A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

Neuronal loss is a major pathological outcome of many common neurological disorders, including ischemia, traumatic brain injury, and Alzheimer disease. Stem cell-based approaches have received considerable attention as a potential means of treatment, although it remains to be determined whether stem cells can ameliorate memory dysfunction, a devastating component of these disorders. We generated a transgenic mouse model in which the tetracycline-off system is used to regulate expression of diphtheria toxin A chain. After induction, we find progressive neuronal loss primarily within the hippocampus, leading to specific impairments in memory. We find that neural stem cells transplanted into the brain after neuronal ablation survive, migrate, differentiate and, most significantly, improve memory. These results show that stem cells may have therapeutic value in diseases and conditions that result in memory loss.

During the past 2 decades, the elucidation of susceptibility and causative genes for Alzheimer disease as well as proteins involved in the pathogenic process has greatly facilitated the development of genetically altered mouse models. These models have played a major role in defining critical disease-related mechanisms and in evaluating novel therapeutic approaches, with many treatments currently in clinical trial owing their origins to studies initially performed in mice. This review discusses the utility of transgenic mice as a research tool and their contributions to our understanding of Alzheimer disease.The most common cause of dementia, AD 2 accounts for 60 -70% of all dementia cases and afflicts Ͼ15 million individuals worldwide. The disorder is characterized by severe memory loss, with episodic memory being particularly impaired during the initial phases. At present, the disorder is not curable. Most AD cases occur sporadically (SAD), although inheritance of certain susceptibility genes enhances the risk. A small minority of AD cases (Ͻ1%) is inheritable (referred to as FAD) and is caused by mutations in genes encoding APP, PS1, or PS2. Pathological Hallmarks of ADDefinitive diagnosis of AD occurs during post-mortem examination upon detection of two hallmark pathologies. The first is amyloid plaques, which consist of A␤. The length of A␤ can vary, but a 42-amino acid variant is considered neurotoxic because of its propensity to readily aggregate into oligomers and fibrils. All mutations associated with FAD affect the aggregation and/or production of A␤, which is sequentially cleaved from the APP holoprotein, first by an enzyme known as BACE (beta-APP-cleaving enzyme) and then by an enzymatic complex known as ␥-secretase, in which the presenilins form the catalytic core (1). FAD-associated mutations in APP cluster around the ␤-secretase cleavage site (e.g. Swedish mutation), in key amino acids affecting its ability to aggregate (e.g. Arctic and Dutch mutations), or around the ␥-secretase cleavage site, which increases production of the longer A␤42 peptide (e.g. London mutation). PS mutations play a similar role by favoring production of A␤42 at the expense of A␤40. In vitro experiments and transgenic mice have shown us that the aggregation state of A␤ is crucial, that it can also accumulate intraneuronally, and that it can mediate a diverse range of pathological effects on cellular function (2).The second pathological hallmark is the appearance of intraneuronal aggregates composed of the microtubule-associated protein tau. Hyperphosphorylation of tau leads it to dissociate from the microtubules and aggregate within the axoplasm as NFTs (3). Furthermore, tau dissociation leads to a reduction in microtubule stability and impaired axonal transport, ultimately leading to neuronal dysfunction and loss of synapses and subsequent retrograde degeneration (4). Mutations in the gene for tau (MAPT) are not associated with AD but cause FTDP-17 (frontal temporal dementia with parkinsonism 17), showing that disruption ...

The current generation of antidepressant drugs acts predominantly by targeting the serotonin transporter (SERT). The original trend to do this selectively (e.g., with SSRIs or selective serotonin reuptake inhibitors) has given way to combining various additional pharmacologic mechanisms with SERT inhibition, including dual actions by single drugs (e.g., SNRIs or serotonin norepinephrine reuptake inhibitors), or by augmenting SSRIs with a second drug of a different mechanism (e.g., bupropion with dopamine and norepinephrine reuptake inhibition; trazodone with 5HT2A antagonism; mirtazapine with 5HT2A/5HT2C/5HT3/alpha2 antagonism; buspirone or some atypical antipsychotics with 5HT1A partial agonism; other atypical antipsychotics with 5HT2C/5HT7 antagonism and other mechanisms). Novel drugs in development include those that combine multiple simultaneous pharmacologic mechanisms in addition to SERT inhibition within the same molecule, such as vilazodone (combining 5HT1A partial agonism with SERT inhibition), triple reuptake inhibitors (combining norepinephrine and dopamine reuptake inhibition with SERT inhibition), and vortioxetine, a multimodal antidepressant combining actions at the G protein receptor mode (5HT1A and 5HT1B partial agonism and 5HT7 antagonism), at the ion channel mode (5HT3 antagonism) as well as the neurotransmitter transporter mode (SERT inhibition). These various strategies that build upon SERT inhibition provide promise for novel therapeutic approaches to depression, including the possibility of targeting residual symptoms not well treated by SERT inhibition alone, and reducing side effects, such as sexual dysfunction.

Here we provide comprehensive guidelines for the assessment and treatment of violence and aggression of various etiologies, including psychotic aggression and impulsive aggression due to schizophrenia, mood disorders, ADHD, or trauma, and predatory aggression due to psychopathy and other personality disorders. These guidelines have been developed from a collection of prescribing recommendations, clinical trial results, and years of clinical experience in treating patients who are persistently violent or aggressive in the California Department of State Hospital System. Many of the recommendations provided in these guidelines employ off-label prescribing practices; thus, sound clinical judgment based on individual patient needs and according to institution formularies must be considered when applying these guidelines in clinical practice.

Insufficient treatment of psychosis often manifests as violent and aggressive behaviors that are dangerous to the patient and others, and that warrant treatment strategies which are not considered first-line, evidence-based practices. Such treatment strategies include both antipsychotic polypharmacy (simultaneous use of 2 antipsychotics) and high-dose antipsychotic monotherapy. Here we discuss the hypothesized neurobiological substrates of various types of violence and aggression, as well as providing arguments for the use of antipsychotic polypharmacy and high-dose monotherapy to target dysfunctional neurocircuitry in the subpopulation of patients that is treatment-resistant, violent, and aggressive. In this review, we focus primarily on the data supporting the use of second-generation, atypical antipsychotics both at high doses and in combination with other antipsychotics.

Cariprazine is one of the newest dopamine-serotonin partial agonists, also known as ‘atypical’ second generation antipsychotics. Originally approved for acute and maintenance treatment of schizophrenia as well as for acute mania and mixed mania/depression, cariprazine has now been approved for bipolar I depression. Additionally, post hoc analyses of bipolar I depressed subjects show that both those with and those without concurrent manic features were improved following treatment with cariprazine. Maintenance studies are in progress in bipolar disorder, as are studies to augment antidepressants in unipolar major depressive episodes insufficiently responsive to treatment. Here, we review specifically the efficacy and safety data of cariprazine in bipolar I disorder and discuss the hypothesized mechanism of action of cariprazine and how it could theoretically be linked to caprazine’s broad therapeutic actions across the mood disorder spectrum.

Guidelines for treating various conditions can be helpful in setting practice standards, but the presence of several sets of guidelines from different countries, experts, and settings, written at different times, can also create confusion. Here we provide a "guideline of guidelines" for the treatment of schizophrenia, or "meta-guidelines, which not only reconcile the various existing standards but also update them to include the use of several newer agents, most of which were marketed following the publication of existing standards.