PRIMER

Major depressive disorder
Christian Otte1, Stefan M. Gold1,2, Brenda W. Penninx3, Carmine M. Pariante4,
Amit Etkin5, Maurizio Fava6, David C. Mohr7 and Alan F. Schatzberg5
Abstract | Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed
mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed
sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in
six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be
approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse
during childhood, are strongly associated with the risk of developing MDD. No established mechanism
can explain all aspects of the disease. However, MDD is associated with alterations in regional brain
volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the
cognitive control network and the affective–salience network. Furthermore, disturbances in the main
neurobiological stress-responsive systems, including the hypothalamic–pituitary–adrenal axis
and the immune system, occur in MDD. Management primarily comprises psychotherapy and
pharmacological treatment. For treatment-resistant patients who have not responded to several
augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with
the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD,
including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

Major depressive disorder (MDD) is a debilitating The genetic contribution to MDD is estimated to be
disease that is characterized by at least one discrete approximately 35%, with higher heritability shown in
depressive episode lasting at least 2 weeks and involv- family and twin-based studies than single-nucleotide
ing clear-cut changes in mood, interests and pleasure, polymorphism-based estimates from genome-wide
changes in cognition and vegetative symptoms. BOX 1 association studies (GWAS). This finding suggests that
describes the current diagnostic criteria and speci­fiers other genetic variables, such as rare mutations, contrib-
(which enable clinical subtyping) of MDD according ute to MDD risk8. In addition, environmental factors,
to the Diagnostic and Statistical Manual of Mental such as sexual, physical or emotional abuse during child-
Disorders 5th edition (DSM‑5), which was released in hood, are strongly associated with the risk of developing
2013 (REF. 1). The cluster of symptoms that characterize a MDD9, although our understanding of how environ­
major depressive episode and MDD overlap with depres- mental factors interact with genetic and epigenetic
sive symptoms in schizophrenia and bipolar disorder; factors is far from complete.
the application of exclusion criteria enables a diagnosis Despite advances in our understanding of the neuro-
of MDD. biology of MDD, no established mechanism can explain
MDD occurs about twice as often in women than all aspects of the disease. However, MDD is associated
in men2 and affects about 6% of the adult population with smaller hippocampal volumes as well as changes
worldwide each year 3. Among all medical conditions, in either activation or connectivity of neural networks,
MDD is the second leading contributor to chronic dis- such as the cognitive control network and the affective–­
Correspondence to C.O.
Department of Psychiatry
ease burden as measured by ‘years lived with disability’ salience network10. Moreover, alterations in the main
and Psychotherapy, Charité (REF. 4). In addition, MDD is associated with an increased neurobiological systems that mediate the stress response
University Medical Center, risk of developing conditions such as diabetes mellitus, are evident in MDD, including the hypothalamic–­
Campus Benjamin Franklin, heart disease and stroke5, thereby further increasing its pituitary–adrenal (HPA) axis, the autonomic nervous
Hindenburgdamm 30,
burden of disease. Furthermore, MDD can lead to death system and the immune system11.
12203 Berlin, Germany.
christian.otte@charite.de by suicide. It is estimated that up to 50% of the 800,000 Both psychotherapy and psychopharmacology are
suicides per year worldwide occur within a depressive effective in treating MDD. However, approximately
Article number: 16065
doi:10.1038/nrdp.2016.65 episode6 and patients with MDD are almost 20‑fold more 30% of patients do not remit from MDD, even after
Published online 15 Sep 2016 likely to die by suicide than the general population7. several treatment attempts12,13. New developments in

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 1
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PRIMER

Author addresses
countries, approximately 50–60% of all people with
severe MDD receive proper treatment 18,19, whereas in
1
Department of Psychiatry and Psychotherapy, Charité low-income countries <10% of patients do18.
University Medical Center, Campus Benjamin Franklin, Women have a twofold increased risk of developing
Hindenburgdamm 30, 12203 Berlin, Germany. MDD than men after puberty 2. This disparity reflects
2
Institute of Neuroimmunology and Multiple Sclerosis
the more-frequent occurrence of episodes in women,
(INIMS), University Medical Center Hamburg-Eppendorf,
Hamburg, Germany.
rather than longer episode duration, differential treat-
3
Department of Psychiatry, VU University Medical Center, ment response or higher recurrence rates in women
Amsterdam, The Netherlands. compared with men20,21. In both sexes, the median
4
Institute of Psychiatry, Psychology and Neuroscience, reported age of onset of MDD is approximately 25 years
King’s College London, London, UK. and the peak risk period for MDD onset ranges from
5
Department of Psychiatry and Behavioural Sciences, mid-to-late adolescence to early 40s3. These findings are
Stanford University School of Medicine, Palo Alto, in line with observations that, especially in high-income
California, USA. countries, the MDD prevalence generally modestly
6
Department of Psychiatry, Massachusetts General decreases with age after early adulthood16.
Hospital, Boston, Massachusetts, USA.
Other consistently reported environmental deter-
7
Department of Preventive Medicine, Feinberg School of
Medicine, Northwestern University, Chicago, Illinois, USA.
minants of MDD in both men and women are the
absence of a partner (for example, owing to divorce
or widowhood) and the experience of recent negative
psychotherapy include the use of behavioural inter- life events, such as illness or loss of close relatives or
vention technologies. With regard to pharma­cological friends, financial or social problems and unemploy-
approaches, glutamatergic antidepressants, such as ment 3,22. In addition, a range of social determinants
ketamine, are currently under scientific scrutiny after (including childhood adversities, socioeconomic status
promising initial findings of efficacy. and low social support) as well as low educational
In this Primer, we provide an overview of the current attainment 23 significantly increases the risk of MDD
evidence of MDD, including its epidemiology, aetiology, in men and women (BOX 2). However, the cause–effect
pathophysiology, diagnosis and treatment. We also out- relationship between lower educational attainment
line the key outstanding research questions in the field and MDD is unclear and a large study with 25,000
that should be addressed in the coming years. individuals recently suggested that it might partly be
due to shared genetics24. Individuals with a history of
Epidemiology childhood trauma have a more than twofold increased
Prevalence and main correlates risk of developing MDD25. Furthermore, patients with
A best estimate of the worldwide MDD prevalence MDD and a history of childhood trauma show higher
comes from the World Mental Health (WMH) Survey, symptom severity, a poorer course and more treat-
which assessed the DSM‑IV criteria for MDD among ment non-response than patients with MDD without
almost 90,000 individuals in 18 countries from every ­childhood trauma26.
continent 3. The average 12‑month prevalence of MDD
is approximately 6%, which is in line with estimates Disease course
from earlier large-scale international studies3. Lifetime The course of MDD is pleomorphic, with consider-
MDD prevalence is typically threefold higher than the able variation in remission and chronicity; higher
12‑month prevalence, indicating that MDD affects one symptom severity, psychiatric comorbidity and a
in every six adults3. Although lifetime prevalence is an ­history of childhood trauma all predict a less favour­
­unreliable metric as it probably suffers from recall bias able course21,26. In population-based samples, the mean
and underestimation14,15, it indicates that about 20% of episode duration varies between 13 and 30 weeks and
all people fulfil the criteria for MDD at some point in approximately 70–90% of patients with MDD recover
their lifetime. within 1 year 27–29. However, in outpatient care settings,
The 12‑month MDD prevalence in the WMH Survey the course is less favourable: only 25% remit within
ranged from 2.2% in Japan to 10.4% in Brazil (FIG. 1). 6 months and >50% of patients still have MDD after
Although estimates varied substantially across countries 2 years21,30,31. After MDD remission, residual symptoms
for reasons that probably involve both substantive and and functional impairment often remain32. In addition,
methodological processes, the 12‑month MDD preva- the chance of MDD recurrence is high, as about 80% of
lence was found to be similar in ten high-­income (5.5%) patients in remittance experience at least one recurrence
and eight low-income and m ­ iddle‑income (5.9%) in their lifetime33. The course trajectory in adults seems
­countries, showing that MDD is not just a ‘modern-­ to be slightly less favourable with increasing age than in
world’ health condition. In addition, the median age younger patients21.
of onset, severity, symptom profile and basic socio­
demographic and environmental correlates (such as Disease burden
sex, education and life events) of MDD are mostly The Global Burden of Disease Consortium found that,
compar­able between countries and cultures16,17. The in 2013, MDD was the second leading contributor to
discrepancy between countries is evident in terms of global disease burden, as expressed in disability­-adjusted
the resources and treatments available. In high-income life years, in both developed and developing countries4.

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significant findings40. 2). Large-scale longitudinal studies converge in Early epidemiological studies focused on stressful events their findings suggesting that MDD increases the risk that are temporally related to MDD.Feelings of worthlessness. MDD separation and bereavement)48 occur most often in adult- increases the mortality risk by 60–80%35. We have known for more than a century that MDD weight gain.Diminished ability to think or concentrate.med.Insomnia or hypersomnia with MDD show a threefold increased risk of MDD -. heart disease. the consequences of MDD extend to physi. with clear evidence of a dose–response can explain all facets of the disease. although the applicability of these findings in humans is still Box 1 | Definition of MDD according to DSM‑5 nascent. the hood. genetic overlap -. Similarly sized studies of other specific plan for committing suicide psychi­atric conditions such as schizophrenia. have convincingly impli.Markedly diminished interest or pleasure in all.747 controls of European descent 45. hypertension.Recurrent thoughts of death (not just fear of dying). that between MDD and other psychiatric disorders. financial insecurity. schizophreniform disorder. exposure to events in childhood as antecedent of MDD later in life. Furthermore. analysis of various GWAS that included 9.36. we restrict our description to pathophysiological models of MDD that are supported • An individual will show five (or more) of the following by findings from clinical studies. This finding holds promise for the ongoing • With peripartum onset search for consistent genetic variants that contribute • With seasonal pattern to MDD risk in a collaborative genome-wide associ- ation study carried out by the Psychiatric Genomics *Depressed mood and/or diminished interest or pleasure must be evident for a diagnosis.Depressed mood* (­ideally also with a meta-analysis level of evidence). exposure to violence.47. These events include physical and sexual Mechanisms/pathophysiology abuse. psychological neglect. A l l r i g h t s r e s e r v e d . Environmental factors cal health. or almost all.unc. the main documented events (such obesity. as indicated by a large-scale recurrent suicidal ideation without a specific plan. impairment in social. severity and chronicity of MDD9. fied38. Indeed. Risk of MDD is highly polygenic and involves effects of a substance or to another medical condition many genes with small effects43. schizophrenia. such is. or decrease or increase in appetite clusters within families. chronic or disease34 (FIG. Animal models relationship between the number and severity of adverse of MDD are available and have enabled the discovery of life events and the risk. Both in the general population and life-threatening health problems. numbers of patients to find signifi­cant associations. -. 15 genetic loci to DSM‑5 (Diagnostic and Statistical Manual of Mental with genome-wide significance have been associated Disorders 5th edition1) are: with risk of self-reported MDD in 75. the search for main genetic effects in or indecisiveness MDD so far has not revealed consistent or replicated -.607 patients and • Severity 231. However.519 controls41. Furthermore. more-recent evidence has focused on contribution of MDD to all-cause mortality is 10%. 108 areas of functioning independent genome-wide significant loci have been • The episode is not attributable to the physiological shown42. • With anxious distress some recent studies in >100. which has • The symptoms cause clinically significant distress or higher heritability than MDD. Consortium (http://www. or excessive or inappropriate guilt. activities* Genetics -. preceding onset. However. exposure to domestic vio- Despite advances in our understanding of the neuro­ lence or early separation from parents as a result of death biology of MDD. giving preference to symptoms. stroke. not merely self-reproach or guilt about being sick as schizo­phrenia and bipolar disorder. First-degree relatives of patients -. which might be delusional. has been identi­ -. currently no established mechanism or separation. Moreover. cancer. Accordingly. p a r t o f S p r i n g e r N a t u r e .39.Psychomotor agitation or retardation and heritability for this disorder has been quantified -. occupational or other important cated at least some genetic loci. a phenotype that is strongly correlated to • With psychotic features MDD46. which should be present during the same 2‑week period nearly every day and should represent aspects that have been confirmed in meta-analyses a change from previous functioning: and pathways that have been targeted in clinical trials -.Fatigue or loss of energy as approximately 35%37.Considerable weight loss when not dieting. PRIMER Moreover.240 cases the individual has made a suicide attempt or a and 9. usually in the year of diabetes mellitus. . many potentially implicated pathways (BOX 3). which coupled with the • The occurrence of the episode is not better explained heterogeneity of MDD phenotypes requires very high by schizoaffective disorder. cognitive impairment and Alzheimer as loss of employment. in populations with specific medical illnesses. delusional disorder A recent genome-wide association study in Chinese or other psychotic disorders patients in which a more homo­geneous phenotypic • The individual has never had a manic episode or approach (recurrent MDD requiring outpatient care) a hypomanic episode was applied was able to confirm two genome-wide Specifiers of major depressive disorder (MDD) according significant genetic loci44.edu/pgc). NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 3 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . for schizophrenia.000 subjects have also • With mixed features indicated several genome-wide significant loci for • With melancholic features neuro­ticism.

tent increases in the activity of corticotropin-releasing hormone (CRH)-containing neural circuits49. a meta-analysis LMICs Grouped prevalence HICs has shown that. as adults. accordingly. that relevant genetic variants confer an increased risk only in the presence of exposure to stressors and other Neuroendocrinology adverse environmental circumstances — the so‑called As mentioned.5%) and low-income and middle-income countries eral randomized controlled trials have examined CRH (LMICs. This novel but response.64. patients with MDD were increased. HPA alterations correlate with impaired cognitive function60 in these patients. approximately 50% of patients had similar 0 2 4 6 8 10 12 12-month prevalence (%) cortisol levels before and after treatment. Importantly. Epigenetics. researched biological systems in MDD57. a finding that is supported glucocorticoid receptor resistance55. allele-specific. the 4 | 2016 | VOLUME 2 www. the HPA axis is among the most gene–environment (G×E) interaction (FIG. sev- in inter-country prevalence of major depressive disorder (MDD) is noted. by the fact that these individuals also show increased Furthermore. Although considerable variation els of CRH in the cerebro­spinal fluid (CSF) have been Nature Reviews | Disease Primers shown in patients with MDD67 and. independent of improved psycho­ pathology. antagonists in the treatment of MDD. MDD (approx- India (Pondicherry) imately twofold) and other severe neuro­psychiatric Spain disorders. such as cancer 53. differences in the timings and the type of long-lasting consequences of early trauma. especially suicide victims who were increased inflammation are all evident in MDD (FIG. HPA axis hyperactivity and patients with MDD. several studies have shown consist- activation of the inflammatory system. 3.9%) are not different. 4).nature. but more-recent unbiased GWAS have impli- burgeoning area of research is providing further evi. peptidyl-prolyl cis-trans isomerase (FKBP5) have been sive neurobiological model that seeks to explain the identified. . Interestingly. Many animal adverse environmental circumstances have hampered studies have shown that early-life stress produces persis. Increased lev- Figure 1 | Average 12‑month prevalence of MDD. However. This find. China (Shenzhen) Despite these findings. For example. data from interventional Italy studies are less clear. stress-­dependent of the HPA axis when exposed to standardized psycho. even when controlling for the underlying Mexico medical disorder 65. glucocorticoid recep. although several potential candidate genes. For example.PRIMER The HPA axis is at the centre of the comprehen. therefore. However. However. of MDD as well as in post-mortem brain samples of glucocorticoid resistance. Indeed. Initial hypothesis-­ Furthermore.58. antidepressants High-income countries Germany Low-income and reduce the levels of cortisol in patients with MDD over Japan middle-income countries the course of the treatment 66. However. molecular mechanisms underlying G×E interactions viduals who have been sexually or physically abused in have shown that they might involve epigenetic regu- childhood show. with a moderate CRH receptor 1 (CRHR1) and the gene encoding effect size. a study France using data from a primary care database including Lebanon >370.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . replication studies of single candidate genes. enthusiasm for epigenetic research in MDD is still limited by the small Gene–environment interactions magnitude of the described epigenetic changes (often The lack of consistent and replicated findings in GWAS <10%). exposed to early-life adversities56. such as cell earliest stages of life52. and Brazil (São Paulo) are more common and more pronounced in severely Ukraine depressed patients with melancholic and/or psychotic United States features61 and in elderly patients who have MDD62.000 individuals indicated that treatment with syn- Belgium South Africa thetic glucocorticoids is associated with an increased risk Netherlands for suicide (approximately sevenfold). several studies have prospectively shown Colombia that increased levels of cortisol is a risk factor for sub- Israel sequent MDD in at‑risk populations63. a markedly enhanced activity lation53. New Zealand Furthermore. For example. This interaction leads to increased FKBP5 tor function is reduced in these individuals (so‑called expression in response to stress. A l l r i g h t s r e s e r v e d . DNA demethylation in glucocorticoid-response social stressors or following endocrine tests that attempt ­e lements of a polymorphism in FKBP5 has been to suppress HPA activity 50. such as two meta-analyses50. Data from REF. p a r t o f S p r i n g e r N a t u r e . 5. studies investigating the ing is supported by clinical studies showing that indi. which is under ent epigenetic changes in the brains of animal models physiological inhibitory control by cortisol. Indeed. the overall estimates in high-income countries (5. implicating the long-lasting effects of environmental insults at the alternative pathophysiological mechanisms. which in turn leads to glucocorticoid resistance). adhesion and cell plasticity 54. cated epigenetic changes in genes that are often unre- dence of the neurodevelopmental origin of MDD and lated to established candidates. especially in comparison with other medical for MDD can at least partly be explained by the fact ­disorders.59 concluded that cortisol levels in sodium-dependent serotonin transporter (SLC6A4). Finally. observed54. 3). in utero stress has also been shown to driven studies examined genes involved in the stress increase the risk of MDD later in life51.

although secondary symptoms by affecting brain function at a cellular level. Thus.222. the autonomic nervous system and the central city have been implicated. such as IL‑2 or (for example. interferon-γ (IFNγ). poverty. PRIMER Box 2 | Social and environmental determinants of MDD mechanisms of inflammation might also be relevant for the development of MDD in patients. reducing adult forward and feedback loops (FIG. conflict. Clinical observations suggest that similar discovered that substances such as the anti­hypertensive NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 5 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . can contribute to the risk for MDD (a so‑called social Increased expression of genes involved in IL‑6 signal- cause). p a r t o f S p r i n g e r N a t u r e . For example. neurogenesis — the process by which new neu- In summary. Recent studies CRH antagonists in the treatment of MDD68. although there is unequivocal evidence rons are generated in the adult brain from pluripotent of HPA alterations in MDD. BDNF mRNA levels are also reduced in the leukocytes Inflammation of patients with MDD. smoking behaviour. stress responsiveness84. Animal models have shown that these routes The monoamine neurotransmitters serotonin (also converge in the CNS to alter molecular programmes known as 5‑hydroxytryptamine). certain social variables. microglial activation in the CNS of patients with MDD. have also yielded mixed results69. including astrocytes. neighbourhood factors patients who receive cytokine treatments. such brain tissue81 have indicated neuroinflammation and as metyrapone. They can be categorized as demographic factors severe infections and autoimmune diseases increase the (for example. In addition. A role for peripheral neurogenesis in rodents in the absence of stress does not immune dysfunction and neuroimmunological mech. The peripheral changes in cortisol levels and inflamma- nist mifepristone (also known as RU‑486) was shown tory mechanisms might ultimately induce depressive to ameliorate psychotic symptoms. income inequality and low education). affect brain corticoid-mediated negative feedback on the HPA axis84. trial71 and to improve cognitive function in patients with MDD in an experimental study 72. reduced anisms in MDD has been supported by a large body neurogenesis can precipitate depression-­like symptoms of evidence from animal studies (BOX 3). In MDD with Neuroplasticity psychotic features. of MDD subtypes of patients who are more likely to BDNF and other regulators of neuroplasticity might respond to a given treatment within the HPA axis. a high-fat or symptoms75. patients with MDD show increased high-sugar diet and physical inactivity). adult neuro- have also provided intriguing insights into how periph. Clinical using PET imaging 80 as well as analyses of post-­mortem ­trials using glucocorticoid-­lowering compounds. .genesis promotes resilience to stress by enhancing gluco- eral cytokines can. age. noradrenaline and (for example. socioeconomic status (for example. a potential role for inflammation in MDD is has been shown to accelerate the onset of action of also supported by clinical trials of NSAIDs. A bidirectional association between these serum levels of cytokines. Deeper clinical and biological trophin brain-derived neurotrophic factor (BDNF) pheno­typing of MDD will lead to the identification have been measured in the sera of patients with MDD. ingly. alcohol use. Fludrocortisone. There have also been a few large. patients with MDD. such as tumour necrosis factor determinants and MDD is evident. Peripheral cytokines can Importantly. acts with the body’s main integrative systems (the HPA Although BDNF and other correlates of neuroplasti- axis. Several social and environmental factors are associated with the risk and the outcome a population-based study has shown that both prior of major depressive disorder (MDD)208. and pharmacological and non-­ The immune system is an important component of the pharmacological antidepressant therapies have been physiological stress-sensing pathways and closely inter.77. In addition. status or lack of social support. low social support. the precise role of neuro­genesis nervous system (CNS)) in mutually regulatory feed-­ in MDD has been debated84. pared with healthy controls78. behaviour and mood. For example. lower levels of the neuro­ therapeutic avenues. Finally.antidepressants in humans. the glucocorticoid receptor antago. These models in the context of stress. circuits. However. which may eventually lead to poverty208. analyses of failed trials indicated that very high doses primarily by disrupting neuroplasticity and. a mineralocorticoid receptor agonist. reviewed in standard antidepressants in one randomized controlled a meta-analysis82. trauma and negative life events) atitis virus infection or cancer often develop depressive and lifestyle factors (for example. it is biologically plausible microglia and neurons. Finally. unemployment. sex and ethnicity).induce depressive-like behaviour.shown to normalize BDNF levels83. affect behaviour through their control of neuro­genesis. overcrowding. risk of subsequently developing MDD74. especially those with a chronic course of the ling in peripheral blood cells has also been observed in disease. prospective studies indicating that increased levels of IL‑6 during childhood significantly increases the overall results have not indicated a major role for risk of developing MDD in adulthood79. By contrast. as confirmed by meta-analyses76. anisms (CNS infiltration by peripheral immune cells) or signalling via the vagus nerve (the ‘inflammatory Monoamines reflex’). migration. Along these lines. difficulties in work. receptor expression). socioenvironmental events (for example. A l l r i g h t s r e s e r v e d .70. often deteriorate in their social functioning. inadequate housing. neurogenesis and dopa­mine were first implicated in MDD after it was plasticity 73. such as low socioeconomic (TNF) and IL‑6. leading to work and family a large-scale cohort study of patients with MDD com- problems (experiencing ‘social drift’).that neurogenesis contributes to the clinical effects of nals can be conveyed to the CNS through cellular mech. inflammatory sig. natural disasters. accord- might be required to reach therapeutic blood levels58. 5). war. At a biological level. effective adult neurogenesis be transported through the blood–brain barrier to act occurs following anti­depressant treatment that reduces directly on CNS-resident cells. this has not yet led to new stem cells. neighbourhood violence and safety). as part of their treatment for hep- discrimination. in rodents. directly and indirectly.

insula and temporal increased in those with major depressive disorder (MDD) compared with those who do lobes in patients with MDD90. Indeed.892 individuals also suggested that the adverse effects of medications and shared pathophysiology (for example. compared with other psychiatric disorders.8 RR= 1. such as the dorsal cingulate smaller volumes in many different brain areas have and anterior insula96. later. They include unhealthy lifestyle. 86). addiction.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . neuro- dominate the field of modern p ­ sychopharmacology imaging studies in MDD have identified abnormalities of MDD.97. on monoamine neurotransmission. findings in MDD is abnormally increased connectivity and heightened activation of the amygdala95. brains of patients with MDD have yielded inconsistent results (reviewed in REF. the iour. Evidence from meta-analyses34 of Nature Reviews | Disease Primers longitudinal studies has revealed that the relative risk (RR) of various diseases is ­anterior and posterior cingulate. not have MDD. as well as post-mortem studies of the control circuit. By con- cal changes in brain structure in MDD as detected by trast. antidepressant effects are often only evident after several and includes projections between the dorsal cingulate. many cross-sectional stud. mation and self-directed thoughts in MDD95.7 RR= 1. cuit plays a central part in guiding motivated behav- tems within hours after administration.94. upregulation hippocampus might be selectively affected in MDD of immune–endocrine stress systems. in either activation or connectivity within the affective– However. Furthermore. Several studies have suggested that stress-associated enhancing the effects of the neurotransmitters. In addition. Changes in brain gene expression anterior insula.6 with MDD than in healthy controls in the basal gan- Cancer MDD glia. effects87. The affective–salience cir- target monoamines affect these neurotransmitter sys. poorer care (or selfcare) adherence. which and cellular mechanisms of the pathobiology reviewed may reflect the increased salience of negative infor- above might ultimately contribute to morphologi. default mode network and the frontoparietal cognitive urine and CSF. The mechanisms that contribute to the diverse somatic consequences Furthermore.6 neuroimaging genetics through meta-analysis) working Obesity group of MRI data from more than a dozen independent Disability research samples detected significantly lower volumes in Cognitive impairment the hippo­campus (but no other subcortical structures)89 as well as cortical thinning in the orbitofrontal cortex. Structural brain alterations much like the amygdala. drugs that Affective–salience circuit. A l l r i g h t s r e s e r v e d .8 Diabetes mellitus individ­uals with MDD. thalamus. A meta-analysis by the ENIGMA (enhancing RR= 1. leading to decreased recruitment of regional brain volumes in patients with MDD. ventral striatum and amygdala. 5). a large-scale trans-diagnostic voxel-­ of MDD are complex and together might explain the unfavourable health outcomes in based morphometry meta-analysis of 193 studies patients with MDD. Indeed. 6 | 2016 | VOLUME 2 www. this could not be confirmed in the amines in MDD was further supported by the discovery most recent meta-analysis of MRI data by the ENIGMA in the 1950s and. schizophrenia. rendering the monoamine hypothesis of MDD One of the most frequently reported neuro­imaging overly simplistic. For example. Figure 2 | The somatic consequences of MDD. Thus. as well that occur after continuous treatment with drugs that as downstream targets.34. which continue to changes in multiple brain networks93. decreased activity and connectivity of the ventral neuro­imaging. the medial prefrontal–medial parietal adrenaline and serotonin metabolites in the plasma. many studies that have measured nor­ salience circuit. such as These contributions are explained in more detail elsewhere5.nature. Although saliency-processing areas. hippocampus and several frontal regions RR= 1. whether smaller volumes of the of the first antidepressant drugs — t­ ricyclic antidepres­ hippocampus seen in MDD are an early manifestation or sants (TCAs) and monoamine oxid­a se inhibitors whether they develop later in the course of the disorder (MAOIs). p a r t o f S p r i n g e r N a t u r e . weeks of treatment.PRIMER Heart disease been reported in individual case–control studies. whether related to emotional or cognitive stimuli.3 (FIG. . bipolar disorder. comprising 15. obsessive– compulsive disorder and anxiety 91. the mechanistic interro­gation working group89. However. which is present in MDD but also in obesity). a meta-analysis of 143 studies88 confirmed smaller volumes in patients RR= 1. TCAs block the reuptake of monoamines in the presynaptic neuron Functional brain circuits and MAOIs prevent their breakdown once reabsorbed. such as hypothalamic and brain target monoamines might underlie their therapeutic stem nuclei. Although an e­ arlier meta-analysis suggested that smaller hippo­campal vol- drug reserpine reduce their levels and that some patients umes might already be present in patients with first-­ taking these drugs developed MDD85. the dorsal anterior cingulate It stands to reason that a combination of the molecular and anterior insula are hyperactive in MDD. Both TCAs and MAOIs have robust effects remains unclear. the best and most consistent evidence from structural MRI Mortality studies support that hippocampal volume is reduced in RR= 1. These alterations in inflammatory and glucocorticoid sig- findings stimulated the development of a long series nalling are associated with corresponding functional of monoamine-­based compounds.8 RR= 1. The role of mono­ episode MDD92. striatum and other reward-related regions have been ies using structural brain imaging have investigated observed in MDD.

Thus. The criteria include anhedonia. hypothesis-driven therapeutic approaches refers to the presence of what has often been referred to for depression have yet made it to the clinic. and/or involvement in network in MDD has been proposed to underlie exces. unusual restless- of a single depressive episode of ≥2 weeks. in which most mental activity is internal or self-directed. Severe symptoms have a substantial effect on function. the clinical relevance of many of these mechanisms for MDD With melancholic features.106. p a r t o f S p r i n g e r N a t u r e . by schizophrenia. The criteria include experiencing at least three of humans. increased Difficulties in dynamic modulation of the default mode activity in goal-directed tasks. PRIMER Default mode network. The differential diagnosis of of MDD. increased speech or pressure of speech. animal or grandiosity. The specifier ‘with mixed features’ is characterized by a clear period of elevated mood reflects an idea that MDD lies on a continuum with bipolar disorder and that patients with either diagnosis can show features of the other during an index episode1. If a patient meets criteria for MDD. trouble concentrating secondary to worry. Moreover. psychotic disorders (BOX 1). The first specifier. schizoaffective disorder or other especially of the dorsolateral prefrontal cortex. many of the symptoms typically experienced by patients with major the following symptoms during the depressive episode: depressive disorder (MDD) are highly subjective (such as depressed mood) and only few elevated and expansive mood. screening and prevention Differential diagnosis With anxious distress. poor default mode deactivation is perturbed in MDD101. features requires a different therapy than MDD without Indeed. Finally. it is possible to meet criteria for per- with MDD. this fascinating and highly active area of investigation has the potential to mixed features. are mourning and who develop symp. patients with MDD show rapid thinking and reduced particularly for psychiatric disorders223. . fear recurrent in the majority of cases1. The fronto­ would receive two diagnoses — MDD and persistent parietal cognitive control network is engaged across depressive disorder. synaptic dysfunction and plasticity227 ing clinical question is whether MDD with mixed and neurogenesis228. Despite these challenges. which are characteristic of bipolar dis- complicated by the lack of consistently identified genetic risk factors of depression in order. that awful things will happen. Indeed. A recent meta-analysis found the depressive episode must not be better explained evidence for frontoparietal hypoconnectivity in MDD. the default Persistent depressive disorder is a chronic dis­order mode is hyperconnected in MDD99. for an MDD diagnosis. toms for >2 years. Apart from depressed mood. heightened self-esteem can be objectively observed and assessed in animals. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 7 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . Moreover. Diagnosis. however. severity of episode. only the dynamic coupling between frontoparietal activ­ation two of six symptoms (appetite disturbance.98. Box 3 | The role of animal models in the understanding of MDD This hypothesis is based on the observation that some Finding the appropriate model systems for a given human disease is always challenging. and with at least three of the following characterized by greater activity during ‘resting’ states symptoms: inflated self-esteem. which With mixed features. then the patient The frontoparietal cognitive control circuit. impli. The specifier acute grieving period.102. in patients with considerable co‑occurring anxiety are more likely who. is cognitive appraisals of negative events105. MDD is distinguished from distress’ was introduced because patients with MDD normal sadness or bereavement. decreased frontoparietal connectivity has Specifiers of MDD been shown both at rest and in response to negative Once a diagnosis of MDD is made. distractibility. increased speech. as endogenous features. These symptoms need to be present bipolar disorder. for example. However. increased energy or directed activity. sistent depressive disorder without having MDD. and/or reduced need for sleep. ‘With melancholic features’ remains uncertain. rated from mild to moderate to severe. suggest. These pathways include but are not limited to neuroendocrine57 and excessive activity in behaviour with possibly negative immune214 mechanisms. but not in response to positive stimuli. risky behaviour. A press- the microbiota and the gut–brain axis226. By contrast. concentration or hopelessness) are required for the which might contribute to cognitive deficits in patients diagnosis. models have enabled the discovery of several target pathways that might contribute to the pathogenesis of MDD and have facilitated the study of the implicated molecular racing thoughts. The specifier ‘with anxious According to DSM‑5 (BOX 1). with persistent depressive disorder most of the days that the patient experiences an ­episode and with schizophrenia. to report suicidal thoughts and be less responsive to toms that are severe enough and that persist beyond the traditional antidepressants than others. many cognitive tasks103. flight of ideas. which correlates and describes patients who have had depressive symp- positively with measures of rumination100. reduced need for sleep. an MDD diagnosis can be given. no newly developed. sive self-focus and rumination95. processes. bipolar disorder rather than MDD rests entirely with the presence of a history of hypomania or mania. further characterized using various modifiers or speci­ ing that this network may contribute to inappropriate fiers1 (BOX 1). uncover novel targets for therapy and ultimately to bring about better treatments for patients. Developing animal models is further need for sleep. requires experience of at least two of the following: Although it is possible to diagnose MDD on the basis a sense of being ‘keyed up’ or tense. The default mode network is or irritability. decreased self-esteem. cating it in goal-directed attention deficits in MDD104. MDD is ness. loss of energy. molecular networks and the transcriptome225. consequences. sleep dis- (which increases with task-directed attention) and turbance. A l l r i g h t s r e s e r v e d . and worry about ­losing The key differential diagnoses of MDD are with self-control. the condition can be stimuli. epigenetics224.

Clinical studiesNature in major depressive Reviews disorder | Disease Primers (MDD) and relevant animal models have identified pathophysiological features in the central nervous system. IL-1β and IL-6) Cortisol Reduced NK cell cytotoxicity Adrenal medulla Reduced T cell proliferation Adrenal cortex Cardiovascular and metabolic systems Increased metabolic and cardiovascular risk Figure 3 | Biological systems involved in the pathophysiology of MDD. adrenocorticotropin. Within the immune system. A l l r i g h t s r e s e r v e d . Conversely. ACTH. chronic stress and associated changes in behaviour can reproduce many of the stress system alterations. These could underlie functional changes in relevant brain circuits (for example. which is one of the most consistently reported biological features of MDD. such as the hypothalamic–pituitary–adrenal (HPA) axis. including monocytes. The sequence of events leading to changes in these interconnected systems and their exact relationship is not known. TNF. cognitive control and affective–salience networks). reduced plasticity and impaired neurogenesis Altered connectivity. chronic hyperactivity impairs feedback regulation of the HPA axis. CRH. which is in contrast Signs and symptoms Alterations in emotion. The criterion of mood reactivity in atypical morning. actual or potential positive events. p a r t o f S p r i n g e r N a t u r e . as confirmed in neuroimaging studies. including HPA feedback impairment and inflammation.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . as well as the major stress response systems. mechanistic studies in animals have shown that alterations in stress response systems can directly and indirectly affect the central nervous system (BOX 3). tumour necrosis factor. which often co‑occur with MDD. corticotropin-releasing hormone. Beyond the central nervous system. other aspects of immunity seem to be impaired as exemplified by reduced natural killer (NK) cell cytotoxicity and T cell proliferative capacity. weight loss and ­depression requires that mood brightens in response to excessive guilty thoughts. the autonomic nervous system and the immune system. The specifier ‘with atypical distinct quality of depressed mood (such as despair).PRIMER lack of pleasure and loss of reactivity to positive stimuli. In the central nervous system.nature. altered neurotransmission and reduced plasticity are evident. features’ refers to a set of symptoms that are common depression worse in the morning. in the hippocampus) and neuroinflammation. psychomotor disturbance. both HPA axis hyperactivity and inflammation might converge with alterations in the autonomic nervous system to contribute to central nervous system pathobiology as well as cardiovascular and metabolic disease. However. However. . With atypical features. 8 | 2016 | VOLUME 2 www. which suggests a bidirectional link between central and peripheral biological features of MDD. Once it becomes chronic. smaller regional brain volumes and neuroinflammation Hippocampus Locus coeruleus Hypothalamus CRH Immune system HPA axis Autonomic nervous system Monocyte activation Impaired ACTH feedback Increased levels of catecholamines regulation and autonomic imbalance Increased cytokine levels Pituitary (TNF. substantial evidence supports increased levels of circulating cytokines and low-grade chronic activation of innate immune cells. waking early in the in MDD. cognition and behaviour Central nervous system Altered neurotransmission. smaller regional brain volumes (for example.

which might • Default mode network • Stress • Cognitive control circuit help to improve current classification systems109. epigenetic mechanisms to produce the phenotype of MDD. prevention (in a whole population group regardless of mood-incongruent psychotic features that do not include risk status). . • Medical illness • Drug abuse Molecular level Screening Protective • Neurotransmission Screening is controversial in the MDD field. that is. The specifier ‘with catatonic prodromal symptoms of depression). the ‘with psychotic strategies such as strengthening protective factors (for features’ specifier in DSM‑IV was included as part of the example. The results indi- features’ refers to marked psychomotor disturbance cated a 21% decrease in the incidence of MDD in the pre- that may involve decreased motor activity. The Different guidelines concur that moderate-to-severe RDoC approach consists of a matrix in which the rows depressive episodes should be treated with medication represent specified functional constructs characterized or with a combination of medication and psychother- by genes. However. psychotic features were separated reducing depressive symptoms before they fulfil criteria from the severity specifier because the two were not for MDD) might have an enormous public health impact always highly correlated (that is. the US National Institute of Management Mental Health (NIMH) developed the Research Domain In the management of MDD. cells. The ultimate goal of RDoC is Aversive to develop a deeper understanding of the biological and • Prenatal factors • Regional brain volumes • Childhood trauma • Affective–salience circuit psycho­social basis of psychi­atric disorders. nihilism or deserved punishment. These patients cluded that prevention of MDD seems feasible and may are often psychotic. The schematic implement universal screening and argue that there is a Nature Reviews | Disease Primers depicts a model that is based on predisposing genetic vulnerabilities that interact with lack of evidence to support screening 111. increasing social support or problem-solving severity continuum from mild to severe with psychotic skills) or diminishing prodromal disease stages (such as features. By contrast. Previously. but the following: significant increase in weight or appe. However. the existing data112 indicate that screening pro- to the ‘with melancholic features’ specifier. in a mild anxiety and loss). increased sleep. death. systems for social processes. which is characterized The authors concluded that the overall evidence of health by alterations on a molecular level. for example. The meta-analysis included studies examining universal ease. Environment Brain network level energy balance and sleep). Furthermore. there are two main initial Criteria (RDoC) that are not meant to be a diagnostic treatment options: psychotherapy and pharma­cotherapy. However. depressive themes of personal inadequacy. In DSM‑5. present with psychotic features)107. turn grouped into five higher-level domains of func. By contrast. guilt. At least some of the environmental effects are mediated through and harms of screening for depression in primary care112. decreased vention groups compared with control groups who did engagement during interview or physical examination. Many • Social support • Neuroplasticity • Coping • Stress hormones experts argue that screening for depression is of obvious • Exercise • Inflammation benefit because MDD is often overlooked in medical set- tings110. p a r t o f S p r i n g e r N a t u r e . not receive preventive interventions113. on a brain network level and on a behavioural level. be an effective way to reduce the numbers of ­incident MDD cases. physiology. Prevention Given the high prevalence of MDD. The authors con- or excessive and peculiar motor activity. and Behavioural level Genome MDD • Affective symptoms arousal and regulatory systems (responsible for gener­ • Cognitive symptoms ating activation of neural systems as appropriate for • Somatic-vegetative symptoms various actions and homeostatic control. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 9 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . A l l r i g h t s r e s e r v e d . A recent system- aversive and protective environmental factors in the development of major depressive atic review included 71 studies and assessed the benefits disorder (MDD). positive valence systems (encompass­ depressive episode it is also possible to pursue an ing reward seeking and consummatory behaviour). self-­report apy 114–117. tite. mild MDD can also in reducing disease burden. Other ­criteria grammes generally increase the likelihood of remission for ‘with atypical features’ include at least two out of and treatment response in general adult populations. groups at increased risk of developing depression) and indicated prevention (in individuals identified as having With catatonic features. selective prevention (in individuals or sub- these typical themes can also occur. Psychotic features in The effects of preventive psychological interventions MDD are mostly mood-congruent. the content of on the incidence of MDD were systematically examined delusions or hallucinations is consistent with the ­typical in a meta-analysis of 32 randomized controlled trials113. system but a framework for organizing research. molecules. circuits. and interpersonal sensitivity. others state that it is impractical to Figure 4 | Model of gene–environment interactions that lead to MDD. a sense of leaden paralysis. always be taken into account. Constructs are in initially treated with psychotherapy alone. dis. only in the presence of subsequent treatment offers. patient preferences and prior treatment history should tioning: negative valence systems (encompassing fear. Research Domain Criteria In addition to DSM‑5. a mild depressive episode can be and paradigms used to measure it 108. ­initial strategy of ‘watchful waiting’ without treatment. effective prevention With psychotic features. benefit of depression screening in primary care is weak. PRIMER Epigenetic mechanisms cognitive systems.

The beneficial effects of cognitive factors explanation — argues that the primary agents therapy have been shown to persist for at least 1 year for change in psychotherapy are mainly those that are post-­treatment. Regional brain volumes as determined by structural Nature MRI|have Reviews been Disease Primers investigated in patients with major depressive disorder (MDD) compared with healthy controls in numerous cross-sectional studies. such as cogni. However. lack of available services and cost131. Volume group differences.3 0. Brain areas with smaller volumes in MDD include the basal ganglia. ment outcomes might be optimized by tailoring specific the most common of which are described in BOX 4.91. suggesting some specificity of these areas for the depressive symptoms that are characteristic of unipolar MDD. proponents of the specific-factors edly shown to be an effective medium for delivering explan­ation argue that treatment-specific strategies psycho­therapy 133. blinding)128. schizophrenia. showed no meaningful differences in out- the efficacy of psychotherapies. obsessive–compulsive disorder or substance use disorder Figure 5 | Structural brain alterations in MDD. only smaller volumes in the hippocampus were specific to patients with MDD when compared with other psychiatric disorders. combining data across 16 trials that dent between different types of psychotherapy 118–120. treat- Psychotherapy for MDD comes in many different forms. warm. no (for example.6 0. comes on self-reported depression or rates of response The first hypothesis — the nonspecific or common or remission 129. caring and genuine stance)122 than in patients who withdraw from medications130. Finally. anxiety disorders.9 1. after comparisons of different psychotherapeutic treatment which time treatment should be started in case the mild models. The common factors approach Although psychotherapy is clearly effective.1 Average volume difference (%) Effect size MDD versus healthy controls MDD versus healthy controls or bipolar disorder MDD versus healthy controls. including time con- ity assurance for these common factors will optimize straints. This compared individual psychotherapy to antidepressant conclusion121 has led to two broad hypotheses to explain medication. bipolar disorder. which is similar to keeping people on common to all psychotherapies. such as the therapeutic antidepressant medications. . schizophrenia. social dysfunction and cognitive and practitioners in their treatment decisions115. particularly for 10 | 2016 | VOLUME 2 www. producing outcomes that are equiv- produce change via different pathways. hippocampus and frontal regions. which are grossly underpowered to detect treat- depressive episode has not resolved116. head‑to‑head less costly way of providing treatment.5% (left graph) and moderate effect sizes (right graph. typically with volume differences between 3.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . in an independent meta-analysis of structural MRI data using voxel-based morphometry. and with lower relapse rates alliance (a positive. Accordingly. obsessive–compulsive disorder or substance use disorder are based on data from Goodkind et al. To the Psychotherapy degree that the specific factors hypothesis is true.0 1. which aims to guide patients. as are the comparisons of MDD and patients with bipolar disorder. although effect sizes from their focus and methods. p a r t o f S p r i n g e r N a t u r e . this period should not exceed 2 weeks. effect sizes and confidence intervals of MDD compared with healthy controls are based on data from Kempton et al.8 0. Comparisons of MDD with bipolar disorder. and therapist factors123.nature. A large number of ran­domized pharmacological and psychotherapeutic trials cannot controlled trials and meta-analyses consistently show be readily compared because of methodological issues that psychotherapy is effective in treating MDD. psychotherapy over the telephone has been repeat- By contrast.4 0.PRIMER Brain region Caudate Putamen Globus pallidus Thalamus Hippocampus Frontal lobe Orbitofrontal cortex Gyrus rectus –20 –15 –10 –5 0 0 0.7 0. A l l r i g h t s r e s e r v e d . which have been shown to differentially predict outcomes for different treatments126.5 0. tive restructuring. FIGURE 6 depicts a ment differences125. carers severity of depression.1 0. people have barriers to access. dysfunction.127. behavioural activation or improved Furthermore. thalamus. different paradigms rely on different conceptual models Psychotherapy produces effects that are mostly equiv- and prescribe techniques that vary to some degree in alent to pharmacotherapy.132.88. Providing treatment outcomes. data meta-analysis.2 0. hide patient variables such as the stepped-care model. alent to face‑to‑face therapy and reducing dropout 134. many would suggest that focusing on training and qual.5% and 15. These interventions to patient characteristics. group therapy is often recommended as a interpersonal functioning 124. A recent individual patient consistent or clinically meaningful differences are evi. anxiety disorders. error bars indicate 95% confidence intervals). Smaller volumes in the basal ganglia and the hippocampus have also been confirmed when comparing patients with MDD to those with bipolar disorder.

tion technologies. enabling just‑in‑time have not shown consistent benefits. Indeed. has been challenged149. combined treatments. presynaptic and postsynaptic receptors. are highly effective at reducing symptoms forms has the potential to shift our treatment tools from of depression138. with a growing comple- ment of sensors. Accordingly. basis of their known pharmaco­logical actions (such If the initial intervention shows no benefit or if the individual declines an intervention. primarily because prompting and reinforcement of treatment-congruent people with MDD do not adhere to them. internet-based behaviours144. An inter- Low-intensity psychosocial interventions. A l l r i g h t s r e s e r v e d . Available from ability and the effects of the specific monoaminergic https://www. whether patients can amines) was overly simplistic.org. high-intensity psychological interventions. psychoeducation. most effective intervention is provided first. incompletely understood. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 11 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . which use computers. unclear. as well as tools that can passively monitor tools. The rapid rate at which technology advances response to the biochemical perturbations in the syn- means that technology-based interventions will continue apse. such and interventions classification. Manchester: NICE. when applied correctly. as selective serotonin reuptake inhibitors (SSRIs) and an appropriate intervention from the next step should be offered. cation of antidepressant drugs. combined treatments. typically based on moderate and severe depression the speci­fic effects on individual monoamine neuro­ Step 3 Medication. An emerging area of technology is digital pheno­ paring individual to group psychotherapy have shown typing. anti­depressants are be identified who might respond better to technology-­ known to induce neural plasticity and the modulation of based treatments than to traditional treatments is monoamines is only the first of their therapeutic effects146. As ­people tend to keep their phones with them. Three decades after monoamine neurotransmitters were However. and/or monoamine transporters.Reviews Nature | Disease Primers sants or anti­psychotics). psychological interventions. PRIMER patients with mild-to-moderate symptoms135. which harnesses the growing availability of individual treatment to be moderately superior to group data generated continuously in the course of daily lives post-treatment. the patients who Mechanisms of action. severe self-neglect adaptive changes147. although the exact mechanism Medication. medication and referral for further assessment and interventions national ­initiative from five scientific organizations with a focus and expertise in neuropsycho­pharmacology All known and suspected presentations of depression recently developed the Neuroscience-based Nomen­ Step 1 Assessment. 3‑month follow-up136. possibility of intervention tools that can detect and react Although standalone technology-based interventions to sensed states and behaviours. as attitudes and expectations about the role of technology in daily life change. monoaminergic neurotransmission complicated by psychotic symptoms and/or is associated with considerable psychiatric comorbidity or psychosocial factors. support. instead of grouping drugs according to indications (such as antidepres- Figure 6 | Stepped-care model in the management of MDD. crisis service. collaborative care‡ and referral for further assessment transmitters. pathways as well as changes in gene expression and neural and synaptic plasticity (including hippocam- pal neurogenesis) might have crucial roles in these Severe and complex depression*. Behavioural interven. are effective of depression in real time143.148. has been useful in mild to moderate depression Step 2 understanding some of their adverse effects. However. has led to their being integrated into national mental health services in several countries. mobile phones. from reactive to proactive and effectiveness of these coached intervention technologies from provider-centred to patient-centred145. although these differences disappear at to create behavioural markers related to depression. combined with low-intensity coaching via phone the risk of depression. it became clear that the narrow of technology-supported care and more-traditional focus on increasing monoamine levels in the synaptic forms of psychotherapy or pharmacotherapy have yet cleft (by blocking reuptake or degradation of mono- to be carried out. the usefulness of the standard classifi­ depression with inadequate response to initial interventions. tablets and phone sensors can continuously estimate the severity phones to teach self-management skills137. including England140 Pharmacotherapy and Australia141. well-designed head‑to‑head comparisons implicated in MDD. From REF. active monitoring and referral for further assessment and interventions clature149 of psychotropic drugs that. 7). by which antidepressants exert their effects remains Step 4 electroconvulsive therapy.139.nice. often reflecting the affinity of drugs for presynaptic and postsynaptic monoamine receptors Persistent subthreshold depressive symptoms. National Institute for Health and Care Excellence (2009. For example.uk/guidance/CG90. . Downstream changes in intracellular signalling to grow and evolve rapidly 142. organizes medications on the The stepped-care model proposes that the least intrusive. transmitter (FIG. Now. includes depression that shows an inadequate response to multiple treatments. Reproduced with permission. multi-professional and in-patient care Given the now understood complexity of the activity Persistent subthreshold depressive symptoms or mild to moderate of these drugs. *Complex depression serotonin–noradrenaline reuptake inhibitors (SNRIs)). Evidence for the efficacy and cost-­ episodic to continuous. high-intensity psychological interventions. is In summary. Trials com. have become personal sensing sys- Technology-supported care.tems. p a r t o f S p r i n g e r N a t u r e . This technology opens the at reducing symptoms of MDD. Only for depression in which the person also has ‡ is extremely complex and includes several neuro­ a chronic physical health problem and associated functional impairment. updated 2016) CG90 transporters and enzymes that determine the avail­ Depression in adults: recognition and management. risk to life. 115. Monoamine-based antidepres- are likely to respond to such treatments will probably sant drugs are thought to initiate an adaptive neuronal change. Harnessing personal sensing plat- or messaging. transmitters.

SNRIs in displacing TCA drugs as first-choice agents including old age. hippocampal neurogenesis-stimulating treat- distorted thinking patterns that contribute to depression ments156 and antiglucocorticoid therapies157. A careful diagnostic re‑assessment is considered Mindfulness has its origins in contemplative practices. (doubling or tripling) of the dose of the antidepressant headaches. high number of hospitalizations file. social roles.nature. but rent depressive episode. moderate-to-high suicidal risk. such as medical feelings and experiences in a non-judgemental manner. Interpersonal therapy focuses on helping people to although varying definitions of treatment resistance identify and to resolve problems in relationships and exist 162. and involves regular meditative More specifically.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . that are devoid of some of the untoward effects of ing the primary antidepressant drug to another of the these drugs and that are able to induce clinical changes same class or of a different class. rather on a generally more favourable adverse-­effect pro. the treatment 12. include psychopharmacological approaches. Several studies have shown that initiating treatment with both psychotherapy and pharmacotherapy prod­ Psychodynamic therapy Psychodynamic therapy helps the patient to explore and uces significantly better outcomes than either treat- gain insight into how emotions. psycho­ However. recently been ­confirmed in two meta-analyses looking In the past two decades. and a high therapeutic index (the ratio of lethal dose to The most established strategies for treating TRD therapeutic dose). Recognizing these patterns can help received when the monotherapy has not achieved a person to cope and to change those patterns. and show a character­istic logical approaches for TRD involve high-dose drug delayed (typically more than several weeks) response to therapy or combination therapy. tial role of several contributing factors. This strategy has sleep disturbances151. . The degree of resistance to learning to accept things as they are without trying to treatment can vary greatly among patients with TRD and change them. the SSRIs and SNRIs are also term high-dose treatment refers to a psychopharmaco­ not devoid of considerable tolerability issues: common logical strategy involving the considerable increase acute treatment adverse effects are nausea. For example. primarily Buddhism. have fundamentally comparable modest efficacy. to identify and to overcome potential barriers The term treatment-resistant depression (TRD) is to goals and to make effective decisions.150. dizziness. Psychopharmaco­ response rates around 50%. including interpersonal conflicts. combined with ease of administration. with Psychopharmacological strategies. typi­cally used to describe a form of MDD that has not Interpersonal therapy responded adequately to at least one antidepressant 161. Problem-solving therapy teaches patients a structured set of skills to generate creative methods to address Treatment-resistant depression problems. long duration of cur- was not based on established differences in efficacy. response following a first antidepressant drug treat- Mindfulness-based therapy ment161. The degree and provides skills to test and challenge these negative thoughts.166. opioid tone modulators and opioid‑κ antago­ major depressive disorder (MDD) to identify negative. all of the monoamine-based anti­depressant therapy and electroconvulsive therapy (ECT). This treatment also frequently focuses on Combined pharmacotherapy and psychotherapy identifying and confronting avoidance processes. a strategy that has been sexual dysfunction. it is important to evaluate the poten- practice in which one pays attention to thoughts. there have been efforts to at SSRI use165. p a r t o f S p r i n g e r N a t u r e . insomnia. A l l r i g h t s r e s e r v e d . role with up to 50–60% of patients not obtaining adequate transitions and diminished or impoverished relationships. The success of the SSRIs and eral variables are associated with treatment resistance. 12 | 2016 | VOLUME 2 www. nists155. whereas common long-term adverse shown to lead to significant improvements particu- effects include weight gain. these different mechanisms. thoughts and earlier life ment alone158. drugs. anti-inflammatory Cognitive–behavioural therapy teaches the patient with agents154. Cognitive–behavioural therapy glutamatergic system modulators153. and psychiatric comorbidity. sexual dysfunction and larly in the event of partial response. However.PRIMER Box 4 | Psychotherapy for MDD in a much more rapid manner. the strategy of switching involves chang- based. regardless of their pharmacological class. A meta-analysis showed sev- Tolerability and efficacy. marital status. satisfactory results is also effective at increasing the Problem-solving therapy response rate160. TRD is frequently observed in clinical practice. although all of these types of compounds have shown some degree of promise in Behavioural activation therapy the treatment of MDD. crucial to the proper management of patients with TRD. some staging methods to classify TRD on the basis of different levels of treatment resistance have been shown to be of use clinically 163. replacing them with more accurate of advancement in the development process varies across positive ones. develop antidepressant drugs that are not monoamine-­ In addition. In the STAR*D study. Similarly. gastrointestinal symptoms and in the face of non-response. anxious comorbidity.159. augmenting psychotherapy experiences have created patterns that contribute to or antidepressant medications with the treatment not current problems. Compounds that are under development include neurokinin 1 antagonists152. Behavioural activation therapy focuses on increasing the patient’s positive activities that provide a sense of pleasure or mastery. such as lack of anticholinergic and cardiac effects and comorbid personality disorders164.

doxepin§. clomipramine§. doxepin§. desvenlafaxine|| and levomilnacipran|| Serotonin Acetylcholine Noradrenaline α2-adrenergic receptor Dopamine Amitriptyline§. Most currently used monoamine oxidase (MAO) inhibitors are noradrenaline reuptake inhibitors (SNRIs. trimipramine§. venlafaxine||. and α1‑adrenergic receptors. Amitriptyline§. PRIMER this strategy led to remission in one in four patients Another approach in TRD is augmentation. muscarinic acetylcholine neurobiological systems (such as γ‑aminobutyric acid. A l l r i g h t s r e s e r v e d . have become somewhat less common in prac- ten patients achieving remission12. denoted with ‡) have also antagonists/agonists primarily bind to serotonin 5‑HT 2 receptors. Muscarinergic G1 Histamine transporter clomipramine§. p a r t o f S p r i n g e r N a t u r e . (NDRIs. . More-selective dual-action serotonin receptor selective noradrenaline reuptake inhibitors (NRIs. TCAs. Vortioxetine* clomipramine§. vilazodone*. The tricyclic antidepressants (TCAs. shown at therapeutically relevant doses to have significant binding to the Agomelatine is a melatonin receptor (MT1 and MT2) agonist (not shown) noradrenaline transporter. Mirtazapine and # duloxetine||. amitriptyline§. denoted and a 5‑HT2C antagonist without anticholinergic or antihistaminergic with §) and other cyclic antidepressants. G1 trimipramine§. acetylcholine Dopamine trimipramine§ receptors G1 and doxepin§ Bupropion¶ Neurotransmission Figure 7 | The mechanisms of action of antidepressant drugs. H1 receptor trazodone** and mianserin# Reboxetine‡. These effects account for the opioids) are probably involved in the neurobiology of MDD and are to some higher adverse-effect burden of the TCAs than the other classes of extent targeted by more experimental antidepressive substances (such as antidepressants. citalopram*. 5-HT2 Postsynaptic neuron mirtazapine#. denoted with ¶) primarily block the reuptake Nature of noradrenaline Reviews and | Disease Primers The selective serotonin reuptake inhibitors (SSRIs. serotonin 5‑HT2 receptors. agomelatine. The relatively α2-autoreceptors. sertraline*. denoted with ||). milnacipran||. tice. whereas augmentation with atypical anti­psychotic 5-HTT G1 Vortioxetine* G1 and vilazodone* 5-HT1A 5-HT1A 5-HT1B Fluoxetine*. desvenlafaxine|| and levomilnacipran|| Vilazodone* G1 Presynaptic Trazodone**. 5-HT1D escitalopram*. trazodone** α1-adrenergic and MAO tranylcypromine α2-adrenergic receptors and moclobemide and mianserin# Noradrenaline Mirtazapine#. are potent blockers of histamine is a selective and reversible MAOA inhibitor. transporter amitriptyline§. as well as the serotonin– properties. **Serotonin antagonist and reuptake inhibitor. but its non-antidepressant drugs. neuron doxepin§ and mianserin# Cell signalling G1 Phenelzine. denoted with *) have dopamine. The noradrenaline–dopamine reuptake inhibitors ketamine). with only one in (T3)167. in which who were citalopram (an SSRI) non-responders (both ongoing antidepressant drug treatment is combined with within the same class or within a different class). vortioxetine*. block the irreversible inhibitors of both MAOA and MAOB. mianserin# doxepin§. glutamate and receptors. Initially well-studied augmen- success in patients who have not responded to two anti­ tation strategies. milnacipran||. NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 13 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . duloxetine||. venlafaxine||. tyramine reuptake of serotonin and noradrenaline by binding to their transporter in and tryptamine being substrates for both isoforms of MAO. amitriptyline§. other H1 receptors. The α2‑adrenergic receptor antagonists (denoted with #) seem been shown to have significant binding (antagonistic) to the serotonin to enhance the release of both serotonin and noradrenaline by blocking transporter (5‑HTT). such as lithium or l‑triiodothyronine depressant trials is extremely modest. In addition. trazodone**. with dopamine. to varying degrees. fluvoxamine*. nortriptyline§. Moclobemide varying ratios. amitriptyline§. paroxetine*. thereby blocking serotonin reuptake. bupropion¶.

. Furthermore. such as Standard rTMS uses an eight‑shaped coil to modu. Finally. and/or highly suicidal patients. best-studied combination strategies. VNS results in the activation of various sub­ sis system of psychotherapy. However. but their efficacy is not well established yet. with TRD184. A recent review of 18 TRD studies of egies use compounds such as S‑adenosyl-methionine186. with regard to efficacy in TRD176.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . intravenous at least two antidepressant treatment failures. which is a specific cortical brain structures and the stimulation of hippo­ ­psychotherapy for chronic depression including TRD172. a seizure is elicited during short anaesthe. In ECT. with It  is commonly used when a rapid anti­d epressant a sustained response rate of 40% and with a ­remission response is required. and reported sia after the patient has provided informed consent. reserved for patients with the most severe forms of ment. which are antagonists of N‑methyl-d‑aspartate (NMDA). the most commonly used form no ­significant cognitive adverse effects178.PRIMER drugs. ated with an increased therapeutic effect over time. Similar results were reported in a trial of netic seizure therapy (MST). TRD and requires further evaluation of administration ical response173. vagus nerve stimulation (VNS). not achieve the pre-specified significance. Other stimulation (tDCS). other potentially favourable characteristics. Newer treatments for TRD include ketamine intravenous infusions elicit a significant numerous approaches. Another approach is to use ultra-brief ­methods and its role in MDD therapy 183. 14 | 2016 | VOLUME 2 www. The main tolerabil. a recent large-scale sant effect in patients with a mood disorder. however. However. long-term.5–2. such as quetiapine or aripiprazole. therapy in citalo­pram non-responders in the STAR*D pulsed electric field in the brain. MST combines elements of rTMS and ECT. omega‑3 fatty acids188. mine. studied in STAR*D. late neuronal activity to a maximum depth of 1. is increasingly a meta-analysis has shown that rTMS is inferior to ECT being used168. low-field magnetic stimulation drugs with NMDA receptor antagonistic properties (LFMS). such as in very severely depressed rate of 29% after a 9‑month follow-up182. mag. DBS is typically unilateral ECT seems to be as effective as bilateral treat. maker-like pulse generator in the chest. Finally. a meta-­analysis a stimulating electrode attached to the vagus nerve in showed efficacy for the cognitive–behavioural analy­ the neck. However.nature. A systematic review of the pertinent electrodes overlying targeted cortical areas179. VNS involves the surgical implantation of a pace- apy as adjunct to pharmacotherapy in TRD170. pulse-width (UBP) stimulation to minimize cognitive A novel pharmacological approach to the treatment adverse effects.5 cm Other emerging pharma­cological augmentation strat­ from the scalp. Right cally placed in specific brain regions. such as repetitive trans­cranial antidepressant effect from 4 hours to 7 days in patients magnetic stimulation (rTMS). trans­cranial direct current a single intravenous infusion of esketamine185. A review of 21 studies showed that single Emerging treatments. rTMS scopolamine189 and the opioid modulator ALKS 5461 is a reasonable. the use of cognitive–behavioural ered in a magnetic field waveform inducing a low. they have shown esketamine. campal neurogenesis182. A l l r i g h t s r e s e r v e d . decreased dissociative or psychotomimetic effects. Two sham-controlled study was associated with comparable efficacy to pilot studies of LFMS have shown a rapid antidepres- pharma­cotherapy 13. a systematic review showed of TRD involves parenteral or intranasal administra- that UBP ECT might have lower efficacy and a slower tion of the glutamatergic drugs ketamine or esketa- speed of remission174. surgi- ­especially anterograde and retrograde amnesia. for patients with MDD with l‑methylfolate187. A review of eight MST studies reported remission rates of 30–40% and Psychotherapy. One simultaneously. but the pro- (a noradrenaline–­dopamine reuptake inhibitor) or cedure is otherwise carried out as ECT using a general ­mirtazapine (an α2‑adrenergic receptor antagonist)12. DBS involves the implantation of a pulse generator ity issues of ECT are its adverse effects on cognition. effective consideration175. In MST. is considered to be the most widely used and effective extension phases of VNS treatment have been associ­ non-pharmacological biological treatment for TRD173. The two ­treatment to pharmacotherapy 177. dTMS modulates to the prescribing of more than one antidepressant neuro­nal activity in deeper regions of the brain. substitute therapy in TRD is sparse and shows mixed LFMS refers to a form of brain stimulation deliv- results169.171. 190). rTMS concluded that. Despite the fact that the only controlled trial in TRD of VNS using a sham control did ECT. are SSRIs or SNRIs combined with either bupropion an rTMS device is used to induce a seizure. deep TMS (dTMS). review concluded that dTMS in patients with TRD tory possibilities have dramatically increased with the is effective both as a monotherapy and as an add‑on introduction of newer antidepressant agents. A recent literature concluded that the current evidence examin­ review concluded that the data do not support the use ing the effect of psychotherapy as augmentation or of tDCS in TRD180. including randomized controlled study showed both efficacy and patients with TRD181. (REF. albeit bilateral treatment might lead to faster clin. ECT modest response rates in the acute phase. of psychotherapy studied is cognitive–behavioural tDCS typically applies a weak direct current via scalp therapy (BOX 4). anaesthetic and a muscle relaxant. In TRD. The array and number of combina. p a r t o f S p r i n g e r N a t u r e . as well as other ­pharmacological approaches. deep brain have been associated with more-modest antidepressant stimulation (DBS). long-term effectiveness of cognitive–behavioural ther. connected to two stimulating electrode wires. parenteral or intranasal ketamine and effects than with ketamine. combination treatment generally refers In contrast to standard rTMS. connected to compared with treatment as usual.

Patients with MDD have a 1. suggesting that cognitive deficits are in MDD in general or only in specific subtypes of the not simply an epiphenomenon of decreased motivation disease? Furthermore. has been shown to be a interact with the genome leading to MDD. neuroimaging and other biological meas- interventions to prevent suicide and suicide attempts ures.8‑fold incre­ whether treatment of comorbid MDD reduces morbidity ased overall mortality and patients with MDD lose and mortality in medical patients. it will be important to learn more about Suicide risk the mechanisms of association between MDD and other The most immediate clinical concern with MDD is medical diseases. In terms of the aetiology and pathophysiology Although the cognitive deficits are modest after of MDD. associated with antidepressants was nonsignificantly MDD is a major risk factor for suicidal ideation and increased in patients <25 years of age. memory and attention as the pre.204. MDD was associated with ity seems to be strongly age dependent 205. signifi­cantly decreased in patients >64 years of age. melan- ing might be effective. For remission (that is. there is a lack of replicated find- during episodes of low mood. which can significantly reduce the decreased in patients 25–64 years of age and highly quality of life of patients and their families. particu. an estimated 10. Strategies to reduce suicides at ‘suicide ides clinicians and researchers with the opportunity to hotspots’ (that is.2 years in A pivotal task in the future of MDD research will women7. Meta- 27. Cognitive impairment ings in both GWAS and G×E studies37. In one analysis. question remains how exactly environmental influences MDD severity. the risk of MDD as a broad DSM‑5 category into more narrowly ­suicide in MDD was almost 20‑fold higher than in the defined disease entities with specific biologies. strong predictor of cognitive dysfunction196. a crucial in MDD partly depends on the patient subgroup studied. public areas often used for suicides) define subtypes of MDD by grouping patients according by aiming to restrict access and to encourage help seek. Overall. effect sizes during a first episode of MDD194. effective treatment in low-income countries in which dominantly affected domains192. The general population7. PRIMER Quality of life Notably. In addition. Action Programme (mhGAP)210 of the WHO is aiming attention. Importantly. measured cognitive deficits in patients with MDD.209. One meta-analysis identified highest priorities in the field should be to implement executive function. such as diabetes mellitus or coronary its strong relation to suicidal intent and ­completed heart disease. to distinct clinical characteristics (for example.2 workdays lost per affected worker per year 191. meta-analyses of randomized controlled Much of the burden of disease associated with MDD is trials have not detected a beneficial effect of antidepres- related to its dramatic effect of on one’s ability to work sants to reduce suicide risk in MDD203.195 and mem. the DSM still prov­ thoughts201.206. Thus. In addition. ­initial goal of DSM‑5 was to define psychiatric diagnoses The effectiveness of behavioural and psychosocial by genetics. and the strain on family life. nonsignificantly of suicide attempts. given the fact that MDD is a strong in MDD198. . lar diseases. analyses revealed that suicidal ideation or behaviour Another aspect affected in MDD is cognition. as it is that are responsible for the increased MDD prevalence negatively associated with psychosocial functioning in women. for example. A l l r i g h t s r e s e r v e d . The currently ongoing Mental Health Gap by meta-­analysis193. example. clinicians should pay special attention to Cognitive impairment suicidal ideation and suicidality in patients with MDD in Considerable literature has described objectively general and during antidepressant  pharmacotherapy 207. p a r t o f S p r i n g e r N a t u r e . our knowledge has not yet sufficiently has been supported by a recent meta-analysis.6 life years in men and 7. how exactly is the immune system dysregu- slight impairments in executive control192. An attentional bias <10% of patients with MDD receive adequate treat- towards negative information has also been confirmed ment 208. However. antidepressant pharmacotherapy risk factor for developing metabolic and cardiovascu- seems to improve cognitive function199. in part. many questions remain unresolved. at least according to a recent cholic versus atypical depression). progressed to reliably base psychiatric diagnoses on larly for interventions that directly address suicidal biological measures. Nevertheless. In any event. Future research should also examine ­suicide200. one of the emotional) cognition. Impairments in psychomotor speed. Finally. Neurocognitive impairment is a and it will be important to examine the mechanisms relevant factor in the quality of life of patients. This is due. how stable are epigenetic alterations of genomic read-out patients with psychotic depression have been shown to and are they reversible with successful therapy? An epi- do significantly worse than patients with non-psychotic demiological phenomenon consists in the repeatedly MDD on tests of verbal learning. Finally. and for a worse course and outcome in these diseases5. to scale‑up services for mental disorders in countries utive function can be detected with small-to-medium with low and lower middle incomes. subtypes have already been associated with different NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 15 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . visual learning and memory. to the increased risk be to break down the heterogeneous clinical picture of of ­suicide in this population. In a large survey carried the association between antidepressants use and suicidal­ out in the United States. lated in MDD? Are immunological alterations present ory 192 can remain. Importantly. in euthymic patients with MDD). visual learning and described sex differences in prevalence rates of MDD2 processing speed197. These deficits affect a wide range of cognitive domains Outlook including both ‘hot’ (emotion-laden) and ‘cold’ (non-­ Given that MDD is prevalent worldwide. as well as exec. these meta-analysis202.

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National Institute of Drug Abuse (NIDA).G. Covidien.P. Clintara. Alkermes. EnVivo Best Practice Project Management.S.M. pathophysiology (C.com/nrdp © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . Inc. Auspex Pharmaceuticals.). Neurontics. LLC. Ganeden membership in a scientific advisory board from Otsuka.... College London. Aspect Medical Systems.P. and honoraria for consulting from Otsuka. Inc. has received honoraria for lectures and for research funding from Jansen Research and is supported by a Pharmaceuticals.O. and D. Organon Pharmaceuticals. Biogen and BioMarin management and eHealth interventions. PamLab. Gilead Incyte. Forum Pharmaceuticals.).O.. Reckitt Benckiser. C. Maudsley NHS Foundation Trust and King’s Johnson & Johnson Pharmaceutical Research & Development. Takeda Servier and for membership in a scientific advisory board from Acadia and Takeda. Medical Research Institute (SMRI). Sunovion and X‑Hale and as a speaker for Pfizer. Inc.M.. Lorex Pharmaceuticals. Icon Clinical Research. Myriad Genetics. and Pfizer. Pfizer Diagnosis. and A. GSK.G. and ‘Immuno-psychiatry: for Research on Schizophrenia & Depression (NARSAD).M. research funding from the Medical Research Medicine (NiiCM). Merck.. A. Lundbeck he holds equity in Amnestix. Mental Health Biomedical Research Centre in Mental Health i3 Innovus/Ingenix.. Naurex. Synthelabo. Mechanisms/ Council (UK) and the Wellcome Trust for research on National Institute of Mental Health (NIMH). Cerecor.C.M.O. Clintara.G. Tal Medical. Covance. at South London. Cervel.P. MedAvante. C.O. American Advisory Board/ Consultant: Abbott Laboratories. CeNeRx BioPharma. Avanir Affectis Pharmaceuticals AG.M.M. Shire. Titan and X‑Hale. Methylation Sciences Inc. VICI grant from the Dutch Scientific Organization. research support for conducting clinical trials from GAIA AG. S. Takeda. D. Inc. Hoffman-LaRoche. National Coordinating Center for Integrated on prediction of antidepressant response. has received honoraria support: Abbot Laboratories. National Alliance Delpor. has received honoraria for lectures from Lundbeck and Resource. BrainCells Inc. Eli Lilly and Company.C. has received a speaker’s fee from Logic. Outlook (C. Inc.F.W.). C. Corcept (co‑founder).).M. has received research funding from Brain Aventis US LLC. Syndrome’ (MR/J002739/1). Inc..S. AstraZeneca. Pharmavite® LLC.P. the grants ‘Persistent fatigue induced by Lichtwer Pharma GmbH. Inc. Lundbeck and Neuraxpharm. Epidemiology (B.. Alkermes. Pfizer.W. AXSOME Therapeutics. Avanir Pharmaceuticals. McKinsey and Company. BioResearch. LLC).F. B. Cephalon. served as a consultant for Alkermes.. Photothera. S. A l l r i g h t s r e s e r v e d .nature. depression and inflammation as part of two large consortia Novartis AG.. of a programme of research on depression and inflammation.F. p a r t o f S p r i n g e r N a t u r e . Pharmacia-Upjohn. Stanley C. Lundbeck and Inc. LLC. 20 | 2016 | VOLUME 2 www.).).. Overview of the Primer (C... GlaxoSmithKline. supported by the National Institute for Health Research Institute. Euthymics Bioscience. Solvay Pharmaceuticals. Introduction (C. Janssen R&D. interferon-α: A New Immunological Model for Chronic Fatigue Inc.W. since 2015. Wyeth-Ayerst Laboratories. Jed Foundation. .P.). Bristol-Myers Inc. PharmoRx Therapeutics. from Novartis and travel reimbursements from Novartis.O.PRIMER Author contributions Council (UK). Aspect Medical Systems. Inc. B.. and research funding from Johnson & Johnson as part Associates. FORUM Pharmaceuticals. One Carbon. Quality of life (S. has received Pharmaceuticals. Roche Pharmaceuticals. Inc. Bayer AG. Pharmaceutical Research (M.P. Management that also include Johnson & Johnson.).. Inc. a commercial developer and vendor of health  care LLC. Acadia. Cervel. Amarin Pharma Merck Serono and Biogen Idec and has received in‑kind Pharmaceuticals..M.S. Neuralstem... A. reports the following research Pharmaceuticals. Harvard Clinical Research has. Sanofi- Competing interests Lundbeck. Inc. Squibb. M.F. A. Cyanamid.E. screening and prevention (A. and he is listed as an inventor on a consortium to test the opportunity for immunotherapeutics National Center for Complementary and Alternative Medicine pharmacogenetic and antiglucocorticoid use patents in psychiatry’ (MR/L014815/1) from the Medical Research (NCCAM).E. LLC (formerly Clinical Trials Solutions.F. Forest Phar.. Seattle Genetics. Neurocrine. was Biotech. RCT In addition.