Last year, the December issue of the Mental Health Clinician was dedicated to highlighting new psychotropics agents recently granted FDA-approval, including iloperidone (Fanapt®, 2009), asenapine (Saphris®, 2009), lurasidone (Latuda®, 2010), and vilazodone (Viibryd®, 2011). Unfortunately, the 2012 year has brought no new agents to the psychotropic drug market; however, numerous investigational agents are “pipelined-up” and optimistically awaiting their market debut. Please see the “toolbox” for an abbreviated review of psychotropic agents currently undergoing Phase III trials.

All antidepressants currently approved for the treatment of depression in the United States act primarily on the monoamine system. These agents often take weeks to months to elicit a response but still leave over one-third of patients with depressive symptoms.1 According to the Medicines for Development in Mental Illnesses report presented by America's Biopharmaceutical Research Companies, there are six novel antidepressant agents currently undergoing Phase III trials.2 Amitifadine, a product of Euthymics® Bioscience, is a “broad spectrum antidepressant” and exhibits triple reuptake inhibition, thereby increasing levels of serotonin, norepinephrine, and dopamine.3 It is thought to model the citalopram and bupropion combination used in level 2 of the STAR*D trial and is claimed to produce less weight gain, sexual dysfunction, and cognitive impairment than other antidepressant agents.4 It is currently being evaluated for patients failing to respond to an antidepressant trial, with hopes of becoming the preferred second-line “go-to” antidepressant therapy.3 Takeda and Lundbeck recently announced their submission of a New Drug Application (NDA) for vortioxetine, an antidepressant that displays multimodal activity through receptor activity modulation and reuptake inhibition.5 ,In vitro studies show that vortioxetine is a 5HT3 and 5HT7 antagonist, 5HT1B partial agonist, 5HT1A agonist, and serotonin transporter inhibitor.5 ,In vivo studies have demonstrated that vortioxetine increases a plethora of neurotransmitters including serotonin, norepinephrine, dopamine, acetylcholine, and histamine. In contrast, edivoxetine, an Eli Lilly product, acts primarily via norepinephrine reuptake inhibition and is currently being evaluated as adjunct therapy to other antidepressants.6 Additionally, a few investigational antipsychotics are also being studied as adjunct therapy to antidepressants for the treatment of MDD and include brexpiprazole (Lundbeck and Otsuka), cariprazine (Forest Laboratories), and pipamperone (PharmaNeuroBoost).2 

Other well -known agents undergoing Phase III clinical trials for MDD include levomilnacipran, lisdexamfetamine (Vyvanse®), lurasidone (Latuda®), and mifepristone (KorlymTM or Corlux). Though milnacipran (Savella®), a dual serotonin-norepinephrine reuptake inhibitor, is indicated only for the treatment of fibromyalgia in the United States, it has been approved for the treatment of MDD in Europe and Asia since the late 1990s.7 Forest Laboratories recently submitted a NDA to the FDA for levomilnacipran, an enantiomer of racemic milnacipran, for the treatment of MDD in adults.8 Levomilnacipran was formulated as a sustained released product, permitting once daily dosing compared to twice daily dosing required with milnacipran.8 Lisdexamfetamine, a dextro-amphetamine prodrug currently indicated for ADHD, is undergoing Phase III clinical trials for use as adjunct therapy to antidepressants for treatment of residual depressive symptoms and bipolar depression.2,9 Lisdexamfetamine prevents the reuptake of dopamine and norepinephrine, as well as increases the release of monoamines.10 Sunovion Pharmaceuticals recently submitted two supplemental NDAs seeking approval of lurasidone, a newer second generation antipsychotic indicated for schizophrenia, for the treatment of bipolar I depressive episodes as monotherapy or adjunct therapy to lithium or valproate.11 Lurasidone, which displays D2, 5HT2A, and 5HT7 receptor antagonism as well as partial 5HT1A agonism, is also in Phase III trials for the treatment of Major Depressive Disorder (MDD) with mixed features, which is proposed to be a future DSM-V diagnosis.12,13 Patients displaying MDD with mixed features meet full criteria for MDD but also display sub-threshold manic symptoms, meaning the duration and/or number of manic symptoms fail to meet diagnostic criteria for mania or hypomania.14 Mifepristone, a glucocorticoid receptor antagonist, has been granted “fast track” status by the FDA and is being assessed for use in conjunction with an antidepressant or immediately prior to the start of antidepressant therapy (for a 7-day period) for patients with psychotic depression.15 This agent targets the hypothalamic-pituitary-adrenal axis, which is thought to be involved in the pathogenesis and etiology of depression.14 Mifepristone regulates cortisol, a hormone naturally produced in response to physical and emotional stress.9 Cortisol levels are theorized to be abnormally high in patients with psychotic depression, thereby overwhelming the stress response system and causing symptoms of psychosis.9 

While numerous drugs are being studied for MDD, novel agents (bitopertin, brexpiprazole, and cariprazine) are also undergoing Phase III clinical trials for schizophrenia.2 Bitopertin, a product of Roche Pharmaceuticals, enhances NMDA receptor activity through glycine reuptake inhibition.15 Psychosis has recently been hypothesized to result from NMDA receptor hypofunctioning.16 Agents increasing NMDA receptor activity, including glycine agonists and glycine transporter reuptake inhibitors, have been shown to improve negative and/or cognitive symptoms of schizophrenia.16 Four Phase III clinical trials are actively recruiting patients for studies evaluating bitopertin for patients with suboptimal controlled symptoms of schizophrenia and for patients with persistent, predominant negative symptoms of schizophrenia.9 In addition, Phase II trials are recruiting participants for studies evaluating the use of bitopertin in patients with an acute exacerbation of schizophrenia and the use of bitopertin in combination with an SSRI for OCD.9 

According to its manufacturers, Lundbeck and Otsuka, brexpiprazole is claimed to display “broad activity across multiple monoamine systems and exhibits reduced partial agonist activity at D2 receptors and enhanced affinity for specific serotonin receptors.”17 Little information regarding brexpiprazole's exact mechanism of action is available; however, it has been said to pharmacodynamically resemble aripiprazole but is noted to provide improved tolerability (e.g., less akathisia, restlessness, and insomnia) compared with other psychotropic agents.18 This agent is currently being evaluated in Phase III trials as adjunct therapy for MDD and as monotherapy schizophrenia.18 

Cariprazine, a product of Gedeon Ritcher Ltd. and Roche, is a potent D3-preferring D3/D2 receptor partial agonist and displays low binding affinity to 5HT2C, histamine (H1), muscarinic and adrenergic receptors, which are often attributed to causing adverse effects such as weight gain, sedation, and orthostasis.19 D3 receptors are primarily located in the limbic system and are thought to play a role in cognitive and emotional regulation.20 Cariprazine is in Phase III trials for bipolar mania and depression, acute exacerbations of schizophrenia, and for adjunct therapy to antidepressants for MDD.2 In a press release from February of 2012, cariprazine was noted to have produced positive results in two Phase III clinical trials for the treatment of acute exacerbations of schizophrenia.19 Additionally, a poster presented at the annual meeting of the American Psychiatric Association in May of 2012 entitled “Cariprazine in the treatment of acute mania in bipolar disorder: a double-blind, placebo controlled, phase III trial” concluded that cariprazine demonstrated significant improvement on the primary efficacy parameter, Young Mania Rating Scale score, compared to placebo at study endpoint (week 3).21 

Last but not least, a more well-known antipsychotic, aripiprazole (Abilify®), has been reformulated into a once monthly depot injection. The aripiprazole depot formulation demonstrated effectiveness in delaying the time-until-impending relapse compared to placebo in patients with schizophrenia.22 Though an NDA was filed in late 2011, due to problems with a third party supplier of sterile water, which is used to reconstitute the lyophilized cake formulation into an injectable suspension, its approval date has been set back to 2014.23 

Thus, although Santa appears to have forgotten to place antipsychotics and antidepressants under the tree this Christmas, he certainly left us with numerous potential psychotropics to wish for next year, along with a few hot topics to keep us occupied until the New Year. This issue of the Mental Health Clinician will review the two new FDA-approved weight loss agents, Belviq® (lorcaserin) and Qsymia™ (phentermine and topiramate extended release), evaluate the evidence supporting the recent FDA approval of high-dose Latuda® (lurasidone), and assess the data leading to the FDA recommended dosing restrictions on Celexa (citalopram). The newer synthetic drugs of abuse will be discussed, along with the pharmacist's role in Transcranial Magnetic Stimulation for MDD. Additionally, an article highlighting the establishment and success of CPNP's collegiate chapter at Purdue University is included for your reading pleasure as well.

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