lurasidone-hydrochloride and Depressive-Disorder

Herein we review the evidence supporting Food and Drug Administration (FDA) approved and emerging treatments for bipolar depression.. A PubMed search of all English-language articles published up to July 2013 was conducted. The search terms were quetiapine, olanzapine-fluoxetine, olanzapine, lurasidone, ketamine, modafinil/armodafinil, and lamotrigine. The search was augmented with a manual review of relevant article reference lists, as well as posters presented at national and international meetings. Articles selected for review were based on the adequacy of sample size, the use of standardized diagnostic instruments, validated assessment measures, and overall manuscript quality.. Olanzapine-fluoxetine combination (OFC), quetiapine, and lurasidone are FDA-approved for the acute treatment of bipolar depression. Lurasidone is the most recently approved agent for bipolar depression. Olanzapine-fluoxetine combination and quetiapine are approved as single modality therapies while lurasidone is approved as a monotherapy and as an adjunct to lithium or divalproex. The overall effect size of the 3 treatments in mitigating depressive symptoms is similar. Clinically significant weight gain and metabolic disruption as well as sedation are significant limitations of OFC and quetiapine. The minimal propensity for weight gain as well as the metabolic neutrality of lurasidone in the bipolar population is a clinically significant advantage. Evidence also supports lamotrigine with compelling evidence as an adjunct to lithium and in recurrence prevention paradigm; suggested evidence also exists for ketamine and modafinil/armodafinil; notwithstanding, these treatments remain investigational.. Relatively few agents are FDA-approved for bipolar depression. The selection and sequencing of agents in bipolar depression should give primacy to those agents that are FDA-approved. Further refinement of the selection process will need to pay careful attention to the relative hazards of weight gain and metabolic disruption in this highly susceptible population. Other agents with differential mechanisms (eg, ketamine) offer a promising alternative in bipolar depression.

Topics: Antidepressive Agents; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzhydryl Compounds; Benzodiazepines; Bipolar Disorder; Central Nervous System Stimulants; Depressive Disorder; Dibenzothiazepines; Drug Approval; Drug Combinations; Excitatory Amino Acid Antagonists; Fluoxetine; Humans; Isoindoles; Ketamine; Lamotrigine; Lurasidone Hydrochloride; Modafinil; Quetiapine Fumarate; Selective Serotonin Reuptake Inhibitors; Thiazoles; Triazines; United States; United States Food and Drug Administration

Characterization of dose-response relationships for psychotropic agents may be difficult to determine based on results of individual clinical studies, particularly those with a flexible dose design. The goal of this pharmacometric analysis was to characterize the dose-response profile for lurasidone in patients with bipolar depression.. The statistical modeling and simulation analyses reported here were derived from 2 randomized, 6-week, double-blind, placebo-controlled, flexible-dose studies (20-60 mg/d or 80-120 mg/d of lurasidone as monotherapy or 20-120 mg/d adjunct to lithium or valproate) in patients with bipolar depression. Pooled data included 5245 Montgomery-Åsberg Depression Rating Scale (MADRS) observations from 825 patients who had received lurasidone or placebo treatments, with or without lithium or valproate background medication.. The time course of placebo effect on the MADRS score was adequately described by an exponential asymptotic placebo model. A linear dose-response model best described the effect of lurasidone. The net improvement in MADRS score due to lurasidone treatment (the drug effect) was significant (P < 0.001), and a positive dose response was detected. Net drug effect after 6 weeks of treatment was estimated to be a 6.0-point decrease in MADRS score per 100 mg of lurasidone. Covariate effects (for age and lithium or valproate use) were significant only for placebo effect parameters; thus, no dose adjustment was necessary related to demographic covariates.. This population dose-response modeling analysis indicates that higher doses of lurasidone are likely to produce greater therapeutic effects in patients with bipolar depression. The linear dose response was consistent for both lurasidone monotherapy and adjunctive therapy in patients with bipolar depression. ClinicalTrials.gov identifiers: NCT00868452, NCT00868699.

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Computer Simulation; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lithium Compounds; Lurasidone Hydrochloride; Male; Middle Aged; Models, Theoretical; Placebo Effect; Psychiatric Status Rating Scales; Valproic Acid

Depressive symptoms are common in schizophrenia and can worsen outcomes and increase suicide risk. Lurasidone is an atypical antipsychotic agent indicated for the treatment of schizophrenia and for the treatment of major depressive episodes associated with bipolar I disorder. This post hoc analysis evaluated the effect of lurasidone on depressive symptoms in patients with schizophrenia.. Patient-level data were pooled from 4 similarly designed, double-blind, placebo-controlled, 6-week registration studies of lurasidone (40-160 mg/d) in adult patients with an acute exacerbation of schizophrenia. Changes in depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), were analyzed for the overall sample and for subgroups of patients stratified by baseline MADRS scores.. MADRS assessments at baseline and endpoint (day 42 or last observation carried forward [LOCF]) were available for 1330 patients. Patients receiving lurasidone experienced significantly greater decreases in MADRS score (-2.8, least-squares [LS] mean change, LOCF) compared with patients receiving placebo (-1.4, P < .001, effect size 0.24). Analysis of change in MADRS score (LOCF) by baseline symptom severity (MADRS score of ≥12, ≥14, ≥16, ≥18) showed significantly greater improvement for lurasidone-treated patients across all severity groups; effect sizes ranged from 0.25 to 0.34. Among patients with a baseline MADRS score of ≥12, depressive symptom remission (defined as MADRS score <10 at LOCF endpoint) was attained by 45.0% of lurasidone-treated patients and 36.3% of patients receiving placebo (P < .05).. In a pooled analysis of short-term, placebo-controlled studies, lurasidone significantly improved depressive symptoms in patients with schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Isoindoles; Lurasidone Hydrochloride; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Thiazoles; Young Adult

Major depression is associated with several alterations, including reduced neuronal plasticity and impaired synaptic function, which represent an important target of pharmacological intervention.. In the present study, we have investigated the ability of the antipsychotic drug lurasidone to modulate behavioral and neuroplastic alterations in the chronic mild stress model of depression.. Rats that show reduced sucrose consumption after 2 weeks of chronic mild stress have reduced expression of the pool of Bdnf transcripts with the long 3' untranslated region (3'-UTR) that may be targeted to the synaptic compartment, suggesting the contribution of the neurotrophin to the behavioral dysfunction produced by chronic mild stress. The downregulation of Bdnf expression persisted also after 7 weeks of chronic mild stress, whereas chronic lurasidone treatment improved anhedonia in chronic mild stress rats and restored Bdnf mRNA levels in the prefrontal cortex. Moreover, chronic lurasidone treatment was able to normalize chronic mild stress-induced defects of Psd95 and Gfap as well as changes in molecular regulators of protein translation at the synapse, including mTOR and eEF2.. These results demonstrate that lurasidone shows antidepressant properties in the chronic mild stress model through the modulation of synaptic and neuroplastic proteins. Such changes may contribute to the amelioration of functional capacities, which are deteriorated in patients with major depression and stress-related disorders.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Chronic Disease; Depressive Disorder; Disease Models, Animal; Disks Large Homolog 4 Protein; Elongation Factor 2 Kinase; Excitatory Amino Acid Transporter 2; Excitatory Amino Acid Transporter 3; Gene Expression; Glial Fibrillary Acidic Protein; Intracellular Signaling Peptides and Proteins; Lurasidone Hydrochloride; Male; Membrane Proteins; Prefrontal Cortex; Random Allocation; Rats, Wistar; RNA, Messenger; Stress, Psychological; TOR Serine-Threonine Kinases; Vesicular Glutamate Transport Protein 1