mdl-100907 and Bipolar-Disorder

Lumateperone (ITI-007) is a tosylate salt with binding affinities to receptors implicated in the therapeutic actions of antipsychotic medications, including the serotonin 5HT2A receptors, dopamine D2 and D1 receptors and the serotonin transporter. It has a unique mechanism of action because it simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, implicated in serious mental illness. It can be considered a multi-target-directed ligand and a multifunctional modulator of serotoninergic system with possible precognitive, antipsychotic, antidepressant and anxiolytic properties. Lumateperone has been investigated as a novel agent for the treatment of schizophrenia, but it represents a new potential option for other psychiatric and neurological diseases, such as behavioural symptoms of dementia or Alzheimer's disease, sleep disturbances, bipolar depression. Besides, it has demonstrated a favourable safety profile without significant extrapyramidal side effects, hyperprolactinemia or changes in cardiometabolic or endocrine factors versus placebo. Additional studies are warranted to confirm and examine the benefit of lumateperone and possible therapeutic targets. This paper is a comprehensive and thorough summary of the most important findings and potential future role of this particular compound in personalized treatments.

Topics: Alzheimer Disease; Bipolar Disorder; Dementia; Dopamine D2 Receptor Antagonists; Drug Partial Agonism; Heterocyclic Compounds, 4 or More Rings; Humans; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Sleep Wake Disorders

Agomelatine is a relatively new antidepressant with a mechanism of action that is different from other antidepressants: it is a melatonergic agonist and a 5-HT2C antagonist. It is an effective treatment for depression, with relatively mild side effects. It may be a valuable pharmacological alternative in the clinical approach on depression.. The literature about agomelatine has been comprehensively reviewed. Agomelatine's efficacy, safety and tolerability are reviewed based on the studies undertaken in patients with major depressive disorder (MDD) and bipolar disorder (BPD).. Agomelatine has shown an antidepressant effect in preclinical models, and the results of a large-scale clinical trial program, conducted in MDD, indicate both an antidepressant activity and a favorable tolerability profile. Agomelatine has no discontinuation syndrome, sexual discomfort is rare, and it is generally weigh neutral. The drug appears to be relatively safe in case of overdose. However, some cases of elevated hepatic transaminases are reported during treatment. As agomelatine has a mechanism of action that differs from other agents, it may represent a valuable additional treatment option in those patients who do not respond fully or who do not tolerate the side effects of other antidepressants.

Topics: Acetamides; Animals; Antidepressive Agents; Bipolar Disorder; Depressive Disorder, Major; Humans; Melatonin; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Quetiapine (Seroquel®) is an orally administered atypical antipsychotic that is indicated for the treatment of schizophrenia and bipolar disorder, including bipolar depression. An extended-release (XR) formulation of quetiapine is also available. This review summarizes the pharmacological properties, efficacy and tolerability of quetiapine and quetiapine XR in patients with bipolar depression. Quetiapine is an antagonist at both serotonin 5-HT2 and dopamine D2 receptors, and its antipsychotic effects are thought to stem from interactions at these receptors. The antidepressant effects of quetiapine are poorly understood, but may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular dopamine release in the region, or to reduced synaptic reuptake of noradrenaline resulting from inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite norquetiapine. The efficacy and tolerability of quetiapine was evaluated in five 8-week, randomized, double-blind, placebo-controlled, multicentre or multinational trials in patients with a major depressive episode (MDE) associated with bipolar disorder. Across trials, monotherapy with oral quetiapine 300 or 600 mg/day (or quetiapine XR 300 mg/day) produced significantly greater improvements than placebo in depressive symptoms (primary endpoint), according to the change in the Montgomery-Asberg Depression Rating Scale total score. In general, quetiapine and quetiapine XR were also associated with significantly higher MDE response and remission rates than placebo. Across trials, quetiapine and quetiapine XR produced significantly greater improvements in global severity of illness scores than placebo, according to changes in the Clinical Global Impressions scale score. There were no differences in treatment outcomes between quetiapine 300 mg/day and 600 mg/day dosage groups. Patients with bipolar depression who responded to quetiapine during two 8-week acute treatment trials also benefited from continuing quetiapine therapy for up to 52 weeks. Compared with quetiapine responders randomized to placebo, quetiapine responders who continued quetiapine 300 or 600 mg/day had a significantly reduced risk of recurrence of any mood events and of depression mood events, but not of hypomanic/manic events. In a randomized, double-blind, placebo-controlled trial, quetiapine maintenance therapy for up to 104 weeks

Topics: Administration, Oral; Antipsychotic Agents; Bipolar Disorder; Delayed-Action Preparations; Dibenzothiazepines; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Humans; Quetiapine Fumarate; Serotonin 5-HT2 Receptor Antagonists

Atypical antipsychotics are now widely used in the acute and long-term treatment in bipolar disorder. The role of atypical antipsychotics as acute agents, add-on medications; or as primary mood stabilizers in different phases of bipolar disorder is an important current research tendency. However, in bipolar disorder the mostly used indication of quetiapine is the management of acute manic phases, clinical data and the actual research results suggest that it may have both antidepressant and long-term antimanic effects. Quetiapine enhances the transmission of the central serotonergic networks, by its high antagonistic affinity for 5-HT(2A) and partial agonistic activity for the 5-HT(1A) receptors. The 5HT(1A) partial agonism causes an increase in the dopaminergic neurotransmission of the prefrontal cortex, and also, the affinity for the alpha 2-adrenoceptor brings a relative increase in extracellular noradrenergic release an tone in the prefrontal cortex. Latest research shows that quetiapine's main, active, human plasma metabolite, N-desalkyl quetiapine (norquetiapine), has a high inhibition affinity for the noradrenergic transporter. These data suggest that comparing to other atypical antipsychotics, norquetiapine may have a relatively strong antidepressant potential. Modifying the dopaminergic transmission by quetiapine's D2 receptor blocking activity results indirect mediating the cAMP-PKA and the arrestin-Akt-GSK-3 intracellular signal transduction pathways, which process may explain its long-term antimanic and mood stabilizing capability. Quetiapine's activity on nerve growth factors, histamine H1 receptor, proinflammatory networks may take an important additional part in its efficacy in bipolar depression. Its very fast dissociation from the D2 receptor is an important pharmakokinetic parameter for managing the optimal quetiapine dose in the daily clinical practice. This review tries to organize the actual information on quetiapine's multiplex activity in bipolar disorder.

Topics: Adult; Aged; Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Dibenzothiazepines; Dopamine; Female; Glutamic Acid; Humans; Male; Middle Aged; Norepinephrine; Quetiapine Fumarate; Receptors, Histamine; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

Ziprasidone, a benzisothiazolyl piperazine-type atypical antipsychotic agent, has a unique receptor-binding profile. A potent antagonist of serotonin 5-HT(2A) and dopamine D(2) receptors, ziprasidone has an affinity for 5-HT(2A) receptors >10-fold higher than its affinity for D(2) receptors. Ziprasidone has been shown to be effective in the treatment of bipolar disorder in patients experiencing manic or mixed episodes. It was significantly more effective than placebo in improving manic symptoms as early as day 2 of treatment in two 3-week placebo-controlled trials as monotherapy. In a 12-week, placebo-controlled trial of patients with acute mania, ziprasidone as monotherapy showed comparable efficacy with, and fewer movement-related adverse events than, haloperidol. It has demonstrated efficacy in two 1-year open-label extension trials, both as monotherapy and in combination with lithium. Ziprasidone has a generally favourable adverse effect profile. In short-term placebo-controlled trials, there were similar discontinuation rates in active treatment and placebo recipients. While twice as many patients treated with ziprasidone compared with placebo discontinued therapy because of adverse events, the number of events was small and adverse effects were generally mild or moderate. The favourable tolerability of ziprasidone has been confirmed in long-term extension studies and its use was not associated with weight gain or dyslipidaemia. Ziprasidone-related movement disorders occurred infrequently.

Topics: Acute Disease; Administration, Oral; Antipsychotic Agents; Bipolar Disorder; Dopamine D2 Receptor Antagonists; Humans; Piperazines; Serotonin 5-HT2 Receptor Antagonists; Thiazoles; Treatment Outcome

Patients with bipolar disorder spend the most time in the depressed phase, and that phase is associated with the most morbidity and mortality. Treatment of bipolar depression lacks a test to determine who will respond to treatment. White matter disruptions have been found in bipolar disorder. Previous reports suggest that white matter disruptions may be associated with resistance to antidepressant medication, but this has never been investigated in a prospective study using a Food and Drug Administration (FDA)-approved medication.. Eighteen subjects with bipolar disorder who were in a major depressive episode and off all medications were recruited. Magnetic resonance imaging was acquired using a 64-direction diffusion tensor imaging sequence on a 3T scanner. Subjects were treated with 8 weeks of open-label lurasidone. The Montgomrey-Asberg Depression Rating Scale (MADRS) was completed weekly. Tract-Based Spatial Statistics were utilized to perform a regression analysis of fractional anisotropy (FA) data with treatment outcome as assessed by percent change in MADRS as a regressor while controlling for age and sex, using a threshold of P (threshold-free cluster enhancement-corrected) <.05.. FA was positively correlated with antidepressant treatment response in multiple regions of the mean FA skeleton bilaterally, including tracts in the frontal and parietal lobes.. Greater disruptions in the white matter tracts in bipolar disorder were associated with poorer antidepressant response to lurasidone. The disruptions may potentially indicate treatment with a different antidepressant medication class. These results are limited by the open-label study design, sample size and lack of a healthy control group.

Topics: Adult; Bipolar Disorder; Depressive Disorder, Treatment-Resistant; Diffusion Tensor Imaging; Female; Humans; Lurasidone Hydrochloride; Magnetic Resonance Imaging; Male; Prospective Studies; Psychiatric Status Rating Scales; Reproducibility of Results; Serotonin 5-HT2 Receptor Antagonists; Statistics as Topic; White Matter

Authors compared the efficacy and safety of valdoxan in the treatment of depression in 22 patients with recurrent depressive disorder (RD) and 23 patients with bipolar affective disorder (BAD). Valdoxan was used on the night in dosage 25-50 mg during 8 weeks. Efficacy was assessed with psychometric scales HAM-D-17, CGI-S, CGI-I and visual analogous scales for falling asleep, night sleep quality, morning status and day activity. The antidepressant effect of the drug and the normalization of circadian rhythms were seen in the first week of treatment. To the end of treatment, there were 90.9% responders in the group with BAD and 91.3% in patients with RD. Percentages of patients with remission were 65.2% and 54.5%, respectively. It has been concluded that valdoxan does not cause unwanted side-effects as well as the risk of the inversion of a phase and/or the development of transitory hypomania in BAD.

Topics: Acetamides; Adult; Antidepressive Agents; Bipolar Disorder; Circadian Rhythm; Depressive Disorder; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychometrics; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Datasets of antimanic potency ratings and receptor-binding affinities [inhibition constants (K(i))] at dopamine D2 and serotonin 5-HT2A brain receptors were accessed from published literature for a large series (n = 24) of typical neuroleptic drugs, many of which are now obsolete and unobtainable. There was a strong positive association between antimanic potency and affinity for D2 receptors, in support of a 'dopamine-blockade hypothesis' of antimanic drug action. Taking the series of neuroleptics as a whole, there was no association between antimanic potency and affinity for 5-HT2A receptors. Despite this, within a subsample of typical neuroleptics with low affinity for D2 receptors resembling new generation atypical antipsychotics, a positive association between antimanic potency and affinity for 5-HT2A receptors emerged. This suggests that blockade of brain 5-HT2A receptors plays at least a subsidiary role in the antimanic effects of some typical neuroleptics. Other considerations also suggest that combining drugs to achieve high affinity for and blockade of both dopamine D2 receptors and serotonin 5-HT2A receptors, possibly with additional direct or indirect stimulation of postsynaptic 5-HT1A receptors, might maximize antimanic efficacy.

Topics: Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

Abnormalities of serotonin (5HT) function have been implicated in mood disorders, and lithium treatment may produce its beneficial effects by modifying serotonergic mechanisms. It has also been observed that 5HT2A receptors are upregulated both in the postmortem brain and platelets of patients with depression and suicidal behavior. However, the role of 5HT2A receptors in bipolar disorders and in the mechanism of action of lithium is unclear.. The major objective of this study was to examine if abnormalities of 5HT2A receptors are associated with bipolar or schizoaffective disorders and if treatment with lithium would cause changes in the 5HT2A receptors.. 5HT2A receptors were studied in the platelets obtained from drug-free normal control subjects and patients with bipolar ( n=41) or schizoaffective ( n=20) disorders during a drug-free washout period and after treatment (4.0+/-0.44 weeks) with lithium ( n=16). The Bmax and K(D) of 5HT2A receptors were quantitated by binding techniques using [125I]lysergic acid diethylamide (LSD) as a ligand.. We observed that the 5HT2A receptor Bmax was increased in platelets obtained from drug-free bipolar or schizoaffective patients as compared with normal control subjects. The 5HT2A receptor density was even more increased in bipolar or schizoaffective suicidal patients, and the 5HT2A receptor Bmax in the non-suicidal bipolar or schizoaffective subgroup also was significantly higher than in normal control subjects. Treatment with lithium caused a significant increase in the B(max) of platelet 5HT2A receptors in bipolar or schizoaffective patients.. Our studies indicate that increased 5HT2A receptors may be associated with the pathophysiology of bipolar illness and that treatment with lithium further increases the density of 5HT2A receptors. Whether this increase in 5HT2A receptors caused by lithium is associated with its therapeutic mechanism of action is unclear. It is also not clear whether the increase in 5HT2A receptors in bipolar or schizoaffective patients, or in suicidal bipolar or schizoaffective patients, is a trait or state marker.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Binding Sites; Bipolar Disorder; Blood Platelets; Drug Therapy, Combination; Female; Humans; Iodine Isotopes; Lithium; Lysergic Acid Diethylamide; Male; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Suicide, Attempted; Tissue Distribution