation of rTMS treatment. Ultimately, when receiving rTMS post-study as a maintenance intervention for MDD (~2 rTMS sessions/week), the positive effects on headache amelioration were sustained. Headache pain is frequently comorbid with mood disorders and has been reported as the most common side effect with rTMS. In these subjects, rTMS was, in fact, associated with relief of depressive symptoms and preexisting headache pain. This indicates that rTMS may be beneficial for both disorders in some patients.

Introduction: While both blunted and enhanced cortisol suppression following a dexamethasone suppression test (DST) are described in eating disorders, some evidence suggests that enhanced cortisol suppression might be associated with the presence of trauma history. The objective of this study is to investigate hypothalamic-pituitary-adrenal axis response to a modified DST in eating disorders and its relationship with childhood trauma.

Methods: Fifty-two patients with eating disorders were studied with a 0.25 mg DST and with measures of childhood trauma.

Conclusion: Patients with bulimia symptoms had significantly greater cortisol suppression than controls and restrictive anorexia patients (F=8.2, P<.05). Cortisol suppression was significantly correlated with intensity of childhood traumatic events (F=0.32, P<.05). Hypersensitive hypothalamic-pituitary-adrenal axis response to DST in eating disorders may be related with a history of childhood trauma and suggests some biological similarities with posttraumatic syndromes that should be further explored.

The goal of this brief review is to explain the role of monoamine oxidase enzymes in the neurobiology, etiology, and presentation of psychiatric illnesses, primarily major depressive disorder. This article will initially focus on the basic science and function of the monoamine oxidase system and some proposed neuropsychiatric symptoms that may arise if this enzyme system is altered by genetic predisposition. These findings and theories will next be translationally discussed in regard to clinical application pertaining to enzyme inhibition and the treatment of major depressive and other psychiatric disorders.

ISSUE:A striking and unexpected pharmacologic synergy has been shown between antagonist actions at serotonergic 5HT2C receptors, and agonist actions at melatonergic receptors by agomelatine, a drug that has both of these properties.