Vilazodone: clinical basis for the US Food and Drug Administration's approval of a new antidepressant.

OBJECTIVE: Vilazodone was recently approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The purpose of this review is to summarize the FDA's approach to its review of the clinical pharmacology and the clinical efficacy and safety data for this new drug application, important issues in its decision-making, and its conclusions. DATA SOURCES: The data sources for this review were the original raw data sets for all clinical trials included in the development program for vilazodone, as well as the sponsor's original analyses of these data. STUDY SELECTION: Data were available from 24 human trials involving vilazodone, and included a total of 2,898 human subjects exposed to 1 or more doses of this drug. DATA EXTRACTION: The FDA had access to original raw data sets for these trials. RESULTS: Vilazodone is effective in treating MDD at a dose of 40 mg/d, but it needs to be incrementally adjusted to this dose to minimize gastrointestinal symptoms. It needs to be taken with food to ensure adequate plasma concentrations. Vilazodone's profile of adverse events is similar to that seen with selective serotonin reuptake inhibitors. No dose adjustment is needed based on age, gender, or renal or hepatic impairment. It is recommended that the vilazodone dose be reduced to 20 mg when it is taken with strong cytochrome P450 (CYP) 3A4 inhibitors, eg, ketoconazole. Vilazodone is not expected to have important effects on the clearance of other drugs that are cytochrome P450 substrates. CONCLUSIONS: Vilazodone is a new treatment for MDD, but it is unknown whether it has any advantages compared to other drugs in the antidepressant class.

Dopamine receptor gene expression in human amygdaloid nuclei: elevated D4 receptor mRNA in major depression.

Previous findings from this laboratory demonstrating changes in dopamine (DA) transporter and D2 receptors in the amygdaloid complex of subjects with major depression indicate that disruption of dopamine neurotransmission to the amygdala may contribute to behavioral symptoms associated with depression. Quantitative real-time RT-PCR was used to investigate the regional distribution of gene expression of DA receptors in the human amygdala. In addition, relative levels of mRNA of DA receptors in the basal amygdaloid nucleus were measured postmortem in subjects with major depression and normal control subjects. All five subtypes of DA receptor mRNA were detected in all amygdaloid subnuclei, although D1, D2, and D4 receptor mRNAs were more abundant than D3 and D5 mRNAs by an order of magnitude. The highest level of D1 mRNA was found in the central nucleus, whereas D2 mRNA was the most abundant in the basal nucleus. Levels of D4 mRNA were highest in the basal and central nuclei. In the basal nucleus, amounts of D4, but not D1 or D2, mRNAs were significantly higher in subjects with major depression as compared to control subjects. These findings demonstrate that the D1, D2 and D4 receptors are the major subtypes of DA receptors in the human amygdala. Elevated DA receptor gene expression in depressive subjects further implicates altered dopaminergic transmission in the amygdala in depression.

Effects of depression, cigarette smoking, and age on monoamine oxidase B in amygdaloid nuclei.

Altered concentrations of dopamine transporter and D2/D3 receptors have been observed in the amygdaloid complex of subjects with major depression. These findings are suggestive of neurochemical abnormalities in the limbic dopamine system in depression. Monoamine oxidase-B (MAO-B) is a key enzyme in the catabolism of biogenic amines, including dopamine, and alterations in this enzyme may underlie dopaminergic abnormalities associated with depression. The specific binding of [(3)H]lazabemide to MAO-B was measured in the right amygdaloid complex of 15 major depressive subjects and 16 psychiatrically normal controls. Subjects of the two study groups were matched as close as possible for age, sex, and postmortem interval. Examination of the regional distribution of MAO-B revealed lower [(3)H]lazabemide binding to MAO-B in the lateral and basal nuclei of the amygdala and higher binding in the medial nucleus. A modest elevation in binding to MAO-B observed in all amygdaloid nuclei in major depressive subjects as compared to control subjects failed to reach statistical significance. A significant decrease in binding to MAO-B was observed when cigarette smokers were compared to nonsmoking subjects. The amount of MAO-B binding positively correlated with the age of subjects in all nuclei investigated. A decreased amount of MAO-B in smokers further validates the pharmacological effect of tobacco smoke on this enzyme.

Serotonin transporter and MAO-B levels in monoamine nuclei of the human brainstem are normal in major depression.

Neurochemical imbalance between noradrenergic and serotonergic systems has been postulated to underlie the pathophysiology of psychiatric illnesses involving mood disorders. The present study was designed to examined the possibility that serotonergic innervation of the locus coeruleus (LC) is abnormal in major depression, by measuring two proteins expressed by serotonergic neurons, but not by noradrenergic neurons, in the region of the LC. The specific binding of [(3)H]paroxetine to serotonin transporter (SERT) and of [(3)H]lazabemide to monoamine oxidase (MAO-B) were measured autoradiographically in tissue sections cut transversely at multiple levels along the rostro-caudal extent of the LC, as well as in the caudal portion of the dorsal raphe nucleus, from psychiatrically normal subjects and age-matched subjects with major depression. Under the conditions of the assays, [(3)H]paroxetine binding in the LC was specific for the SERT, based on the rank order of affinity of compounds for inhibiting [(3)H]paroxetine binding in the LC, i.e. citalopram > imipramine > desipramine > mazindol. The binding of [(3)H]paroxetine to SERT and [(3)H]lazabemide to MAO-B were higher in the raphe nuclei than in the LC. Comparison of control subjects to major depressive subjects revealed no differences in the amount of [(3)H]paroxetine binding to SERT and [(3)H]lazabemide to MAO-B in the LC, as well as in the raphe nuclei. These findings imply that serotonergic innervation of the LC is intact in major depression.

Elevated concentrations of CRF in the locus coeruleus of depressed subjects.

Research evidence that corticotropin-releasing factor (CRF) plays a role in the pathophysiology of major depressive disorder (MDD) has accumulated over the past 20 years. The elevation of lumbar cerebrospinal fluid (CSF) concentrations of CRF decreased responsiveness of pituitary CRF receptors to challenge with synthetic CRF, and increased levels of serum cortisol in MDD subjects support the hypothesis that CRF is chronically hypersecreted in at least the endocrine circuits of the hypothalamic-pituitary-adrenal (HPA) axis and may also involve other CRF brain circuits mediating emotional responses and/or arousal. One such circuit includes the excitatory CRF input to the locus coeruleus (LC), the major source of norepinephrine in the brain. Furthermore, there are now reports of decreased levels of CRF in lumbar CSF from MDD patients after symptom relief from chronic treatment with antidepressant drugs or electroconvulsive therapy. Whether this normalization reflects therapeutic effects on both endocrine- and limbic-associated CRF circuits has not yet been effectively addressed. In this brief report, we describe increased concentrations of CRF-like immunoreactivity in micropunches of post-mortem LC from subjects with MDD symptoms as established by retrospective psychiatric diagnosis compared to nondepressed subjects matched for age and sex.

Elevated agonist binding to alpha2-adrenoceptors in the locus coeruleus in major depression.

BACKGROUND: Recent postmortem studies demonstrate disrupted neurochemistry of the noradrenergic locus coeruleus (LC) in major depression (MD). Increased levels of tyrosine hydroxylase and decreased levels of norepinephrine transporter implicate a norepinephrine deficiency in the LC in MD. Here we describe a study of alpha2-adrenoceptors in the LC and raphe nuclei of subjects with MD compared with psychiatrically normal control subjects. METHODS: The specific binding of p-[125I]iodoclonidine to alpha2-adrenoceptors was measured at multiple levels along the rostrocaudal extent of the LC in postmortem tissue from 14 control and 14 MD subjects. In addition, p-[125I]iodoclonidine binding was measured in the dorsal and median raphe nuclei in the same tissue sections. RESULTS: The specific binding of p-[125I]iodoclonidine to alpha2-adrenoceptors was significantly elevated throughout the LC from MD compared with matched control subjects. No significant differences were observed in p-[125I]iodoclonidine binding to alpha2-adrenoceptors in the raphe nuclei comparing MD and control subjects. CONCLUSIONS: Given that alpha2-adrenoceptors are upregulated in laboratory animals by treatment with drugs that deplete norepinephrine, our findings implicate a premortem deficiency of brain norepinephrine in the region of the locus coeruleus in subjects with MD.

Dopaminergic abnormalities in amygdaloid nuclei in major depression: a postmortem study.

BACKGROUND: A deficiency of mesolimbic dopamine (DA) is a leading candidate for the etiology of certain symptoms of depression (e.g., anhedonia and loss of motivation). Here we show amounts of dopaminergic proteins in the amygdala, a key brain structure involved in the integration of emotions and stress, in subjects with major depression and in psychiatrically normal control subjects. METHODS: The specific binding of [(125)I]RTI 55 to the DA transporter, [(3)H]SCH 23390 to the D1 receptor and [(125)I]epidepride to D2/D3 receptors were measured in the right amygdaloid complex in postmortem brains from 11 subjects with major depression and 11 matched control subjects. RESULTS: The binding of [(125)I]RTI 55 to DA transporter was significantly lower in the basal and central amygdaloid nuclei, whereas the binding of [(125)I]epidepride to D2/D3 receptors was significantly higher in the basal, central, and lateral amygdaloid nuclei in major depression compared with control subjects. No difference in the binding of [(3)H]SCH 23390 to D1 receptors was observed. CONCLUSIONS: Given that DA depletion in rats can induce a reduction in the DA transporter and an upregulation of D2/D3 receptors, our data are consistent with the hypothesis that major depression is associated with a deficiency of mesolimbic DA.