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CLINICAL SYNTHESIS   |    
Developments in Psychopharmacology for Major Depressive Disorder
Trina E. Chang, M.D., M.P.H.; Stephen M. Stahl, M.D., Ph.D.
FOCUS 2012;10:452-460. doi:10.1176/appi.focus.10.4.452
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Author Information and CME Disclosure

Trina E. Chang, M.D., M.P.H., Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA.

Stephen M. Stahl, M.D., Ph.D., Department of Psychiatry, University of California-San Diego, San Diego, CA; Department of Psychiatry, University of Cambridge, Cambridge, U.K.

Dr. Chang has received research support for work with Alkermes, AstraZeneca, CeNeRx, Euthymics, Forest, GlaxoSmithKline, Johnson &Johnson, Neuralstem, and Pfizer and has received travel reimbursement from Bristol-Myers Squibb.

In the past 12 months, Dr. Stahl has served as a consultant for Acadia, AstraZeneca, Avanir, Biomarin, Bristol-Myers Squibb, CeNeRx, Dey, Eli Lilly, Forest, GenoMind, GlaxoSmithKline, Johnson & Johnson, Jazz, Lundbeck, Merck, Neuronetics, Novartis, Noven, ONO, Orexigen, Otsuka, PamLabs, Pfizer, RCT Logic, Rexahn, Roche, Servier, Shire, Solvay, Sunovion, Trius, and Valeant. He has served on speakers’ bureaus for Arbor Scientia, AstraZeneca, Eli Lilly, Forest, J&J, Merck, Neuroscience Education Institute, Pfizer, Servier, and Sunovion. He has received research and/or grant support from AstraZeneca, CeNeRx, Eli Lilly, Forest, GenOmind, Merck, Neuronetics, PamLabs, Pfizer, Roche, Schering Plough, Sepracor, Servier, Shire, Sunovion, Torrent, and Trovis.

Address correspondence to Trina Chang, M.D., M.P.H., Depression Clinical and Research Program, Massachusetts General Hospital, 1 Bowdoin Square, 6th Floor, Boston, MA 02114; e-mail: techang@partners.org

Abstract:  After years of emphasizing the same monoamine-based neurotransmitter mechanisms for treating depression, the antidepressant medication pipeline is broadening its reach. While serotonin, norepinephrine, and dopamine remain important treatment targets, researchers are working on compounds targeting their receptors in novel ways, as well as different combinations of monoaminergic actions that they hope will lead to improved efficacy and/or decreased side effects. At the same time, other researchers are focusing on completely different avenues of drug development, such as medications that target glutamate or acetylcholine neurotransmission, opioid receptors, or hormonal systems such as vasopressin and melatonin. Advances in pharmacogenetics also offer the possibility of targeting medications more specifically to individuals depending on their likelihood of response or side effects. This article outlines some promising directions for antidepressant drug development and discusses examples for each that have been undergoing testing.

Abstract Teaser
Figures in this Article

The last major development in the pharmacotherapy of major depressive disorder (MDD) was indeed revolutionary. The approval in the 1980s of selective serotonin reuptake inhibitors (SSRIs) for depression, which appeared to match the effectiveness of older antidepressants without as much of a side effect burden, may have been one of the main reasons that the use of antidepressants tripled in the following years, with SSRIs accounting for more than half of all antidepressant medication prescriptions by 2006 (1).

In the two decades since, much of the action in antidepressant development has revolved around expanding upon the currently known antidepressant medication classes by identifying other selective reuptake inhibitors, developing other medications that mimic the action of already-known antidepressants, or testing medications approved for other indications as depression augmentation or monotherapy agents. Still, these new medications have not yielded a substantial advance in the rate of treatment response for depression, with only half of patients in the STAR*D trial achieving symptomatic remission within the first two treatment stages (2, 3).

More recently, however, advances in knowledge about the pathophysiology of depression have opened up additional potential directions for drug development. For example, discoveries about the role of other neurotransmitters in MDD have led to the development of potential antidepressants tapping the glutamatergic and nicotinic neurotransmitter systems (Table 1). Other avenues for drug development have targeted hormonal systems such as the hypothalamic-pituitary-adrenal axis, known to be involved in the body’s response to stress, and the circadian system, which might affect depression via its effects on sleep. At the same time, the increasing ease of gene sequencing and the growing body of research on genetic polymorphisms associated with antidepressant response means that it may soon be possible not only to profile an individual patient’s likelihood of experiencing side effects with a given medication but also to choose the most promising pharmacological treatment. This article will outline some of the mechanisms for antidepressant action that are attracting the most attention from drug developers and that could represent the next wave of antidepressants.

 
Anchor for Jump
Table 1.Antidepressant Medications in the Pipeline

All of the antidepressant medications prescribed today capitalize on some aspect of monoamine neurotransmission, whether serotonin, norepinephrine, or dopamine. The most common are the serotonergic agents, which includes selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). These agents all inhibit the serotonin transporter, with varying degrees of agonism or antagonism at specific receptor subtypes; some also inhibit the norepinephrine transporter.

One of the newer variations on this class is vilazodone, which was approved by the FDA for depression in 2011. This medication both inhibits the serotonin transporter and acts as a partial agonist at 5HT1A receptors; thus, it is sometimes also called a SPARI (serotonin partial agonist reuptake inhibitor) (4, 5). Whether this additional action of 5HT1A partial agonism boosts the efficacy of serotonin inhibition or mitigates the side effects of 5HT1A partial agonism remains unknown, but this combination of mechanisms may result in lower rates of sexual dysfunction and weight gain. (4)

Another multimodal serotonergic medication in development is vortioxetine, a 5HT3a receptor antagonist, 5HT7 receptor antagonist, 5HT1B partial agonist, 5HT1A agonist, and 5HT transporter inhibitor (6). Vortioxetine has been found to reduce symptoms of depression in several Phase III trials (79) and has been associated with a more favorable cognitive effect profile (9); it has also been found to be effective in preventing relapse of depression in an open-label trial (10). In a “failed study,” while vortioxetine did not separate from placebo, neither did the other active treatment, duloxetine (11).

Among medications that combine noradrenergic and serotonergic activity is the serotonin-norepinephrine reuptake inhibitor levomilnacipran. This compound, which is an enantiomer of the fibromyalgia medication milnacipran, has received approval as an antidepressant in Europe. The manufacturer recently presented evidence of greater improvement in depressive symptoms with levomilnacipran compared with placebo from two Phase III trials (12). Another possibility is the selective norepinephrine reuptake inhibitor edivoxetine. While it primarily has been studied for attention deficit hyperactivity disorder, it is also being considered as a potential treatment for major depression; a recent study showed greater symptomatic improvement and higher response and remission rates with edivoxetine compared with placebo in patients with major depression (13).

In addition, there is interest in developing antidepressants with dopaminergic activity, perhaps in combination with serotonergic and noradrenergic actions. The idea is that targeting dopaminergic neurotransmission will enhance overall efficacy; reduce anhedonia, apathy, and cognitive impairment; and minimize residual fatigue and sleepiness (as suggested by the dopamine reuptake inhibitor modafinil augmentation studies of SSRIs (14)). In addition, given that dopaminergic medications have been used to treat SSRI-induced sexual dysfunction (15, 16), there is hope that dopaminergic antidepressants may cause less sexual dysfunction than SSRIs and SNRIs.

One dopaminergic compound currently under study is the dopamine (D2) and 5HT1a partial agonist/5HT2 antagonist brexpiprazole, which is structurally related to the atypical antipsychotic (and depression augmentation agent) aripiprazole. Brexpiprazole showed promise in a Phase II trial as an augmentation treatment for MDD (17). Another potential antidepressant with dopaminergic activity is lisdexamfetamine. This ADHD medication is a prodrug of the stimulant dextroamphetamine, which blocks presynaptic reuptake of norepinephrine and dopamine and increases their release. Shire has reported positive Phase II results from a trial using lisdexamfetamine as an augmentation treatment for major depression in full or partial remission but with continued executive dysfunction (18, 19).

Because of the role of dopamine in the brain’s reward circuit and addictive behaviors, there has been some concern about the risk of abuse with dopaminergic medications, perhaps limiting enthusiasm for studying dopaminergic antidepressants. But there have been animal studies that have found no evidence of abuse liability with certain dopaminergic medications. For example, in a study of rats given a medication with dopaminergic as well as serotonergic and noradrenergic activity, the rats did not exhibit self-administration of the medication (a marker of abuse liability) (20); another study found that administration of a similar medication was associated with decreased ethanol consumption in alcohol-preferring rats (21).

Triple uptake inhibitors (TUIs) are attracting particular interest because of the promise of modulating three monoamine neurotransmitter systems at once. The hope is that these “all-in-one” compounds would have the synergistic effects of triple inhibition and lead to more robust antidepressant effects without requiring high occupancy of the serotonin transporter, thus minimizing many of the side effects seen with SSRIs. The TUI amitifadine has demonstrated positive results on several depression outcome measures, including an anhedonia measure, without significant weight gain or sexual dysfunction in a small phase 2 trial (22).

Finally, in a parallel line of research, pharmaceutical companies are pursuing variations on monoamine oxidase inhibitors, which decrease the breakdown of serotonin, norepinephrine, and dopamine and thus increase their levels. One of the major limitations of the early monoamine oxidase inhibitors was that they affected both the MAO-A and MAO-B forms of the enzyme and are generally irreversible, making it particularly dangerous to ingest dietary tyramine. Without either form of the enzyme available to break down tyramine for 2 weeks (the length of time it takes to regenerate the enzyme), patients were at high risk for hypertensive crisis after consuming foods containing tyramine. This was the impetus behind the development of reversible MAOIs, such as moclobemide and the newer CX 157 (TriRima). TriRima is thought to be more potent than moclobemide and also to be a powerful inhibitor of MAO-A (23), which is primarily responsible for breaking down serotonin, norepinephrine, melatonin and epinephrine (dopamine is equally metabolized by MAO-A and MAO-B).

Breaking away from the traditional focus on serotonin, norepinephrine, and dopamine, a number of researchers are investigating drugs that work on other neurotransmitters that have been implicated in depression, including glutamatergic medications and compounds that target nicotinic receptors.

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Glutamatergic drugs

Glutamate is one of the main excitatory neurotransmitters in the CNS, exerting its effects primarily via one of several receptor subtypes: N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, kainate receptors, and type I, II, III metabotropic glutamate receptors. Because of evidence of glutamate dysfunction in major depression and of neuroprotective properties of NMDA receptor antagonists (24), there is speculation that they may be effective antidepressants.

Of the NMDA antagonists currently under study for depression, the anesthetic ketamine may have the most buzz. A number of small studies have found rapid and in some cases sustained antidepressant effects after ketamine injections, for a total sample size of 163 patients (25). A number of trials are attempting to confirm these effects in larger, more rigorous trials and to examine how the effects can be sustained. The main drawback of ketamine at this point is that it must be administered intravenously in a hospital setting.

Other NMDA antagonists receiving attention for depression include riluzole, amantadine, traxoprodil, and dextromethorphan. Riluzole, a medication that noncompetitively inhibits NMDA receptors as well as the release of glutamic acid and that was originally approved for amyotrophic lateral sclerosis, has demonstrated antidepressant-like effects in several small studies (26, 27). Amantadine, which possesses dopaminergic activity in addition to antagonizing NMDA receptors, showed positive effects in a double-blind augmentation study for depressed imipramine nonresponders (28). Another NMDA receptor antagonist, traxoprodil, has demonstrated antidepressant effects in patients who have not responded to SSRI treatment (29). Finally, the cold remedy dextromethorphan is attracting attention as well because it has some actions similar to ketamine, such as NMDA antagonism, serotonin transporter inhibition, and mu (opiate) receptor potentiation. As Nuedexta (dextromethorphan/quinidine), it has already received FDA approval for the treatment of pseudobulbar affect, and some researchers speculate that it could find utility as a conventional antidepressant, rapid-acting antidepressant, or treatment for treatment-refractory depression (30).

However, results with memantine have been somewhat disappointing. Despite promising results from a small open-label study with depressed patients (31) and a double-blind randomized controlled trial of memantine plus escitalopram in major depression comorbid with alcohol dependence (32), Zarate et al. found no effect in a double-blind, randomized, controlled study of memantine for depression monotherapy (33).

Additionally, several concerns about glutamatergic medications have reduced enthusiasm for them, most notably questions about psychedelic effects. Some of these agents possess hallucinogenic properties and may induce psychosis-like symptoms in subjects who have no previous history of psychosis (34, 35).

The potential role of glutamatergic agents that act on AMPA, kainate, or metabotropic glutamate receptors in treating psychiatric disorders is not as well studied, although there is considerable interest in these compounds as well. Given the beneficial effects of glutamatergic agents such as AMPA receptor modulators on cognition, there was hope that agents could be effective in the treatment of cognitive dysfunction in depression, or in the treatment of MDD presenting with prominent cognitive dysfunction (3637). Unfortunately, one of the first trials of an AMPA receptor modulator, farampator (CX-691/Org 24448), was terminated early due to concerns about adverse effects observed in other studies (38).

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Nicotinic Medications

Several lines of evidence have led to interest in nicotinic medications for depression. Several antidepressants, such as the tricyclic antidepressant imipramine, have antagonist activity at the nicotinic receptor, and there is evidence of nicotinic receptor dysfunction in depression (39). The link between nicotine dependence and depression is well established, with higher rates of smoking in patients with major depressive disorder (40) and vice versa (41). In addition, the nicotinic receptor may be involved in memory, cognition and behavioral reinforcement/addiction. For example, the alpha4beta2 subtype of nicotinic receptors has been reported to play a role in acetylcholine-mediated dopamine release in areas of the brain that are involved in behavioral reinforcement and addiction—specifically, the striatum, ventral tegmental area, and nucleus accumbens (4244). The alpha7 receptors have been linked to learning and memory in preclinical studies (45).

An early open-label study of the alpha4beta2 partial agonist and alpha7 full agonist varenicline, already approved for smoking cessation, found an improvement in mood when depressed smokers started taking the medication to augment their existing psychotropic treatment (46). However, despite promising Phase II studies, the noncompetitive nicotinic receptor antagonist mecamylamine did not meet primary endpoints in Phase III trials and has been pulled from development (47).

With evidence accumulating for the role of the endogenous opioid system in regulating mood, attention is turning to opioid-based medications for their potential role in depression treatment. There are three types of opioid receptors—delta, kappa, and mu—and all three have been linked variously to monoaminergic activity (4850), behaviors in stressful situations such as the forced swim test (51), and antidepressant response (52, 53). In humans, depressed individuals and healthy comparison subjects exhibited different patterns of mu opioid receptor availability in emotionally neutral and sad states (54), supporting a role for opioids in mood. In addition, polymorphisms in the mu opioid receptor gene were associated with citalopram response in STAR*D (55).

While much remains to be understood about the relationship between the opioid system and mood disorders—it may play a role in schizophrenia and impulse control disorders as well as mood disorders and addiction (56, 57)—researchers are already proceeding with studies of opioid-based medications for depression. As early as 1982, some studies were finding antidepressant effects of buprenorphine, a mu opioid receptor agonist and kappa opioid receptor antagonist (58), and it is currently being tested as monotherapy or augmentation for depression. Another drug in Phase II testing is ALKS 5461, which combines buprenorphine and the mu antagonist samidorphan; it showed improvements in depression symptoms in treatment-resistant patients after one week in Phase II trials (59).

Unsurprisingly given their powerful and far-ranging effects on the body, a number of hormones can influence psychiatric symptoms. Hypothyroidism, for example, often causes depressive symptoms, while corticosteroids can induce mood lability, mood disturbance, or even psychosis. Thus a number of antidepressant development approaches are focusing on hormonal pathways.

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Treatments That Act on the Hypothalamic-Pituitary-Adrenal Axis

Disturbances in the hypothalamic-pituitary-adrenal (HPA) axis are a well-established feature of depression. In particular, basic and clinical studies have found evidence of increased secretion of the hypothalamic neuropeptides vasopressin and corticotrophin-releasing factor (CRF) in depression and anxiety, leading to interest in treatments addressing these mechanisms. Vasopressin is released from the pituitary during stress and potentiates the body’s release of adrenocorticotropin in response to CRF. Animal studies in rats and birds first suggested that vasopressin may be essential to the body’s ability to adapt to stress (6062). Because the V1b receptor is responsible for the pituitary response to vasopressin, it has become a target for drug development in depression and anxiety. The nonpeptide V1b receptor antagonist SSR149415 showed mixed results on efficacy for depression in several phase IIb studies for efficacy and tolerability, though the studies did not yield significant results for efficacy as treatment for generalized anxiety disorder. The authors concluded that “the antidepressant potential of SSR149415 needs to be further evaluated” (62).

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Melatonergic Medications

The circadian system plays an important role in mood disorders. Sleep disturbances are a core feature of both major depression and bipolar disorder; seasonal affective disorder is tied to the length of daylight in different seasons; and there is even some evidence that sleep deprivation can cause mood symptoms. Thus, the hormone melatonin, which is a serotonin precursor that maintains the body’s internal clock and may also play a neuroprotective role, has drawn significant attention for its potential in depression treatment.

One melatonergic drug under study for depression as well as anxiety and obsessive-compulsive disorder is agomelatine, which is a melatonergic receptor agonist (MT1/MT2) as well as a 5HT2c antagonist. While early research concentrated on its utility for sleep disorders, the first dose-finding trials for its use in major depression were published in 2002 (63), and it gained approval for treating depression in Europe in 2009. Because it has minimal serotonergic action other than 5HT2c antagonism, agomelatine is thought to be less likely to cause gastrointestinal, sexual, and metabolic side effects; its main side effect appears to be dizziness (64). Discontinuation syndrome may also be less frequent with this medication (65). However, in some studies, approximately 1%–4.5% of patients taking the medication developed a transient and reversible elevation in hepatic transaminases, sometimes only at higher doses (6668). Due to these concerns as well as poor Phase III trial results in the U.S (69), Novartis discontinued development of agomelatine in the U.S. in October 2011, although clinical trials by other groups are continuing.

The hot word in medicine is pharmacogenetics, and the field of antidepressant research is no exception. The idea is that by knowing a person’s genetic profile with regard to variants that affect response to medication treatment, it would be possible to personalize his or her treatment to be more effective while reducing side effects.

The targets attracting the most interest in depression research are genes coding for neurotransmitter or drug transporters or receptors and genes coding for enzymes that break down those neurotransmitters or drugs. Some of the earliest studies focused on polymorphisms in the promoter region of the serotonin transporter gene, such as 5-HTTLPR, which was linked to affective disorders more than 15 years ago (70) and has been implicated in response to antidepressants and antidepressant-induced mania (71). More recently, it has become possible to screen the genome with hundreds or thousands of single-nucleotide polymorphisms (SNPs) in genome-wide association studies (GWAS) to identify other potential targets. For example, STAR*D collected DNA from approximately 2,000 study participants with nonpsychotic major depressive disorder; this data were used to identify new genes associated with citalopram response and resistance, evaluate the role of genes previously thought to be associated with some aspect of depression treatment, and examine markers associated with side effects such as suicidal ideation (72). Another GWAS, the Genome-based Therapeutic Drugs for Depression (GENDEP) study of 760 adults with moderate-to-severe depression, focused on serotonergic, noradrenergic, neurotrophic, and glutamatergic mechanisms (73).

Perhaps not unexpectedly given the limited sample sizes and the large number of polymorphisms being evaluated, these large studies have sometimes produced contradictory results. For example, the STAR*D data did not confirm earlier suggestions of a significant relationship between treatment response and polymorphisms in the BDNF gene (74) and provided a complicated picture about the role of the serotonin transporter gene and its promoter region (reported variously to have no relationship to citalopram response, a relationship to tolerability but not treatment response, and a relationship to citalopram response in non-Hispanic whites in STAR*D) (72). The Munich Antidepressant Response Signature (MARS) study of 387 adults with depressive disorders (including about 10% with bipolar depression) failed to replicate the STAR*D findings, although a predictive model including effects of and interactions between three genes involved in serotonergic, glutamatergic, and HPA activity accounted for 13% of the variance in remission after 5 weeks, consistent with the STAR*D findings (75). Part of the difficulty is that the magnitude of the relationship between individual variants and treatment response has generally been modest (76). Another problem is that multiple genetic variations may influence response to an individual drug, making it even more difficult to predict response with the knowledge currently available.

Another major question with pharmacogenetics and personalized medicine is cost effectiveness. Perlis et al. calculated that testing 40-year-old men with major depression for response to SSRIs and using bupropion in likely nonresponders would cost $93,520 per additional quality-adjusted life-year (QALY) compared with treating all patients with an SSRI first and switching in the case of nonresponse (77); by contrast, the average cost per QALY for dialysis compared with the next cheaper options is $129,090 (78). An analysis of the economics of using 5-HTTLPR genotyping in Europe concluded that testing would be cost-effective in middle-income countries if it cost $100 or less (79).

Ethical and legal questions pose another area of concern. Among the potential risks cited in a survey of 75 psychiatrists at “early adopter” institutions offering pharmacogenetic testing clinically, respondents expressed the most concern about the risks of getting secondary information about disease risks and endorsed the importance of confidentiality and informed consent; however, there was a lack of consensus overall about risks and the safeguards needed to protect patients (80).

Nevertheless, pharmacogenetic testing is already available for several hundred dollars a test (81) at a number of institutions. In the survey by Hoop et al. cited above, 64% of respondents had ordered at least one pharmacogenetic test in the last year. Genetic testing appears to be ordered most often for cases of treatment-resistant depression or medication intolerance (80, 82). Thus researchers have recommended developing guidelines for testing that take into account clinical severity and indicators of treatment resistance (82).

Despite mixed or disappointing results from some of these drug trials and difficult times for psychiatric drug development in general, there are nevertheless promising signs in antidepressant medication research. Our increasing ability to target individual neurotransmitter receptors with specific agonist or antagonist activity could lead to more effective and more tolerable medications. After a long drought in the development of truly novel pathways for antidepressant action, the fact that mechanisms other than monoamine neurotransmission are being targeted is encouraging. Furthermore, in addition to allowing for the personalization of medication treatment, the study of psychiatric genetics and biomarkers of antidepressant response could expand knowledge about the pathophysiology of depression and unearth new treatment targets for the future.

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Sanacora  G:  Do glutamatergic agents represent a new class of antidepressant drugs? Part 1.  J Clin Psychiatry 2009; 70:1473–1475
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Aan Het Rot  M;  Zarate  CA  Jr;  Charney  DS;  Mathew  SJ:  Ketamine for depression: where do we go from here? Biol Psychiatry 2012; 72:537–547
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Sanacora  G;  Kendell  SF;  Levin  Y;  Simen  AA;  Fenton  LR;  Coric  V;  Krystal  JH:  Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms.  Biol Psychiatry 2007; 61:822–825
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Zarate  CA  Jr;  Payne  JL;  Quiroz  J;  Sporn  J;  Denicoff  KK;  Luckenbaugh  D;  Charney  DS;  Manji  HK:  An open-label trial of riluzole in patients with treatment-resistant major depression.  Am J Psychiatry 2004; 161:171–174
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Rogóz  Z;  Skuza  G;  Daniel  WA;  Wójcikowski  J;  Dudek  D;  Wróbel  A:  Amantadine as an additive treatment in patients suffering from drug-resistant unipolar depression.  Pharmacol Rep 2007; 59:778–784
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Preskorn  SH;  Baker  B;  Kolluri  S;  Menniti  FS;  Krams  M;  Landen  JW:  An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder.  J Clin Psychopharmacol 2008; 28:631–637
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Lauterbach  EC:  An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan.  Med Hypotheses 2012; 78:693–702
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Ferguson  JM;  Shingleton  RN:  An open-label, flexible-dose study of memantine in major depressive disorder.  Clin Neuropharmacol 2007; 30:136–144
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Muhonen  LH;  Lönnqvist  J;  Juva  K;  Alho  H:  Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence.  J Clin Psychiatry 2008; 69:392–399
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Zarate  CA  Jr;  Singh  JB;  Quiroz  JA;  De Jesus  G;  Denicoff  KK;  Luckenbaugh  DA;  Manji  HK;  Charney  DS:  A double-blind, placebo-controlled study of memantine in the treatment of major depression.  Am J Psychiatry 2006; 163:153–155
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Canan  F;  Ataoglu  A:  Memantine-related psychotic symptoms in a patient with bipolar disorder.  J Clin Psychiatry 2010; 71:957
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Smith  EJ:  Amantadine-induced psychosis in a young healthy patient.  Am J Psychiatry 2008; 165:1613
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Mathew  SJ;  Keegan  K;  Smith  L:  Glutamate modulators as novel interventions for mood disorders.  Rev Bras Psiquiatr 2005; 27:243–248
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Sanacora  G:  Do glutamatergic agents represent a new class of antidepressant drugs? Part 2.  J Clin Psychiatry 2009; 70:1604–1605
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Saricicek  A;  Esterlis  I;  Maloney  KH;  Mineur  YS;  Ruf  BM;  Muralidharan  A;  Chen  JI;  Cosgrove  KP;  Kerestes  R;  Ghose  S;  Tamminga  CA;  Pittman  B;  Bois  F;  Tamagnan  G;  Seibyl  J;  Picciotto  MR;  Staley  JK;  Bhagwagar  Z:  Persistent β(2)*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder.  Am J Psychiatry 2012; 169:851–859
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Zimmerman  M;  Chelminski  I;  McDermut  W:  Major depressive disorder and axis I diagnostic comorbidity.  J Clin Psychiatry 2002; 63:187–193
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Grant  BF;  Hasin  DS;  Chou  SP;  Stinson  FS;  Dawson  DA:  Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions.  Arch Gen Psychiatry 2004; 61:1107–1115
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Chen  Y;  Sharples  TJ;  Phillips  KG;  Benedetti  G;  Broad  LM;  Zwart  R;  Sher  E:  The nicotinic alpha 4 beta 2 receptor selective agonist, TC-2559, increases dopamine neuronal activity in the ventral tegmental area of rat midbrain slices.  Neuropharmacology 2003; 45:334–344
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Grilli  M;  Patti  L;  Robino  F;  Zappettini  S;  Raiteri  M;  Marchi  M:  Release-enhancing pre-synaptic muscarinic and nicotinic receptors co-exist and interact on dopaminergic nerve endings of rat nucleus accumbens.  J Neurochem 2008; 105:2205–2213
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Sharples  CG;  Kaiser  S;  Soliakov  L;  Marks  MJ;  Collins  AC;  Washburn  M;  Wright  E;  Spencer  JA;  Gallagher  T;  Whiteaker  P;  Wonnacott  S:  UB-165: a novel nicotinic agonist with subtype selectivity implicates the alpha4beta2* subtype in the modulation of dopamine release from rat striatal synaptosomes.  J Neurosci 2000; 20:2783–2791
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Levin  ED:  α7-Nicotinic receptors and cognition.  Curr Drug Targets 2012; 13:602–606
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Philip  NS;  Carpenter  LL;  Tyrka  AR;  Whiteley  LB;  Price  LH:  Varenicline augmentation in depressed smokers: an 8-week, open-label study.  J Clin Psychiatry 2009; 70:1026–1031
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Margolis  EB;  Hjelmstad  GO;  Bonci  A;  Fields  HL:  Kappa-opioid agonists directly inhibit midbrain dopaminergic neurons.  J Neurosci 2003; 23:9981–9986
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Margolis  EB;  Hjelmstad  GO;  Bonci  A;  Fields  HL:  Both kappa and mu opioid agonists inhibit glutamatergic input to ventral tegmental area neurons.  J Neurophysiol 2005; 93:3086–3093
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Land  BB;  Bruchas  MR;  Schattauer  S;  Giardino  WJ;  Aita  M;  Messinger  D;  Hnasko  TS;  Palmiter  RD;  Chavkin  C:  Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking.  Proc Natl Acad Sci USA 2009; 106:19168–19173
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Ide  S;  Sora  I;  Ikeda  K;  Minami  M;  Uhl  GR;  Ishihara  K:  Reduced emotional and corticosterone responses to stress in mu-opioid receptor knockout mice.  Neuropharmacology 2010; 58:241–247
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Berrocoso  E;  Rojas-Corrales  MO;  Micó  JA:  Non-selective opioid receptor antagonism of the antidepressant-like effect of venlafaxine in the forced swimming test in mice.  Neurosci Lett 2004; 363:25–28
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Ide  S;  Fujiwara  S;  Fujiwara  M;  Sora  I;  Ikeda  K;  Minami  M;  Uhl  GR;  Ishihara  K:  Antidepressant-like effect of venlafaxine is abolished in μ-opioid receptor-knockout mice.  J Pharmacol Sci 2010; 114:107–110
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Kennedy  SE;  Koeppe  RA;  Young  EA;  Zubieta  JK:  Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women.  Arch Gen Psychiatry 2006; 63:1199–1208
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Garriock  HA;  Tanowitz  M;  Kraft  JB;  Dang  VC;  Peters  EJ;  Jenkins  GD;  Reinalda  MS;  McGrath  PJ;  von Zastrow  M;  Slager  SL;  Hamilton  SP:  Association of mu-opioid receptor variants and response to citalopram treatment in major depressive disorder.  Am J Psychiatry 2010; 167:565–573
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Tejeda  HA;  Shippenberg  TS;  Henriksson  R:  The dynorphin/κ-opioid receptor system and its role in psychiatric disorders.  Cell Mol Life Sci 2012; 69:857–896
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Carlezon  WA  Jr;  Béguin  C;  Knoll  AT;  Cohen  BM:  Kappa-opioid ligands in the study and treatment of mood disorders.  Pharmacol Ther 2009; 123:334–343
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Emrich  HM;  Vogt  P;  Herz  A:  Possible antidepressive effects of opioids: action of buprenorphine.  Ann N Y Acad Sci 1982; 398:108–112
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Fava M, Bodkin JA, Thase M, Trivedi M, Leigh-Pemberton R, Du Y, Ehrich E: A pilot study of ALKS 5461 (buprenorphine combined with ALKS 33) in treatment-resistant depression. Poster presented at NCDEU annual meeting, May 31, 2012, Phoenix, AZ.
 
Ebner  K;  Wotjak  CT;  Landgraf  R;  Engelmann  M:  Forced swimming triggers vasopressin release within the amygdala to modulate stress-coping strategies in rats.  Eur J Neurosci 2002; 15:384–388
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Goodson  JL;  Evans  AK:  Neural responses to territorial challenge and nonsocial stress in male song sparrows: segregation, integration, and modulation by a vasopressin V1 antagonist.  Horm Behav 2004; 46:371–381
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Griebel  G;  Beeske  S;  Stahl  SM:  The V1b receptor antagonist SSRI49415 in the treatment of major depressive and generalized anxiety disorders: results from four double-blind, placebo-controlled studies.  J Clin Psychiatry  (in press)
 
Lôo  H;  Hale  A;  D’haenen  H:  Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study.  Int Clin Psychopharmacol 2002; 17:239–247
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Demyttenaere  K:  Agomelatine: a narrative review.  Eur Neuropsychopharmacol 2011; 21(Suppl 4):S703–S709
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Montgomery  SA;  Kennedy  SH;  Burrows  GD;  Lejoyeux  M;  Hindmarch  I:  Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study.  Int Clin Psychopharmacol 2004; 19:271–280
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Kennedy  SH;  Rizvi  SJ:  Agomelatine in the treatment of major depressive disorder: potential for clinical effectiveness.  CNS Drugs 2010; 24:479–499
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Stahl  SM;  Fava  M;  Trivedi  MH;  Caputo  A;  Shah  A;  Post  A:  Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebo-controlled trial.  J Clin Psychiatry 2010; 71:616–626
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Zajecka  J;  Schatzberg  A;  Stahl  S;  Shah  A;  Caputo  A;  Post  A:  Efficacy and safety of agomelatine in the treatment of major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled trial.  J Clin Psychopharmacol 2010; 30:135–144
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Collier  DA;  Stöber  G;  Li  T;  Heils  A;  Catalano  M;  Di Bella  D;  Arranz  MJ;  Murray  RM;  Vallada  HP;  Bengel  D;  Müller  CR;  Roberts  GW;  Smeraldi  E;  Kirov  G;  Sham  P;  Lesch  KP:  A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders.  Mol Psychiatry 1996; 1:453–460
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Mundo  E;  Walker  M;  Cate  T;  Macciardi  F;  Kennedy  JL:  The role of serotonin transporter protein gene in antidepressant-induced mania in bipolar disorder: preliminary findings.  Arch Gen Psychiatry 2001; 58:539–544
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Laje  G;  Perlis  RH;  Rush  AJ;  McMahon  FJ:  Pharmacogenetics studies in STAR*D: strengths, limitations, and results.  Psychiatr Serv 2009; 60:1446–1457
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Uher  R;  Huezo-Diaz  P;  Perroud  N;  Smith  R;  Rietschel  M;  Mors  O;  Hauser  J;  Maier  W;  Kozel  D;  Henigsberg  N;  Barreto  M;  Placentino  A;  Dernovsek  MZ;  Schulze  TG;  Kalember  P;  Zobel  A;  Czerski  PM;  Larsen  ER;  Souery  D;  Giovannini  C;  Gray  JM;  Lewis  CM;  Farmer  A;  Aitchison  KJ;  McGuffin  P;  Craig  I:  Genetic predictors of response to antidepressants in the GENDEP project.  Pharmacogenomics J 2009; 9:225–233
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Domschke  K;  Lawford  B;  Laje  G;  Berger  K;  Young  R;  Morris  P;  Deckert  J;  Arolt  V;  McMahon  FJ;  Baune  BT:  Brain-derived neurotrophic factor (BDNF) gene: no major impact on antidepressant treatment response.  Int J Neuropsychopharmacol 2010; 13:93–101
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Horstmann  S;  Lucae  S;  Menke  A;  Hennings  JM;  Ising  M;  Roeske  D;  Müller-Myhsok  B;  Holsboer  F;  Binder  EB:  Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment.  Neuropsychopharmacology 2010; 35:727–740
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Laje  G;  McMahon  FJ:  The pharmacogenetics of major depression: past, present, and future.  Biol Psychiatry 2007; 62:1205–1207
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Perlis  RH;  Patrick  A;  Smoller  JW;  Wang  PS:  When is pharmacogenetic testing for antidepressant response ready for the clinic? A cost-effectiveness analysis based on data from the STAR*D study.  Neuropsychopharmacology 2009; 34:2227–2236
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Lee  CP;  Chertow  GM;  Zenios  SA:  An empiric estimate of the value of life: updating the renal dialysis cost-effectiveness standard.  Value Health 2009; 12:80–87
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Olgiati  P;  Bajo  E;  Bigelli  M;  De Ronchi  D;  Serretti  A:  Should pharmacogenetics be incorporated in major depression treatment? Economic evaluation in high- and middle-income European countries.  Prog Neuropsychopharmacol Biol Psychiatry 2012; 36:147–154
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Hoop  JG;  Lapid  MI;  Paulson  RM;  Roberts  LW:  Clinical and ethical considerations in pharmacogenetic testing: views of physicians in 3 “early adopting” departments of psychiatry.  J Clin Psychiatry 2010; 71:745–753
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Rundell  JR;  Staab  JP;  Shinozaki  G;  Saad-Pendergrass  D;  Moore  K;  McAlpine  D;  Mrazek  D:  Pharmacogenomic testing in a tertiary care outpatient psychosomatic medicine practice.  Psychosomatics 2011; 52:141–146
[CrossRef] | [PubMed]
 
References Container
Anchor for Jump
Table 1.Antidepressant Medications in the Pipeline
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References

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Henigsberg  N;  Mahableshwarkar  AR;  Jacobsen  P;  Chen  Y;  Thase  ME:  A randomized, double-blind, placebo-controlled 8-week trial of the efficacy and tolerability of multiple doses of lu aa21004 in adults with major depressive disorder.  J Clin Psychiatry 2012; 73:953–959
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Pangallo  B;  Dellva  MA;  D’Souza  DN;  Essink  B;  Russell  J;  Goldberger  C:  A randomized, double-blind study comparing LY2216684 and placebo in the treatment of major depressive disorder.  J Psychiatr Res 2011; 45:748–755
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Fava  M;  Thase  ME;  DeBattista  C;  Doghramji  K;  Arora  S;  Hughes  RJ:  Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness.  Ann Clin Psychiatry 2007; 19:153–159
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Clayton  AH;  Warnock  JK;  Kornstein  SG;  Pinkerton  R;  Sheldon-Keller  A;  McGarvey  EL:  A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction.  J Clin Psychiatry 2004; 65:62–67
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Thase M, Fava M, Hobart M, Skuban A, Zhang P, McQuade RD, Carson WH, Sanchez R, Forbes RA: Efficacy and safety of adjunctive OPC-34712 in major depressive disorder: a phase II, randomized, placebo-contolled study. Poster presented at the American Psychiatric Association annual meeting, Honolulu, HI, May 16, 2011.
 
Harvey P, Roth RM, Bilder RM, Richards C, Lasser R, Geibel B, Gao J, Scheckner B, Trivedi M: Assessment of executive dysfunction in adults with major depressive disorder receiving lisdexamfetamine dismesylate augmentation of escitalopram. Poster presented at the American Psychiatric Association annual meeting, May 6, 2012, Philadelphia, PA.
 
Keefe R, Boyd A, Madhoo M, Roth RM, Sambunaris A, Wu J, Trivedi M, Anderson CS, Lasser R: Lisdexamfetamine dimesylate in the treatment of cognitive dysfunction in patients with partially or fully remitted major depressive disorder. Poster presented at the American Psychiatric Association annual meeting, May 8, 2012, Philadelphia, PA.
 
Liang  Y;  Shaw  AM;  Boules  M;  Briody  S;  Robinson  J;  Oliveros  A;  Blazar  E;  Williams  K;  Zhang  Y;  Carlier  PR;  Richelson  E:  Antidepressant-like pharmacological profile of a novel triple reuptake inhibitor, (1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS).  J Pharmacol Exp Ther 2008; 327:573–583
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McMillen  BA;  Shank  JE;  Jordan  KB;  Williams  HL;  Basile  AS:  Effect of DOV 102,677 on the volitional consumption of ethanol by Myers’ high ethanol-preferring rat.  Alcohol Clin Exp Res 2007; 31:1866–1871
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Fowler  JS;  Logan  J;  Azzaro  AJ;  Fielding  RM;  Zhu  W;  Poshusta  AK;  Burch  D;  Brand  B;  Free  J;  Asgharnejad  M;  Wang  GJ;  Telang  F;  Hubbard  B;  Jayne  M;  King  P;  Carter  P;  Carter  S;  Xu  Y;  Shea  C;  Muench  L;  Alexoff  D;  Shumay  E;  Schueller  M;  Warner  D;  Apelskog-Torres  K:  Reversible inhibitors of monoamine oxidase-A (RIMAs): robust, reversible inhibition of human brain MAO-A by CX157.  Neuropsychopharmacology 2010; 35:623–631
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Sanacora  G:  Do glutamatergic agents represent a new class of antidepressant drugs? Part 1.  J Clin Psychiatry 2009; 70:1473–1475
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Aan Het Rot  M;  Zarate  CA  Jr;  Charney  DS;  Mathew  SJ:  Ketamine for depression: where do we go from here? Biol Psychiatry 2012; 72:537–547
[CrossRef] | [PubMed]
 
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References Container
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CME Activity

Add a subscription to complete this activity and earn CME credit.
Sample questions:
1.
It appears that peripheral cytokines enter or communicate with the CNS through which of the following mechanisms:

See Soskin and Fava: Peripheral cytokine signals can access the brain, p 145
2.
Pre-treatment with the antidepressant paroxetine, in patients receiving the pro-inflammatory cytokine, interferon-alpha, for hepatitis C or malignant melanoma has been shown to dramatically reduce rates of depression during cytokine therapy?

See Soskin and Fava: Interferon model, p 414
3.
Following a first episode of major depression lasting less than two years, the estimated likelihood of another episode across the lifespan is approximately which of the following:

See Shelton and Hollon, Introduction, p 434
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