The keys to improving depression outcomes

European Neuropsychopharmacology (2011) 21, S694–S702

www.elsevier.com/locate/euroneuro

REVIEW

The keys to improving depression outcomes Sakina J. Rizvi a, b , Sidney H. Kennedy b, c,⁎ a

Departments of Pharmaceutical Sciences and Neuroscience, University of Toronto, Toronto, Ontario Canada Department of Psychiatry, University Health Network, Toronto, Ontario Canada c Department of Psychiatry, University of Toronto, Toronto, Ontario Canada b

KEYWORDS: Antidepressants; Depression; Circadian rhythms; Cytokines; Glutamate; Melatonin; Neuropeptides; Neurostimulation

Abstract The heterogeneity of symptoms within major depressive disorder poses significant challenges for treatment and it is likely that current pharmacotherapies do not target all symptoms equally, although they have similar efficacy rates. While there is still continuing interest in understanding monoamine interactions and consequent downstream effects, the limited efficacy and tolerability achieved with classical antidepressants provides a compelling argument to move beyond the monoamines. Several lines of biological research in depression exploring immune function, neurotrophins, amino acid and neuropeptide neurotransmitters, neuroanatomical function and circadian rhythms, may lead to novel therapeutic targets and enhance depression outcomes. This review will evaluate the evidence for emerging treatments as well as recommendations from current international guidelines regarding antidepressant management. © 2011 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction In the past decade, research in major depressive disorder (MDD) and its treatment has focused on biological variables and gene-environment interactions that may predispose an individual to depression or influence the outcome of specific treatments. The need to integrate genetic, neurochemical, and neural circuitry variables into treatment development is emphasized by modest outcomes with conventional antidepressants (Warden et al., 2007). This review will consider several lines of biological research in depression that may

⁎ Corresponding author at: University Health Network, Room 222, Eaton North Wing 8th Floor, 200 Elizabeth Street, Toronto Canada ON M5G 2C4. Tel.: + 1 416 340 3888; fax: +1 416 340 4198. E-mail address: [email protected] (S.H. Kennedy).

direct the pursuit of novel targets and enhance outcomes with existing treatments. These include exploring various aspects of stress biology, including disruptions to immune function, neural structure and function, as well as circadian rhythms. Table 1 summarizes these targets as well as putative antidepressants (see Kennedy & Rizvi, 2009 for review).

2. Diagnostic issues The first step in treating depression effectively is the ability to make an accurate diagnosis. However, patients with MDD experience a wide array of symptoms beyond the mandatory core symptoms of depressed mood and anhedonia (APA, 2000). This heterogeneity poses significant challenges in treating depression and it is likely that current pharmacotherapies do not target the same symptoms equally, although they have

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The keys to improving depression outcomes Table 1

S695

Targets for antidepressant development.

System

Targets

Monoamines

Serotonin transporters/receptors, Norepinephrine transporters/receptors, Dopamine transporters/receptors Glucocorticoids, Neurokinin receptors, TNFα, COX-2 inhibitors, IL-6

Stress hormones and cytokines Neurogenesis Glutamate Brain structure and function Circadian rhythms

Putative antidepressants

Vilazodone Lu-AA21004 DOV 216,303 Mifepristone Saredutant Infliximab Celecoxib BDNF BCI-540 NMDA receptors Ketamine Riluzole Traxopridil Tianeptine Frontal cortex, Subcallosal cingulate gyrus, Nucleus Accumbens, rTMS DBS VNS Ventral Striatum, Vagus nerve Melatonin receptors, Serotonin receptors Agomelatine

BDNF: brain-derived neurotrophic factor; DBS: deep brain stimulation; IL: interleukin; NMDA: n-methyl-D-aspartate; rTMS: repetitive transcranial magnetic stimulation; TNF: tumor necrosis factor; VEGF: vascular endothelial growth factor; VNS: vagus nerve stimulation.

similar efficacy rates. For example, selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have generally comparable anxiolytic properties, while bupropion is less effective in treating anxiety in depressed patients (Papakostas et al., 2008); however, bupropion is more effective than SSRIs in reducing fatigue and daytime sleepiness (Papakostas et al., 2006). On the other hand, longitudinal studies have not supported the value of different symptom profiles as predictors of antidepressant response (Mulder et al., 2006). Better characterization of MDD subtypes and the variety of symptoms experienced may help to improve homogeneity of diagnosis. For example, more than 50% of MDD patients meet the criteria for a comorbid anxiety disorder (Simon et al., 2003). This is reflected in a proposed revision of the upcoming Diagnostic and Statistical Manual of Mental Disorders — edition 5 (DSM-5) to include an anxiety dimension across all mood disorder categories and a separate category for “Mixed Anxiety Depression”, defined by MDD symptoms along with significant anxiety distress without having a concurrent anxiety disorder (First, 2011). Consequently, developing treatments for subpopulations identified by symptom variables may enhance antidepressant outcomes. Furthermore, having patients with different symptom profiles without accurate subtyping presents difficulties in defining potential biomarkers for diagnosis and treatment selection.

3. Classic antidepressant targets: monoamines Given the role of serotonin, norepinephrine, and dopamine in depression (Nutt, 2008), there is continuing interest in understanding monoamine interactions and consequent downstream effects. Currently available antidepressants largely target serotonin or serotonin and norepinephrine, and to a lesser extent dopamine systems. Given the modest remission rates achieved with these drugs, there is a compelling argument to move beyond the monoamines. However, the multitude of evidence implicating monoamines in depression provides support for continued development of drugs targeting these systems, especially if early improvement and increased tolerability can be achieved.

There has been considerable evidence demonstrating that monoamine antidepressants have a delayed onset of action of approximately 2 weeks or more; however, more recent data suggests antidepressants have effects as early as one week (Anderson et al., 2008; Szegedi et al., 2009). Combining 5HT1A agonism and serotonin transporter blockade is of interest based on the hypothesis that the delay in antidepressant onset of action is due to a paradoxical decrease in serotonin transmission through inhibition of 5HT1A receptors. Consequently, desensitization of this receptor in depression is thought to be necessary in order to achieve early clinical response (Rausch et al., 2006). Vilazodone, an antidepressant recently approved by the FDA, exhibits these properties and preliminary studies report antidepressant efficacy as early as one week, with good tolerability (Rickels et al., 2009). Notably, no treatment–emergent sexual dysfunction was observed. Other multimodal serotonergic agents are under development with 5HT1A effects in addition to other 5HT receptor actions (Adell, 2010). It has to be noted, however, that previous attempts to develop other antidepressants with prominent 5HT1A agonist effects (e.g., flibanserin, gepirone) have been disappointing. Concomitantly, the combination of norepinephrine reuptake inhibition and 5HT1A agonism is also being explored (Pettersson et al., 2011). Renewed interest in the role of dopamine in depression (Dunlop & Nemeroff, 2007) is an example of linking specific symptom clusters (motor/anhedonia) to neurobiology and how this can inform antidepressant development. Many prominent MDD symptoms are linked to dopamine dysfunction, with a recent study showing a correlation between increased brain activity in the nucleus accumbens, a key dopaminergic structure, and levels of anhedonia, a core depressive symptom (Hasler et al., 2008). Other investigators have explored psychomotor retardation, a depressive symptom also subserved by the dopamine system, as a predictor of antidepressant response (Caligiuri et al., 2003; Meyer et al., 2006). Unfortunately, due to concerns about abuse potential and safety risks, no medications with a direct effect on dopamine receptors are approved to treat MDD, although medications such as methylphenidate, modafinil, and pramipexole are used adjunctively for depression accompanied by low energy and motivation or sexual dysfunction (Aiken, 2007; Balon & Segraves, 2008;

S696 Candy et al., 2008). While bupropion is often described as a dopamine-modulating drug, it has a low occupancy of dopamine transporters (Meyer et al., 2002), and fails to increase dopamine firing rates (El-Mansari et al., 2008), suggesting that any effects of bupropion on dopamine reflect a secondary mechanism. It is important to note that multidirectional structural and functional relationships exist among serotonin, norepinephrine, and dopamine systems (Arencibia-Albite et al., 2007; Guiard et al., 2008), so affecting one network will consequently impact the others. Current drug development in monoamines is attempting to capitalize on these findings, and several triple reuptake inhibitors are under investigation (Prins et al., 2010).

S.J. Rizvi, S.H. Kennedy depressive symptoms, there is considerable evidence to suggest that neuronal growth, via BDNF, plays a key role in antidepressant efficacy and MDD. Most antidepressants appear to affect BDNF expression (Duman & Monteggia, 2006; Rantamäki et al., 2007; Watanabe et al., 2010), and while this may be the case for all antidepressants, it is unclear if there are significant differences among antidepressants in their ability to affect BDNF levels (Rantamäki et al., 2007). While antidepressant development in this area is still in its infancy, several potentially neurogenic compounds are being investigated at this time.

4.3. Stress biology

4. Emerging antidepressant targets 4.1. Immune function The effect of immune system dysfunction on mood has been well documented and linked to alterations in cytokines (Connor and Leonard, 1998; Miller et al., 2009). Depression is associated with higher levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) and these levels decrease with antidepressant response (Capuron et al., 2003; Hernández et al., 2008; O'Brien et al., 2007). While pro-inflammatory cytokines are also linked to medical illness such as cancer, comorbidity with depression induces higher than normal levels of IL-6 compared with cancer patients without depression (Musselman et al., 2001). Subsequent neuroimaging findings indicate that increases in IL-6-induced mood deterioration are associated with higher activity in the subgenual cingulate gyrus (Harrison et al., 2009), an area implicated in the pathophysiology of depression (Mayberg et al., 1999; Drevets et al., 2008). There is also preclinical evidence that administration of IL-6 or TNFα leads to depressive behavior, particularly psychomotor retardation, decreased sexual activity, and anhedonia. (Anisman et al., 2005; JanickiDeverts et al., 2007). Consequently several biologic agents have been evaluated as putative antidepressants, including infliximab (TNF-alpha inhibitor) (Maas et al., 2010). Antiinflammatory agents such celecoxib (COX-2 inhibitor) have also displayed potential antidepressant effects (Akhondzadeh et al., 2009; Müller, 2010).

4.2. Neurotrophins and neurogenesis In the past two decades, investigations into neurotrophins, which are necessary for the survival or growth of neurons, have significantly enhanced our understanding of neuroplasticity and areas of the brain where this occurs. Preliminary findings of increased brain-derived neurotrophic factor (BDNF), the most widely explored neurotrophin, with antidepressant treatment (Nibuya et al., 1995) fueled further research into the relationship between BDNF activity and depression. In clinical populations, serum BDNF levels have been explored as biomarkers for antidepressant response (Schmidt & Duman, 2010), and in preclinical models of depression BDNF knock-out mice also show a reduced antidepressant response (Duman & Monteggia, 2006). Although the antagonism of BDNF or its deletion in knock-out rats does not consistently result in

Stress has long been considered a key pathway to depression due to its physiological and behavioral effects through the hypothalamic-pituitary-adrenal (HPA) axis (Holsboer, 2000). Arguably, all of the potential antidepressant pathways discussed herein are affected directly or indirectly by stress. For example, stress can trigger disruptions in sleep/wake cycles, immune function, dopamine levels, and neurogenesis and may ultimately be responsible for altered brain structures (Licinio & Wong, 1999; McEwen, 2003; Mizoguchi et al., 2000). It is also recognized that the stress response involves increased glutamate neurotransmission triggered through neuropeptides, and this pattern is also observed in depression (Moghaddam, 2002; Feyissa et al., 2009; Zarate et al., 2004; Gutman et al., 2005). Consistently high levels of glutamate and neuropeptides can lead to stress-related neurotoxicity and cell death. Consequently, they are being investigated as potential antidepressant targets. Glutamate is an excitatory neurotransmitter that binds to NMDA receptors (Machado-Vieira et al., 2009). Open-label studies and one small randomized control trial of treatmentresistant MDD patients suggest that ketamine, an NMDA antagonist, has the potential to produce rapid alleviation of depressive symptoms within hours of administration (Zarate et al., 2006; Phelps et al., 2009). However, most patients relapsed within a week and the use of ketamine is limited by route of administration (intravenous), as well as significant safety concerns about its psychotomimetic properties (Zarate et al., 2006; Machado-Vieira et al., 2009). Preliminary studies in depression using riluzole and traxopridil, both NMDA antagonists, have given promising results (Sanacora et al., 2004; Preskorn et al., 2008). Other data have demonstrated that the mechanism of action of tianeptine, an antidepressant with limited availability worldwide, involves normalization of glutamatergic tone, which may be a key function in altering neuroplasticity in depression (McEwen et al., 2010). Several neuropeptides have been implicated in depression, including substance P, a neurotransmitter which binds to neurokinin (NK)-1 receptors (Mussap et al., 1993), corticotropin-releasing factor (CRF), which mediates neuroendocrine, immune, behavioral, and autonomic responses to stress (Holsboer and Ising, 2008), and the glucocorticoid receptor (GR2) (Pariante & Miller, 2001). Substance P networks are co-localized with the serotonin and norepinephrine systems. There is also evidence that depressive behaviors occur in NK-1 knock-out mice (Bilkei-Gorzo et al., 2002; Maubach et al., 2002; Conley et al., 2002), and that

The keys to improving depression outcomes substance P downregulation occurs with antidepressant response (Shirayama et al. 1996). Mifepristone, a GR antagonist, has been evaluated in MDD subpopulations and demonstrated preliminary efficacy in psychotic depression (Blasey et al., 2009; DeBattista et al., 2006), although subsequent large-scale trials were less convincing (Blasey et al., 2009). Mifepristone has also been shown to rapidly increase adult neurogenesis (Mayer et al., 2006), and block corticosterone-induced 5HT2A receptor upregulation in preclinical models (Trajkovska et al., 2009).

4.4. Brain structure and function In a recent meta-analysis of neuroanatomical volumes in MDD, the most consistent findings of brain atrophy were in the orbitofrontal, prefrontal, and anterior cingulate cortices, while moderate decreases were observed in the hippocampus and striatum (Koolschijn et al., 2009). There is also evidence of reduced hippocampal volume from the first episode of depression (Kronmüller et al., 2009), although it is not clear whether this deficit is present prior to depression onset. Functional neuroimaging studies demonstrate consistent evidence of changes in striatal activity after antidepressant therapy (Larisch et al., 1997; Meyer et al., 2006), while baseline activity in the subcallosal cingulate — Area 25 (SCg25) has also been identified as a predictor of antidepressant response (Konarski et al., 2009). Not surprisingly, these advances have helped to focus the development of new wave neurostimulation therapies. Repetitive transcranial magnetic stimulation (rTMS) involves repeated subconvulsive magnetic stimulation to the dorsal lateral prefrontal cortex, which can directly stimulate superficial cortical areas of the brain. This offers the promise of greater control over location and stimulation parameters than electroconvulsive therapy (ECT). Several studies have been published supporting the role of rTMS for treatment resistant depression (TRD) (Martiny et al., 2010; Baeken et al., 2010; Lam et al., 2008), although rTMS was less effective from clinical and cost perspectives in a randomized comparison to ECT (McLoughlin et al., 2007). Vagus Nerve Stimulation (VNS) was first indicated for epilepsy with subsequent findings of improved mood in this population (Elger et al., 2000), prompting the exploration of its use in MDD. In preclinical models, chronic VNS treatment has been found to increase the firing rate of serotonin and norepinephrine neurons (Manta et al., 2009), justifying its evaluation as an antidepressant. During surgery, electrodes are wrapped around the left vagus nerve and connected to a subcutaneous pulse generator implanted in the chest that remotely delivers electrical stimulation. Findings from openlabel studies of VNS in TRD have been more positive than results from a sham-controlled trial (Rush et al., 2000; Rush et al., 2005), although increased response rates were observed in an extension phase (Nahas et al., 2005). Deep Brain Stimulation (DBS) involves the implantation of electrodes to a specified neuroanatomical region, which are connected to a pulse generator that remotely delivers electrical stimulation. Several regions have been investigated in TRD trials including SCg25 (Mayberg et al., 2005; Lozano et al., 2008; Kennedy et al., 2011), the nucleus accumbens (Bewernick et al., 2010) and the ventral striatum (Malone et

S697 al., 2009), with the majority of cases having DBS to the SCg25. Similar response rates ranging from 50 to 60% across anatomical locations have been observed. A follow-up of an initial cohort of 20 patients receiving DBS to SCg25 demonstrated sustained effectiveness of treatment over 4– 6 years (Kennedy et al., 2011).

4.5. Circadian rhythm targets In humans, circadian rhythms are bodily physiological processes that follow a 24-hour cycle (Wirz-Justice, 2008). These include the sleep/wake cycle, as well as shifts in body temperature, cortisol, and melatonin (Souetre et al., 1989; Germain & Kupfer, 2008; Czeisler et al., 1980), which primarily respond to lightness and darkness in a person's environment. The suprachiasmatic nucleus (SCN) regulates these rhythms and mainly expresses melatonin (MT1 and MT2) and serotonin (5HT2C) receptors, which control the production of melatonin. Circadian rhythm shifts of even a few hours can have adverse bodily consequences (Burgess, 2010; Penev et al., 1998). In MDD, sleep, hormone, and body temperature cycles are all significantly disturbed, reflective of underlying circadian rhythm disruption. These observations provide support for the development of drugs targeting circadian rhythms as putative antidepressants (Legros et al., 2007). Agomelatine is a new antidepressant approved in Europe and elsewhere which is a melatoninergic receptor (MT1/2) agonist and serotonin 5-HT(2 C) receptor antagonist of proven efficacy and tolerability (Lemoine et al., 2007; Kennedy & Emsley 2006, Kasper et al., 2010). In preclinical (Descamps et al., 2009; Millan et al., 2003) and clinical (Quera-Salva et al., 2010; Kasper et al., 2010) studies it has also been shown to restore circadian rhythms. Polysomnography findings in MDD patients receiving agomelatine have demonstrated improvements in sleep efficiency and slowwave sleep architecture. Depressed patients also reported improvements in subjective quality of sleep from one week onward compared with SSRIs and venlafaxine (Quera-Salva et al., 2010, in press). Circadian rest-activity cycles of MDD patients were captured using actigraphy and demonstrated cycle improvements from one week onwards with agomelatine compared with sertraline (Kasper et al., 2010a). Circadian rhythms also influence or are influenced by stress hormones, monoamines, and neuronal growth (Burke et al., 2005; Ramírez-Rodríguez et al., 2009; Paulson & Robinson, 1994). Consistent with these findings and the effect of agomelatine in restoring circadian rhythms, enhanced dopaminergic activity in the prefrontal cortex of freely moving rats (Millan et al., 2003) as well as increased BDNF levels in the hippocampus of animals have been reported during agomelatine treatment (Calabrese et al., . 2011; Dagyt e et al., 2011; Soumier et al., 2009).

5. Current treatment options and adherence Antidepressant development based on these biological models is an example of hypothesis-driven psychiatry research to improve treatment outcomes. However, it is still important to assess and use currently available treatment options to their full potential. Various guidelines for the management of MDD provide recommendations for

S698 best practices. These include the American Psychiatric Association (APA, 2010), the British Association for Psychopharmacology (BAP; Anderson et al., 2008), the Canadian Network for Mood and Anxiety Treatments (CANMAT; Kennedy et al., 2009), and the National Institute for Health and Clinical Excellence (NICE; NICE, 2010). Although there are differences in recommendations based on depression severity, there is considerable agreement on treatment for an acute major depressive episode. All guidelines recommend psychotherapy (cognitive behavior therapy or interpersonal therapy) as options in mild to moderate depression, subject to availability and patient preference. There is also consensus that the first-line treatment should be an SSRI or SNRI (CANMAT guidelines include agomelatine as a first-line treatment). There are some differences in interpretation of data comparing efficacy across treatments. For example, the APA guidelines conclude that “there is no replicable or robust difference across agents”, while CANMAT identifies clinical studies where superiority was demonstrated including a comparison of 12 new-generation antidepressants, in which escitalopram and sertraline had the best balance between efficacy and tolerability (Cipriani et al., 2009). It is noteworthy that newer agents such as agomelatine, which has demonstrated comparable or greater antidepressant efficacy with paroxetine (Lôo et al., 2002), fluoxetine (Hale et al., 2010), venlafaxine (Lemoine et al., 2007; Kennedy et al., 2008), sertraline (Kasper et al., 2010), and escitalopram (QueraSalva et al., 2011), and better tolerability compared to venlafaxine and sertraline (Lemoine et al., 2007; Kennedy et al., 2008; Kasper et al., 2010), were not included in this analysis. Despite limited evidence, combination or augmentation strategies are common in psychiatry (Mojtabai & Olfson, 2010), clinically driven by either the goal of increasing response or remission rates or alleviating specific symptoms (e.g., sleep or attention disturbance). These strategies utilize the increased understanding of psychopharmacologic mechanisms to select agents that target specific neurochemical pathways underlying certain symptoms (Nutt, 2008). For example, sleep disturbance is a common symptom in depression and is a frequent residual symptom even in remission (Nierenberg et al., 1999). While trazodone, mirtazapine, and atypical antipsychotics are frequently prescribed in low doses to restore sleep (Mendlewicz, 2009), the evidence to support this is limited and these treatments also result in excessive daytime sleepiness and in some cases, weight gain (Kennedy et al., 2007). Agomelatine monotherapy may offer advantages in these instances due to its positive effects on sleep and weight neutrality (Rouillon, 2006). There is also some evidence to suggest that starting treatment with two antidepressants from the outset may improve MDD outcomes. The addition of mirtazapine to fluoxetine, venlafaxine, or bupropion for 6 weeks resulted in significantly higher rates of remission in some groups compared with fluoxetine monotherapy (Blier et al., 2010). This multi-target approach from the outset of treatment lends further support to the need to target different systems for an enhanced antidepressant response (Guiard et al., 2009), and this may be more pertinent to specific patient groups. On the other hand, a comparison of escitalopram monotherapy with escitalopram added to bupropion and mirtazapine added to venlafaxine did not yield any significant differences in efficacy

S.J. Rizvi, S.H. Kennedy across groups (Rush et al., 2011). Furthermore, the limitations of multi-drug regimens, including increased risk of adverse effects and drug interactions, must be acknowledged. Recommendations from guidelines are based on evidence from antidepressant clinical trials, where remission rates are 30–40% (Gartlehner et al., 2009; Thase et al., 2010); however, in real-world studies and in practice, these rates tend to be lower (Warden et al., 2007). There are several reasons why remission rates may differ: (1) inadequate dosing, based on lack of adherence to treatment guidelines, (2) medication adherence: one study reported approximately 40% of patients are not fully compliant with an antidepressant regimen after 30 days (Olfson et al., 2006), (3) high comorbidity in the general MDD population compared with patients who meet the narrower criteria for clinical trials, and (4) additional variables including personality dimensions, social support, attitudes and beliefs about depression and its treatment are usually not accounted for in trials. To ameliorate these issues and close the ‘remission gap’ between efficacy and effectiveness trials, increased clinician drug monitoring and patient knowledge through psychoeducation should be carried out in order to increase compliance significantly, the physiological overlap among comorbid conditions and consequent implications for treatment need to be explored, and use of evidence regarding clinical and biological predictors of outcome should be incorporated into trials in an effort to build strategies to improve remission rates.

6. Conclusion Two approaches to improving antidepressant outcomes are discussed: exploring novel therapeutic targets, and doing better with existing treatments. The first step in improving outcomes requires an increased focus on adherence to guideline-compliant care during both acute and maintenance phases of therapy. While development of monoamine therapies continues, new targets have been identified, including cytokines, neurotrophins, amino acid neurotransmitters, neuropeptides, melatonin, as well as specific neuroanatomical regions for somatic treatments. Future research should focus on detecting early manifestations of risk or illness, combined with other biological markers to predict optimal matching of patient to treatment (Insel, 2009).

Role of the funding source Neither SJR nor SHK received funding for the preparation of this manuscript.

Contributors SJR and SHK were responsible for writing the manuscript and editing the final version.

Conflict of interest During the past 5 years, Sidney H. Kennedy has received honoraria or research support from AstraZeneca, Boehringer Ingelheim, BrainCells Inc., Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen

The keys to improving depression outcomes Ortho, Lundbeck, Merck Frosst, Pfizer, Servier and St. Jude Medical. Sakina J. Rizvi has no conflicts.

Acknowledgments None.

References Adell, A., 2010. Lu-AA 21004, a multimodal serotonergic agent, for the potential treatment of depression and anxiety. IDrugs 13, 900–910. Aiken, C.B., 2007. Pramipexole in psychiatry: a systematic review of the literature. J. Clin. Psychiatry 68, 1230–1236. Akhondzadeh, S., Jafari, S., Raisi, F., Nasehi, A.A., Ghoreishi, A., Salehi, B., Mohebbi-Rasa, S., Raznahan, M., Kamalipour, A., 2009. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety 26, 607–611. American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Author, Washington, DC. text revision. American Psychiatric Association, 2010. Practice Guideline For The Treatment of Patients With Major Depressive Disorder, 3rd ed. Anderson, I.M., Ferrier, I.N., Baldwin, R.C., Cowen, P.J., Howard, L., Lewis, G., Matthews, K., McAllister-Williams, R.H., Peveler, R.C., Scott, J., Tylee, A., 2008. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J. Psychopharmacol. 22, 343–396. Anisman, H., Merali, Z., Poulter, M.O., Hayley, S., 2005. Cytokines as a precipitant of depressive illness: animal and human studies. Curr. Pharm. Des. 11, 963–972. Arencibia-Albite, F., Paladini, C., Williams, J.T., Jiménez-Rivera, C.A., 2007. Noradrenergic modulation of the hyperpolarizationactivated cation current (Ih) in dopamine neurons of the ventral tegmental area. Neuroscience 149, 303–314. Baeken, C., De Raedt, R., Santermans, L., Zeeuws, D., Vanderhasselt, M.A., Meers, M., Vanderbruggen, N., 2010. HF-rTMS treatment decreases psychomotor retardation in medication-resistant melancholic depression. Prog. Neuropsychopharmacol. Biol. Psychiatry. doi:10.1016/j.pnpbp. 2010.03.021. Balon, R., Segraves, R.T., 2008. Survey of treatment practices for sexual dysfunction(s) associated with anti-depressants. J. Sex Marital Ther. 34, 353–365. Bewernick, B.H., Hurlemann, R., Matusch, A., Kayser, S., Grubert, C., Hadrysiewicz, B., Axmacher, N., Lemke, M., Cooper-Mahkorn, D., Cohen, M.X., Brockmann, H., Lenartz, D., Sturm, V., Schlaepfer, T.E., 2010. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol. Psychiatry 67, 110–116. Bilkei-Gorzo, A., Racz, I., Michel, K., Zimmer, A., 2002. Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. J. Neurosci. 22, 10046–10052. Blasey, C.M., Debattista, C., Roe, R., Block, T., Belanoff, J.K., 2009. A multisite trial of mifepristone for the treatment of psychotic depression: a site-by-treatment interaction. Contemp. Clin. Trials 30, 284–288. Blier, P., Ward, H.E., Tremblay, P., Laberge, L., Hébert, C., Bergeron, R., 2010. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am. J. Psychiatry 167, 281–288. Burgess, H.J., 2010. Partial sleep deprivation reduces phase advances to light in humans. J. Biol. Rhythms 25, 460–468. Burke, H.M., Davis, M.C., Otte, C., Mohr, D.C., 2005. Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology 30, 846–856.

S699 Calabrese, F., Molteni, R., Gabriel, C., Mocaer, E., Racagni, G., Riva, M.A., 2011. Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine. Psychopharmacology 215, 267–275. Caligiuri, M.P., Gentili, V., Eberson, S., Kelsoe, J., Rapaport, M., Gillin, J.C., 2003. A quantitative neuromotor predictor of antidepressant non-response in patients with major depression. J. Affect. Disord. 77, 135–141. Candy, M., Jones, L., Williams, R., Tookman, A., King, M., 2008. Psychostimulants for depression. Cochrane Database Syst. Rev. 2, CD006722. Capuron, L., Neurauter, G., Musselman, D.L., Lawson, D.H., Nemeroff, C.B., Fuchs, D., Miller, A.H., 2003. Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol. Psychiatry 54, 906–914. Cipriani, A., Furukawa, T.A., Salanti, G., Geddes, J.R., Higgins, J.P., Churchill, R., Watanabe, N., Nakagawa, A., Omori, I.M., McGuire, H., Tansella, M., Barbui, C., 2009. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 373, 746–758. Conley, R.K., Cumberbatch, M.J., Mason, G.S., Williamson, D.J., Harrison, T., Locker, K., Swain, C., Maubach, K., O'Donnell, R., Rigby, M., Hewson, L., Smith, D., Rupniak, N.M., 2002. Substance P (neurokinin 1) receptor antagonists enhance dorsal raphe neuronal activity. J. Neurosci. 22, 7730–7736. Connor, T.J., Leonard, B.E., 1998. Depression, stress and immunological activation: the role of cytokines in depressive disorders. Life Sci. 62, 583–606. Czeisler, C.A., Weitzman, E., Moore-Ede, M.C., Zimmerman, J.C., Knauer, R.S., 1980. Human sleep: its duration and organization depend on its circadian phase. Science 210, 1264–1267. . Dagyte, G., Crescente, I., Postema, F., Seguin, L., Gabriel, C., Mocaër, E., Boer, J.A., Koolhaas, J.M., 2011. Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress. Behav. Brain Res. 218, 121–128. DeBattista, C., Belanoff, J., Glass, S., Khan, A., Horne, R.L., Blasey, C., Carpenter, L.L., Alva, G., 2006. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol. Psychiatry 60, 1343–1349. Descamps, A., Rousset, C., Millan, M.J., Spedding, M., Delagrange, P., Cespuglio, R., 2009. Influence of the novel antidepressant and melatonin agonist/serotonin2C receptor antagonist, agomelatine, on the rat sleep–wake cycle architecture. Psychopharmacol 205, 93–106. Drevets, W.C., Savitz, J., Trimble, M., 2008. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 13, 663–681. Duman, R.S., Monteggia, L.M., 2006. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 1116–1127. Dunlop, B.W., Nemeroff, C.B., 2007. The role of dopamine in the pathophysiology of depression. Arch. Gen. Psychiatry 64, 327–337. El Mansari, M., Ghanbari, R., Janssen, S., Blier, P., 2008. Sustained administration of bupropion alters the neuronal activity of serotonin, norepinephrine but not dopamine neurons in the rat brain. Neuropharmacology 55, 1191–1198. Elger, G., Hoppe, C., Falkai, P., Rush, A.J., Elger, C.E., 2000. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res. 42, 203–210. Feyissa, A.M., Chandran, A., Stockmeier, C.A., Karolewicz, B., 2009. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 70–75. First, M.B., 2011. DSM-5 proposals for mood disorders: a cost-benefit analysis. Curr. Opin. Psychiatry 24, 1–9. Gartlehner, G., Thaler, K., Hansen, R.A., Gaynes, B.N., 2009. The general and comparative efficacy and safety of duloxetine in major depressive disorder: a systematic review and metaanalysis. Drug Saf. 32, 1159–1173.

S700 Germain, A., Kupfer, D.J., 2008. Circadian rhythm disturbances in depression. Hum. Psychopharmacol. 23, 571–585. Guiard, B.P., El Mansari, M., Merali, Z., Blier, P., 2008. Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions. Int. J. Neuropsychopharmacol. 11, 625–639. Guiard, B.P., El Mansari, M., Blier, P., 2009. Prospect of a dopamine contribution in the next generation of antidepressant drugs: the triple reuptake inhibitors. Curr. Drug Targets 10, 1069–1084. Gutman, D.A., Owens, M.J., Nemeroff, C.B., 2005. CRF receptor and glucocorticoid receptor antagonists: new approaches to antidepressant treatment. In: den Boer, J.A., George, M.S., ter Horst, G.T. (Eds.), Current and future developments in psychopharmacology. Benecke NI, Amsterdam, pp. 133–158. Hale, A., Corral, R.M., Mencacci, C., Ruiz, J.S., Severo, C.A., Gentil, V., 2010. Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized, doubleblind study. Int. Clin. Psychopharmacol. 25 (6), 305–314. Harrison, N.A., Brydon, L., Walker, C., Gray, M.A., Steptoe, A., Critchley, H.D., 2009. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol. Psychiatry 66, 407–414. Hasler, G., Fromm, S., Carlson, P.J., Luckenbaugh, D.A., Waldeck, T., Geraci, M., Roiser, J.P., Neumeister, A., Meyers, N., Charney, D.S., Drevets, W.C., 2008. Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects. Arch. Gen. Psychiatry 65, 521–531. Hernández, M.E., Mendieta, D., Martínez-Fong, D., Loría, F., Moreno, J., Estrada, I., Bojalil, R., Pavón, L., 2008. Variations in circulating cytokine levels during 52 week course of treatment with SSRI for major depressive disorder. Eur. Neuropsychopharmacol. 18, 917–924. Holsboer, F., 2000. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501. Holsboer, F., Ising, M., 2008. Central CRH system in depression and anxiety—evidence from clinical studies with CRH1 receptor antagonists. Eur. J. Pharmacol. 583, 350–357. Insel, T.R., 2009. Translating scientific opportunity into public health impact: a strategic plan for research on mental illness. Arch. Gen. Psychiatry 66, 128–133. Janicki-Deverts, D., Cohen, S., Doyle, W.J., Turner, R.B., Treanor, J.J., 2007. Infection-induced proinflammatory cytokines are associated with decreases in positive affect, but not increases in negative affect. Brain Behav. Immun. 21, 301–307. Kasper, S., Hajak, G., Wulff, K., Hoogendijk, W.J., Montejo, A.L., Smeraldi, E., Rybakowski, J.K., Quera-Salva, M.A., Wirz-Justice, A.M., Picarel-Blanchot, F., Baylé, F.J., 2010. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J. Clin. Psychiatry 71, 109–120. Kennedy, S.H., Emsley, R., 2006. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur. Neuropsychopharmacol. 16, 93–100. Kennedy, S.H., Rizvi, S.J., 2009. Emerging drugs for major depressive disorder. Expert Opin. Emerg. Drugs 14, 439–453. Kennedy, S.H., Lam, R.W., Nutt, D.J., Thase, M.E., 2007. Treating Depression Effectively: Applying Clinical Guidelines (2nd ed). Informa, London. Kennedy, S.H., Rizvi, S., Fulton, K., Rasmussen, J., 2008. A doubleblind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J. Clin. Psychopharmacol. 28 (3), 329–333. Kennedy, S.H., Lam, R.W., Parikh, S.V., Patten, S.B., Ravindran, A.V., 2009. Canadian Network for Mood and Anxiety Treatments

S.J. Rizvi, S.H. Kennedy (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. J. Affect. Disord. 117 (Suppl. 1), S1–S2. Kennedy, S.H., Giacobbe, P., Rizvi, S.J., Placenza, F.M., Nishikawa, Y., Mayberg, H., Lozano, A.M., 2011. Deep brain stimulation for treatment-resistant depression: Follow-up after 3 to 6 years. Am. J. Psychiatry 168, 502–510. Konarski, J.Z., Kennedy, S.H., Segal, Z.V., Lau, M.A., Bieling, P.J., McIntyre, R.S., Mayberg, H.S., 2009. Predictors of nonresponse to cognitive behavioural therapy or venlafaxine using glucose metabolism in major depressive disorder. J. Psychiatry Neurosci. 34, 175–180. Koolschijn, P.C., van Haren, N.E., Lensvelt-Mulders, G.J., Hulshoff Pol, H.E., Kahn, R.S., 2009. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum. Brain Mapp. 30, 3719–3735. Kronmüller, K.T., Schröder, J., Köhler, S., Götz, B., Victor, D., Unger, J., Giesel, F., Magnotta, V., Mundt, C., Essig, M., Pantel, J., 2009. Hippocampal volume in first episode and recurrent depression. Psychiatry Res. 174, 62–66. Lam, R.W., Chan, P., Wilkins-Ho, M., Yatham, L.N., 2008. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. Can. J. Psychiatry 53, 621–631. Larisch, R., Klimke, A., Vosberg, H., Löffler, S., Gaebel, W., MüllerGärtner, H.W., 1997. In vivo evidence for the involvement of dopamine-D2 receptors in striatum and anterior cingulate gyrus in major depression. NeuroImage 5, 251–260. Legros, C., Chalivoix, S., Gabriel, C., Mocaer, E., Delagrange, P., Fuchs, E., Malpaux, B., 2007. First evidence of melatonin receptors distribution in the suprachiasmatic nucleus of tree shrew brain. Neuro. Endocrinol. Lett. 28, 267–273. Lemoine, P., Guilleminault, C., Alvarez, E., 2007. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J. Clin. Psychiatry 68, 1723–1732. Licinio, J., Wong, M.L., 1999. The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol. Psychiatry 4, 317–327. Lôo, H., Hale, A., D'haenen, H., 2002. 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. 17 (5), 239–247. Lozano, A.M., Mayberg, H.S., Giacobbe, P., Hamani, C., Craddock, R.C., Kennedy, S.H., 2008. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol. Psychiatry 64, 461–467. Maas, D.W., Westendorp, R.G., Willems, J.M., de Craen, A.J., van der Mast, R.C., 2010. TNF-alpha antagonist infliximab in the treatment of depression in older adults: results of a prematurely ended, randomized, placebo-controlled trial. J. Clin. Psychopharmacol. 30, 343–345. Machado-Vieira, R., Manji, H.K., Zarate, C.A., 2009. The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist 15, 525–539. Malone Jr., D.A., Dougherty, D.D., Rezai, A.R., Carpenter, L.L., Friehs, G.M., Eskandar, E.N., Rauch, S.L., Rasmussen, S.A., Machado, A.G., Kubu, C.S., Tyrka, A.R., Price, L.H., Stypulkowski, P.H., Giftakis, J.E., Rise, M.T., Malloy, P.F., Salloway, S.P., Greenberg, B.D., 2009. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol. Psychiatry 65, 267–275. Manta, S., Dong, J., Debonnel, G., Blier, P., 2009. Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation. J. Psychiatry Neurosci. 34, 272–280.

The keys to improving depression outcomes Martiny, K., Lunde, M., Bech, P., 2010. Transcranial Low Voltage Pulsed Electromagnetic Fields in Patients with Treatment-Resistant Depression. Biol. Psychiatry 68, 163–169. Maubach, K.A., Martin, K., Chicchi, G., Harrison, T., Wheeldon, A., Swain, C.J., Cumberbatch, M.J., Rupniak, N.M., Seabrook, G.R., 2002. Chronic substance P (NK1) receptor antagonist and conventional antidepressant treatment increases burst firing of monoamine neurones in the locus coeruleus. Neuroscience 109, 609–617. Mayberg, H.S., Liotti, M., Brannan, S.K., McGinnis, S., Mahurin, R.K., Jerabek, P.A., Silva, J.A., Tekell, J.L., Martin, C.C., Lancaster, J.L., Fox, P.T., 1999. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675–682. Mayberg, H.S., Lozano, A.M., Voon, V., McNeely, H.E., Seminowicz, D., Hamani, C., Schwalb, J.M., Kennedy, S.H., 2005. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660. Mayer, J.L., Klumpers, L., Maslam, S., de Kloet, E.R., Joëls, M., Lucassen, P.J., 2006. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalises the corticosteroneinduced reduction of adult hippocampal neurogenesis. J. Neuroendocrinol. 18, 629–631. McEwen, B.S., 2003. Mood disorders and allostatic load. Biol. Psychiatry 54, 200–207. McEwen, B.S., Chattarji, S., Diamond, D.M., Jay, T.M., Reagan, L.P., Svenningsson, P., Fuchs, E., 2010. The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Mol. Psychiatry 15, 237–249. McLoughlin, D.M., Mogg, A., Eranti, S., Pluck, G., Purvis, R., Edwards, D., Landau, S., Brown, R., Rabe-Heskith, S., Howard, R., Philpot, M., Rothwell, J., Romeo, R., Knapp, M., 2007. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis. Health Technol. Assess. 11, 1–54. Mendlewicz, J., 2009. Sleep disturbances: core symptoms of major depressive disorder rather than associated or comorbid disorders. World J. Biol. Psychiatry 10, 269–275. Meyer, J.H., Goulding, V.S., Wilson, A.A., Hussey, D., Christensen, B.K., Houle, S., 2002. Bupropion occupancy of the dopamine transporter is low during clinical treatment. Psychopharmacol. 163, 102–105. Meyer, J.H., McNeely, H.E., Sagrati, S., Boovariwala, A., Martin, K., Verhoeff, N.P., Wilson, A.A., Houle, S., 2006. Elevated putamen D(2) receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study. Am. J. Psychiatry 163, 1594–1602. Millan, M.J., Gobert, A., Lejeune, F., Dekeyne, A., NewmanTancredi, A., Pasteau, V., Rivet, J.M., Cussac, D., 2003. The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J. Pharmacol. Exp. Ther. 306, 954–964. Miller, A.H., Maletic, V., Raison, C.L., 2009. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741. Mizoguchi, K., Yuzurihara, M., Ishige, A., Sasaki, H., Chui, D.H., Tabira, T., 2000. Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J. Neurosci. 20, 1568–1574. Moghaddam, B., 2002. Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamineassociated psychiatric disorders. Biol. Psychiatry 51, 775–787. Mojtabai, R., Olfson, M., 2010. National trends in psychotropic medication polypharmacy in office-based psychiatry. Arch. Gen. Psychiatry 67, 26–36. Mulder, R.T., Joyce, P.R., Frampton, C.M., Luty, S.E., Sullivan, P.F., 2006. Six months of treatment for depression: outcome and predictors of the course of illness. Am. J. Psychiatry 163, 95–100.

S701 Müller, N., 2010. COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr. Opin. Investig. Drugs 11, 31–42. Mussap, C.J., Geraghty, D.P., Burcher, E., 1993. Tachykinin receptors: a radioligand binding perspective. J. Neurochem. 60, 1987–2008. Musselman, D.L., Miller, A.H., Porter, M.R., Manatunga, A., Gao, F., Penna, S., Pearce, B.D., Landry, J., Glover, S., McDaniel, J.S., Nemeroff, C.B., 2001. Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am. J. Psychiatry 158, 1252–1257. Nahas, Z., Marangell, L.B., Husain, M.M., Rush, A.J., Sackeim, H.A., Lisanby, S.H., Martinez, J.M., George, M.S., 2005. Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J. Clin. Psychiatr. 66, 1097–1104. National Institute for Clinical Excellence, 2010. Depression: management of depression in adults. Clinical practice guideline No 90, Updated Edition. National Institute for Clinical Excellence, London, p. 580. Nibuya, M., Morinobu, S., Duman, R.S., 1995. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 15, 7539–7547. Nierenberg, A.A., Keefe, B.R., Leslie, V.C., Alpert, J.E., Pava, J.A., Worthington 3rd, J.J., Rosenbaum, J.F., Fava, M., 1999. Residual symptoms in depressed patients who respond acutely to fluoxetine. J. Clin. Psychiatry 60, 221–225. Nutt, D.J., 2008. Relationship of neurotransmitters to the symptoms of major depressive disorder. J. Clin. Psychiatry 69 (Suppl. E1), 4–7. O'Brien, S.M., Scully, P., Fitzgerald, P., Scott, L.V., Dinan, T.G., 2007. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J. Psychiatr. Res. 41, 326–331. Olfson, M., Marcus, S.C., Tedeschi, M., Wan, G.J., 2006. Continuity of antidepressant treatment for adults with depression in the United States. Am. J. Psychiatry 163, 101–108. Papakostas, G.I., Nutt, D.J., Hallett, L.A., Tucker, V.L., Krishen, A., Fava, M., 2006. Resolution of sleepiness and fatigue in major depressive disorder: a comparison of bupropion and the selective serotonin reuptake inhibitors. Biol. Psychiatry 60, 1350–1355. Papakostas, G.I., Stahl, S.M., Krishen, A., Seifert, C.A., Tucker, V.L., Goodale, E.P., Fava, M., 2008. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies. J. Clin. Psychiatry 69, 1287–1292. Pariante, C.M., Miller, A.H., 2001. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol. Psychiatry 49, 391–404. Paulson, P.E., Robinson, T.E., 1994. Relationship between circadian changes in spontaneous motor activity and dorsal versus ventral striatal dopamine neurotransmission assessed with on-line microdialysis. Behav. Neurosci. 108, 624–635. Penev, P.D., Kolker, D.E., Zee, P.C., Turek, F.W., 1998. Chronic circadian desynchronization decreases the survival of animals with cardiomyopathic heart disease. Am. J. Physiol. 275 (6 Pt 2), H2334–H2337. Pettersson, M., Campbell, B.M., Dounay, A.B., Gray, D.L., Xie, L., O'Donnell, C.J., Stratman, N.C., Zoski, K., Drummond, E., Bora, G., Probert, A., Whisman, T., 2011. Design, synthesis, and pharmacological evaluation of azetedine and pyrrolidine derivatives as dual norepinephrine reuptake inhibitors and 5-HT(1A) partial agonists. Bioorg. Med. Chem. Lett. 21, 865–868. Phelps, L.E., Brutsche, N., Moral, J.R., Luckenbaugh, D.A., Manji, H.K., Zarate Jr., C.A., 2009. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol. Psychiatry 65, 181–184. Preskorn, S.H., Baker, B., Kolluri, S., Menniti, F.S., Krams, M., Landen, J.W., 2008. An innovative design to establish proof of

S702 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. 28, 631–637. Prins, J., Denys, D.A., Westphal, K.G., Korte-Bouws, G.A., Quinton, M.S., Schreiber, R., Groenink, L., Olivier, B., Korte, S.M., 2010. The putative antidepressant DOV 216,303, a triple reuptake inhibitor, increases monoamine release in the prefrontal cortex of olfactory bulbectomized rats. Eur. J. Pharmacol. 633, 55–61. Quera-Salva, M.A., Lemoine, P., Guilleminault, C., 2010. Impact of the novel antidepressant agomelatine on disturbed sleep-wake cycles in depressed patients. Hum. Psychopharmacol. 25, 222–229. Quera-Salva, M.A., Hajak, G., Philip, P., Montplaisir, J., Keufer-Le Gall, S., Laredo, J., Guilleminault, C., 2011. Comparison of agomelatine and escitalopram on nighttime sleep and daytime condition and efficacy in major depressive disorder patients. Int. Clin. Psychopharmacol. 26, 252–262. Ramírez-Rodríguez, G., Klempin, F., Babu, H., Benítez-King, G., Kempermann, G., 2009. Melatonin modulates cell survival of new neurons in the hippocampus of adult mice. Neuropsychopharmacology 34, 2180–2191. Rantamäki, T., Hendolin, P., Kankaanpää, A., Mijatovic, J., Piepponen, P., Domenici, E., Chao, M.V., Männistö, P.T., Castrén, E., 2007. Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology 32, 2152–2162. Rausch, J.L., Johnson, M.E., Kasik, K.E., Stahl, S.M., 2006. Temperature regulation in depression: functional 5HT1A receptor adaptation differentiates antidepressant response. Neuropsychopharmacology 31, 2274–2280. Rickels, K., Athanasiou, M., Robinson, D.S., Gibertini, M., Whalen, H., Reed, C.R., 2009. Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. J. Clin. Psychiatry 70, 326–333. Rouillon, F., 2006. Efficacy and tolerance profile of agomelatine and practical use in depressed patients. Int. Clin. Psychopharmacol. 21 (Suppl 1), S31–S35. Rush, A.J., George, M.S., Sackeim, H.A., Marangell, L.B., Husain, M.M., Giller, C., Nahas, Z., Haines, S., Simpson Jr., R.K., Goodman, R., 2000. Vagus nerve stimulation (VNS) for treatment-resistant depressions: A multicenter study. Biol. Psychiatry 47, 276–286. Rush, A.J., Marangell, L.B., Sackeim, H.A., George, M.S., Brannan, S.K., Davis, S.M., Howland, R., Kling, M.A., Rittberg, B.R., Burke, W.J., Rapaport, M.H., Zajecka, J., Nierenberg, A.A., Husain, M.M., Ginsberg, D., Cooke, R.G., 2005. Vagus nerve stimulation for treatment resistant depression: a randomized, controlled acute phase trial. Biol. Psychiatry 58, 347–354. Rush, A.J., Trivedi, M.H., Stewart, J.W., Nierenberg, A.A., Fava, M., Kurian, B.T., Warden, D., Morris, D.W., Luther, J.F., Husain, M.M., Cook, I.A., Shelton, R.C., Lesser, I.M., Kornstein, S.G., Wisniewski, S.R., 2011. Combining Medications to Enhance Depression Outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am. J. Psychiatry. doi:10.1176/appi.ajp. 2011.10111645. Sanacora, G., Kendell, S.F., Fenton, L., Coric, V., Krystal, K.H., 2004. Riluzole augmentation for treatment-resistant depression. Am. J. Psychiatry 161, 2132.

S.J. Rizvi, S.H. Kennedy Schmidt, H.D., Duman, R.S., 2010. Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 35, 2378–2391. Shirayama, Y., Mitsushio, H., Takashima, M., Ichikawa, H., Takahashi, K., 1996. Reduction of substance P after chronic antidepressants treatment in the striatum, substantia nigra and amygdala of the rat. Brain Res. 739, 70–78. Simon, N.M., Smoller, J.W., Fava, M., Sachs, G., Racette, S.R., Perlis, R., Sonawalla, S., Rosenbaum, J.F., 2003. Comparing anxiety disorders and anxiety-related traits in bipolar disorder and unipolar depression. J. Psychiatr. Res. 37, 187–192. Souetre, E., Salvati, E., Belugou, J.L., Pringuey, D., Candito, M., Krebs, B., Ardisson, J.L., Darcourt, G., 1989. Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality. Psychiatry Res. 28, 263–278. Soumier, A., Banasr, M., Lortet, S., Masmejean, F., Bernard, N., Kerkerian-Le-Goff, L., Gabriel, C., Millan, M.J., Mocaer, E., Daszuta, A., 2009. Mechanisms contributing to the phasedependent regulation of neurogenesis by the novel antidepressant, agomelatine, in the adult rat hippocampus. Neuropsychopharmacology 34, 2390–2403. Szegedi, A., Jansen, W.T., van Willigenburg, A.P., van der Meulen, E., Stassen, H.H., Thase, M.E., 2009. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J. Clin. Psychiatry 70, 344–353. Thase, M.E., Nierenberg, A.A., Vrijland, P., van Oers, H.J., Schutte, A.J., Simmons, J.H., 2010. Remission with mirtazapine and selective serotonin reuptake inhibitors: a meta-analysis of individual patient data from 15 controlled trials of acute phase treatment of major depression. Int. Clin. Psychopharmacol. 25, 189–198. Trajkovska, V., Kirkegaard, L., Krey, G., Marcussen, A.B., Thomsen, M.S., Chourbaji, S., Brandwein, C., Ridder, S., Halldin, C., Gass, P., Knudsen, G.M., Aznar, S., 2009. Activation of glucocorticoid receptors increases 5-HT2A receptor levels. Exp. Neurol. 218, 83–91. Warden, D., Rush, A.J., Trivedi, M.H., Fava, M., Wisniewski, S.R., 2007. The STAR*D Project results: a comprehensive review of findings. Curr. Psychiatry Rep. 9, 449–459. Watanabe, K., Hashimoto, E., Ukai, W., Ishii, T., Yoshinaga, T., Ono, T., Tateno, M., Watanabe, I., Shirasaka, T., Saito, S., Saito, T., 2010. Effect of antidepressants on brain-derived neurotrophic factor (BDNF) release from platelets in the rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 1450–1454. Wirz-Justice, A., 2008. Diurnal variation of depressive symptoms. Dialogues Clin. Neurosci. 10, 337–343. Zarate Jr., C.A., Du, J., Quiroz, J., Gray, N.A., Denicoff, K.D., Singh, J., Charney, D.S., Manji, H.K., 2004. Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system. Ann. N.Y. Acad. Sci. 1003, 273–291. Zarate Jr., C.A., Singh, J.B., Carlson, P.J., Brutsche, N.E., Ameli, R., Luckenbaugh, D.A., Charney, D.S., Manji, H.K., 2006. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864.