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DOI: 10.1038/nrdp.2016.65
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Citation for published version (APA): Otte, C., Gold , S. M., Penninx, B. W., Pariante, C. M., Etkin, A., Fava, M., C. Mohr, D., & Schatzberg , A. (2016). Major Depressive Disorder. Nature Review Disease Primers, 2, [16065]. https://doi.org/10.1038/nrdp.2016.65
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Download date: 08. Aug. 2023
Otte et al.
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1 Major Depressive Disorder 2
3
Christian Otte 1, Stefan M. Gold 1, Brenda W. Penninx 2, Carmine M. Pariante 3, Amit 4
Etkin 4, Maurizio Fava 5, David C. Mohr 6 and Alan Schatzberg 4 5
6
1 Department of Psychiatry and Psychotherapy, Charité University Medical Center, 7
Campus Benjamin Franklin, Berlin, Germany 8
2 Department of Psychiatry, VU University Medical Center, Amsterdam, The 9
Netherlands 10
3 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 11
United Kingdom 12
4 Department of Psychiatry and Behavioral Sciences, Stanford University School of 13
Medicine, USA 14
5 Department of Psychiatry, Massachusetts General Hospital, Boston, 15
Massachusetts, USA 16
6 Department of Preventive Medicine, Feinberg School of Medicine, Northwestern 17
University, Chicago, IL, USA 18
19
Correspondence to: C.O. 20
21 Email: [email protected] 22 23 24 CO has received honoraria for lectures from Lundbeck and Servier and for 25 membership in a scientific advisory board from Lundbeck and Neuraxpharm. DCM 26 has received honoraria for lectures and for membership in a scientific advisory board 27 from Otsuka. SMG has received honoraria from Novartis and travel reimbursements 28 from Novartis, Merck Serono and Biogen Idec and has received in-kind research 29 support for conducting clinical trials from GAIA AG, a commercial developer and 30 vendor of healthcare management and eHealth interventions. BWP has received 31 research funding from Jansen Research and is supported by a VICI grant from the 32
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Dutch Scientific Organization. CMP was supported by the National Institute for Health 1 Research Mental Health Biomedical Research Centre in Mental Health at South 2 London and Maudsley NHS Foundation Trust and King's College London, the grant 3 'Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for 4 Chronic Fatigue Syndrome' (MR/J002739/1), and the grant 'Immuno-psychiatry: a 5 consortium to test the opportunity for immunotherapeutics in psychiatry' 6 (MR/L014815/1), from the Medical Research Council (UK); research funding from the 7 Medical Research Council (UK) and the Wellcome Trust for research on depression 8 and inflammation as part of two large consortia that also include Johnson & Johnson, 9 GSK, Lundbeck and Pfizer; research funding from Johnson & Johnson as part of a 10 programme of research on depression and inflammation. In addition, CMP has 11 received speakers fee from Lundbeck. AE has received research funding from Brain 12 Resource, Inc and honoraria for consulting from Otsuka, Acadia, and Takeda. MF 13 reports the following lifetime disclosure: Research Support: Abbot Laboratories; 14 Alkermes, Inc.; American Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir 15 Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx 16 BioPharma; Cephalon; Cerecor; Clintara, LLC; Covance; Covidien; Eli Lilly and 17 Company;EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest 18 Pharmaceuticals, Inc.; FORUM Pharmaceuticals; Ganeden Biotech, Inc.; 19 GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon 20 Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson 21 & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; 22 Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc; 23 National Alliance for Research on Schizophrenia & Depression (NARSAD); National 24 Center for Complementary and Alternative Medicine (NCCAM);National Coordinating 25 Center for Integrated Medicine (NiiCM); National Institute of Drug Abuse (NIDA); 26 National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon 27 Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical 28 Research Associates., Inc.; Pharmavite® LLC;PharmoRx Therapeutics; Photothera; 29 Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials 30 Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; 31 Stanley Medical Research Institute (SMRI); Synthelabo; Takeda Pharmaceuticals;Tal 32 Medical; Wyeth-Ayerst Laboratories; Advisory Board/ Consultant: Abbott 33 Laboratories; Acadia; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma 34 Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir 35 Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project 36 Management, Inc.; Biogen; BioMarin Phar. AFS has served as a consultant for 37 Alkermes, Cervel, Clintara, Forum Pharmaceuticals, McKinsey and Company, Myriad 38 Genetics, Neuronetics, Naurex, One Carbon, Pfizer, Takeda, Sunovion, and X-Hale 39 and as a speaker for Pfizer; he holds equity in Biotie, Corcept (co-founder), Gilead, 40 Incyte. Intersect ENT, Merck, Neurocrine, Seattle Genetics, Titan, and X-Hale; and 41 he is listed as an inventor on pharmacogenetic and mifepristone patents from 42 Stanford University.43
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Abstract 1 2
Major depressive disorder (MDD) is a debilitating disease characterized by 3
depressed mood, diminished interests, impaired cognitive function and vegetative 4
symptoms such as disturbed sleep or appetite. MDD occurs about twice as often in 5
women than in men and affects 1 out of every 6 adults during life. 6
The etiology of MDD is multifactorial and its heritability is estimated to be around 7
35%. In addition, environmental factors such as sexual, physical, or emotional abuse 8
during childhood are strongly associated with the risk of developing MDD. There is 9
currently no established mechanism that explains all aspects of the disease. 10
However, MDD is associated with alterations in regional brain volumes, particularly 11
the hippocampus, and with functional changes in brain circuits such as the cognitive 12
control network and the affective-salience network. Furthermore, disturbances in the 13
major neurobiological stress-responsive systems including the hypothalamic-14
pituitary-adrenal axis and the immune system are present in MDD. Treatment 15
primarily comprises psychotherapy and pharmacological treatment. For treatment-16
resistant patients, who have not responded to several augmentation or combination 17
treatment attempts, electroconvulsive therapy is the treatment with the best empirical 18
evidence. 19
In this Primer, we provide an overview on the current evidence of MDD, including its 20
epidemiology, etiology, pathophysiology, diagnosis, and treatment. 21
22
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[H1]Introduction 1
Major Depressive Disorder (MDD) is a debilitating disease that is characterized by 2
one ore more discrete depressive episodes of at least two weeks’ duration involving 3
clear-cut changes in affect, cognition, and vegetative symptoms. Box 1 describes the 4
current diagnostic criteria and specifiers of MDD according to the Diagnostic and 5
Statistical Manual (DSM) 5th edition (DSM 5), which was released in 20131. 6
7
After puberty, MDD occurs about twice as often in women than in men2 and affects in 8
a specific year about 6% of the adult population worldwide3. Among all medical 9
conditions, MDD is the second leading cause for chronic disease burden as 10
measured by “years lived with disability”4. In addition, MDD is associated with an 11
increased risk of developing medical disorders such as diabetes, heart disease, and 12
stroke5, thereby further increasing its burden of disease. Furthermore, MDD can itself 13
lead to death by suicide. Many of the 800,000 suicides per year worldwide occur 14
within a depressive episode6 and depressed patients are almost 20-fold more likely 15
to die by suicide than the general population7. 16
17
The genetic contribution to MDD is estimated between 30-40%, with higher 18
heritability in family and twin-based studies than single nucleotide polymorphism 19
(SNP)-based estimates from genome-wide association studies (GWAS). This 20
suggests that other genetic variables such as rare mutations contribute to MDD 21
risk8,9. In addition, environmental factors such as sexual, physical, or emotional 22
abuse during childhood are strongly associated with the risk of developing MDD10,11. 23
Most studies so far have typically examined single candidate genes in interaction 24
with environmental factors and have not yielded consistently replicated results. 25
Furthermore, GWAS have so far not revealed consistent and replicated associations 26
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with specific genes12. However, environmental influences can affect genomic read-1
out through the action of epigenetic alterations to produce a depressed phenotype13. 2
3
Despite advances in our understanding of the neurobiology of MDD, an established 4
mechanism that explains all aspects of the disease is unavailable. However, MDD is 5
associated with smaller volumes of brain structures such as the hippocampus as well 6
as changes in either activation or connectivity of brain networks such as the cognitive 7
control network and the affective-salience network14. Moreover, alterations in the 8
major neurobiological systems that mediate the stress response are present in MDD 9
including the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous 10
system, and the immune system15. 11
12
Both psychotherapy and psychopharmacology are effective in treating MDD; 13
however, about 30% of patients do not remit from MDD, even after several treatment 14
attempts16,17. Thus, there is an urgent need to further improve MDD therapy. New 15
developments in psychotherapy include the use of behavioral intervention 16
technologies. With regard to pharmacological approaches, glutamatergic 17
antidepressants such as ketamine are currently under scientific scrutiny. 18
19
In this Primer, we provide an overview on the current evidence of MDD, including its 20
epidemiology, etiology, pathophysiology, diagnosis, and treatment. We also outline 21
the key outstanding research questions in the field that should be addressed in the 22
next few years. 23
24
[H1] Epidemiology 25
[H2] Prevalence and main correlates 26
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A best estimate of the world-wide MDD prevalence comes from the World 1
Mental Health (WMH) Survey, which used similar protocols to assess DSM-IV criteria 2
for MDD in 18 countries among almost 90,000 individuals from every continent.3 The 3
average 12-month prevalence of MDD was around 6%, in line with estimates from 4
earlier large-scale international studies18,19. Lifetime MDD prevalence is typically 5
about threefold higher than the 12-month prevalence, indicating that MDD affects 1 6
out of every 6 adults at some point in their life3,18,19. Although a lifetime prevalence is 7
less reliable and likely suffers from recall bias and underestimation20,21, it indicates 8
that at least 20% of all persons face MDD during life. 9
The 12-month MDD prevalence in the WMH Survey ranged from 2.2% in 10
Japan to 10.4% in Brazil (Figure 1). Although estimates varied substantially across 11
countries for reasons that likely involve both substantive and methodological 12
processes, the 12-month MDD prevalence was found to be similar in 10 high-income 13
(5.5%) and 8 low- to middle-income (5.9%) countries, illustrating that MDD is not just 14
a ‘modern-world’ health condition. Also, the median age of onset, severity, symptom 15
profile and basic sociodemographic and environmental correlates (such as sex, 16
education and life events) of MDD are mostly comparable across countries and 17
cultures22,23. However, despite these similarities, a clear-cut discrepancy across 18
countries is present in terms of both the resources and treatments availability for 19
mental health, including MDD. In high-income countries approximately 40-50% of all 20
people with severe MDD do not receive proper treatment24,25, but in low-income 21
countries fewer than 10% of patients received adequate treatment24. 22
Starting after puberty, women have a twofold increased risk of MDD than 23
men2. This is mainly due to a higher first occurrence of episodes in women, and not 24
because female sex is associated with longer episode duration, differential treatment 25
response or higher recurrence rates26,27. In both sexes, the median reported age of 26
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onset of MDD is around 25 years, and the peak risk period for MDD onset ranges 1
from mid-late adolescence to the early 40s3. These findings are in line with 2
observations that, especially in high-income countries, the MDD prevalence generally 3
goes slightly down with age after early adulthood22,28. Other consistently reported 4
environmental determinants of MDD in both men and women are the absence of a 5
partner (due to divorce or widowhood) and the experience of recent negative life 6
events such as illness or loss of close persons, financial or social problems and 7
unemployment3,29. In addition, a range of childhood adversities including physical 8
abuse, sexual abuse and emotional neglect significantly increases the MDD 9
development risk in men and women. Depressed patients with childhood trauma not 10
only have a more than twofold increased MDD risk, but also higher symptom 11
severity, a poorer course and more treatment non-response30-32. Finally, other 12
important determinants of MDD are unhealthy lifestyles, as excessive alcohol use, 13
smoking behavior, a high fat or sugar diet and physical inactivity have been 14
associated with (the onset of) MDD and reversing these unhealthy lifestyles appears 15
to reduce depressive symptoms33-35. 16
17
[H2] Course and public health impact 18
The course of MDD is pleomorphic, with considerable variation in remission 19
and chronicity. In population-based samples the mean episode duration varies 20
between 13-30 weeks and approximately 70-90% of depressed persons recover 21
within 1 year36-38. However, in clinical care settings, the course pattern of patients 22
with MDD is less favorable: only 25% remit within 6 months and >50% of patients are 23
still depressed after 2 years27,39,40. After MDD remission, residual symptoms and 24
functional impairment often remain41. Also, the chance of MDD recurrence is high, as 25
about 80% of remitted patients experience one or more recurrences during their 26
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lifetime42. The course trajectory in adults seems to be slightly less favorable with 1
older age27 . However, the most important course determinants are clinical 2
characteristics. Higher symptom severity, psychiatric comorbidity and a history of 3
childhood trauma all predict a less-favorable course27,31. 4
5
The Global Burden of Disease Consortium found that, in 2013, MDD was the 6
second leading contributor to global disease burden, as expressed in disability 7
adjusted life years, both in developed as well as in developing countries4. Moreover, 8
the consequences of MDD extend to physical health. Large-scale longitudinal studies 9
converge in their findings that MDD increases the onset risk of diabetes, heart 10
disease, stroke, hypertension, obesity, cancer, cognitive impairment and Alzheimer’s 11
disease (Figure 2)43. Both in the general population as well as in populations with 12
specific medical illnesses, MDD increases the mortality risk by 60–80%44,45. Indeed, 13
the contribution of MDD to all-cause mortality is 10%, indicating that mortality rates 14
would decrease by 10% if MDD could be eliminated completely. 15
16
[H1] Mechanisms/pathophysiology 17
Despite advances in our understanding of the neurobiology of MDD, there is currently 18
no established mechanism that could explain all facets of the disease. In box 2, we 19
briefly discuss the potential and the challenges of animal models for MDD and 20
provide recent references that discuss in detail molecular mechanisms of candidate 21
neurobiological systems that have been identified in animal models. In the main text, 22
we largely restrict our discussion to findings in clinical studies of patients with MDD, 23
giving preference to those aspects that have been confirmed in meta-analyses and 24
pathways that have been targeted in clinical trials (ideally also with a meta-analysis 25
level of evidence). 26
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[H2] Genetics 2 3 We have known for more than a century that MDD clusters within families. First-4
degree relatives of patients with MDD show a threefold increased risk of MDD, and 5
heritability for this disorder has been quantified as 30-40%8. Furthermore, there is a 6
genetic overlap between MDD and other psychiatric disorders46,47. However, the 7
search for main genetic effects in MDD so far has not revealed consistent and 8
replicated genome-wide significant genetic findings for MDD48 as indicated by a 9
mega-analysis of various GWAS including 9,240 cases and 9,519 controls49. 10
Similarly sized studies of other psychiatric conditions such as schizophrenia, which 11
have a higher heritability, have convincingly implicated at least some genetic loci; for 12
schizophrenia, 108 independent genome-wide significant loci have been shown50. 13
Risk of MDD is highly polygenic and involves many genes with small effects51. 14
Furthermore, the heterogeneity of the depressed phenotype further increases the 15
number of subjects needed to find significant genetic associations. A recent Chinese 16
GWAS in which a more homogeneous phenotypic approach was applied was able to 17
confirm two genome-wide significant genetic loci52. This holds promise for some 18
ongoing and soon to be finalized GWAS, which contain increased numbers of 19
depressed cases or focus on huge samples with uniform relevant phenotype 20
information such as depressive symptom reports or neuroticism. 21
22
[H2] Environmental factors 23 24 Early epidemiological studies focused on stressful events that are temporally related 25
to MDD, usually in the year preceding onset; the primarily documented events (such 26
as loss of employment, financial insecurity, chronic or life-threatening health 27
problems, exposure to violence, separation and bereavement)53 occur most often 28
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during adulthood. However, more recent evidence has focused on exposure to life 1
events in childhood as antecedent of MDD later in life. These events include physical 2
and sexual abuse, psychological neglect, exposure to domestic violence, or early 3
separation from parents due to death or separation, with clear evidence of a dose–4
response relationship between number and severity of adverse life events and risk, 5
severity, and chronicity of MDD11. 6
A variety of data derived from animal models and clinical research have led to a 7
comprehensive neurobiological model of the long-lasting consequences of early 8
trauma. At the center of this model is the endocrine hypothalamus-pituitary-adrenal 9
(HPA) axis. Many animal studies have demonstrated that early life stress produces 10
persistent increases in the activity of corticotrophic releasing factor (CRF)-containing 11
neural circuits54. This finding is paralleled by clinical studies showing that both 12
women and men who have been sexually or physically abused in childhood exhibit, 13
as adults, a markedly enhanced activity of the HPA axis when exposed to 14
standardized psychosocial stressors or following endocrine tests that attempt to 15
suppress HPA activity. Thus, glucocorticoid receptor function is reduced in adult 16
individuals who have experienced childhood adversities (so-called glucocorticoid 17
resistance), a notion that is supported by the fact that these individuals also show 18
increased activation of the inflammatory system, which is under physiological 19
inhibitory control by cortisol. Indeed, glucocorticoid resistance, HPA axis hyperactivity 20
and increased inflammation are all present in MDD (figure 3). 21
22
Furthermore, in utero stress during the antenatal period has also been shown to 23
increase the risk of MDD later in life55. This novel but burgeoning area of research is 24
providing further evidence of the neurodevelopmental origin of MDD and the long-25
lasting effects of environmental insults at the earliest stages of life56. 26
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[H2] Gene × environment interactions 2
The lack of consistent and replicated findings in GWAS for MDD can at least in part 3
be explained by the fact that relevant genetic variants confer an increased risk only in 4
the presence of exposure to stressors and other adverse environmental 5
circumstances — the so-called gene–environment (G×E) interaction (figure 4). 6
However, although a number of potential candidate genes such as the serotonin 7
transporter gene (SLC6A4), the corticotropin releasing hormone receptor 1 gene 8
(CRHR1), and the gene encoding peptidyl-prolyl cis-trans isomerase (FKBP5) have 9
been identified, differences in the timings and type of adverse environmental 10
circumstances have hampered replication studies of single candidate genes. 11
12
[H2] Epigenetics 13
Interestingly, studies investigating the molecular mechanisms underlying G×E 14
interactions have shown that they may involve epigenetic regulation. For example, 15
one polymorphism in FKBP5 that has been shown to interact with life adversities 16
predicting MDD is associated with allele-specific, stress-dependent DNA 17
demethylation in glucocorticoid response elements57. This leads to increased FKBP5 18
expression in response to stress, which in turn leads to glucocorticoid receptor 19
resistance, which is often found in MDD58. 20
21
Furthermore, a number of studies have shown consistent epigenetic changes in the 22
brain of animal models of MDD as well as in post-mortem brain samples of 23
depressed patients, especially suicide victims who were exposed to early life 24
adversities59. Initial hypothesis-driven studies have examined genes involved in the 25
stress response, but more recent unbiased genome-wide studies have implicated 26
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epigenetic changes in genes often unrelated to established candidates implicating 1
alternative pathophysiological mechanisms, such as cell adhesion and cell 2
plasticity57. However, enthusiasm for epigenetic research in MDD is still limited by the 3
small magnitude of the described epigenetic changes, often <10%, especially in 4
comparison with other medical disorders such as cancer60. 5
6 7 [H2] Neuroendocrinology 8
The endocrine hypothalamus-pituitary adrenal (HPA) axis is among the most 9
researched biological systems in MDD61,62. While the hope for sufficient specificity 10
and sensitivity on an individual level was not met for MDD-specific diagnostic HPA 11
tests63, evidence suggests that overall HPA axis regulation is altered in patients with 12
MDD. Two meta-analyses64,65 concluded that cortisol levels in MDD were elevated, 13
with a moderate effect size. Importantly, HPA alterations correlate with impaired 14
cognitive function66,67 in depressed patients and they are more common and more 15
pronounced in severely depressed patients with melancholic and/or psychotic 16
features68 and in elderly depressed patients69. Furthermore, several studies have 17
prospectively shown that elevated cortisol is a risk factor for subsequent MDD70-72. 18
Finally, in a study using data from a primary care database including more than 19
370,000 individuals indicated that treatment with synthetic glucocorticoids is 20
associated with an increased risk for suicide (approx. 7-fold), MDD (approx. 2-fold) 21
and other severe neuropsychiatric disorders, even when controlling for the underlying 22
medical disorder73. 23
24
Antidepressants reduce cortisol levels in depressed patients over the course of the 25
treatment74. However, a meta-analysis has shown that independent of improved 26
psychopathology about 50% of depressed patients had similar cortisol levels before 27
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and after treatment. Elevated CRF in the cerebrospinal fluid (CSF) has been found in 1
patients with MDD75 and, accordingly, several randomized controlled trials have 2
examined CRF-antagonists in the treatment of MDD. However, the overall results 3
have not indicated a major role for CRF antagonists in the treatment of MDD76. 4
Clinical trials using glucocorticoid-lowering compounds such as metyrapone have 5
also yielded mixed results77,78. Fludrocortisone, a mineralocorticoid receptor agonist, 6
has been shown to accelerate the onset of action of standard antidepressants in one 7
randomized controlled trial79 and to improve cognitive function in depressed patients 8
in an experimental study80. In psychotic MDD, the glucocorticoid receptor antagonist 9
mifepristone (RU-486) was shown to ameliorate psychotic symptoms, although 10
secondary analyses of failed trials indicated that very high doses might be required to 11
reach therapeutic blood levels62. 12
13
[H2] Inflammation 14
A role of peripheral immune dysfunction and neuroimmunological mechanisms in 15
MDD has been supported by a large body of evidence from animal studies (box 2). 16
These models have also provided intriguing insights into how peripheral cytokines 17
can, directly and indirectly, affect brain circuits, behavior and mood. Such 18
mechanisms may also underlie clinical observations in MDD: A population-based 19
study has shown that both prior severe infections as well as autoimmune diseases 20
increase the risk of subsequently developing MDD81. Patients who receive cytokine 21
treatments such as IL-2 or IFNγ as part of their treatment for hepatitis or cancer often 22
develop depressive symptoms82. Finally, patients with MDD show elevated serum 23
levels of tumor necrosis factor (TNF) and IL-6 as confirmed by a meta-analysis83,84. 24
Increased expression of genes involved in IL-6 signaling in peripheral blood cells has 25
also been observed in a large-scale cohort study of patients with MDD compared 26
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with healthy controls85. There have also been a few large, prospective studies 1
indicating that elevated levels of IL-6 during childhood significantly increase the risk 2
of developing MDD in adulthood86. Recent studies using PET imaging87 as well as 3
analyses of post-mortem brain tissue88 have indicated neuroinflammation and 4
microglial activation in the central nervous systems of patients with MDD. Finally, a 5
potential role of inflammation in MDD is also supported by clinical trials of 6
nonsteroidal anti-inflammatory drugs (NSAIDs) such as COX-2 inhibitors reviewed by 7
a recent meta analysis89. 8
9
[H2] Neuroplasticity 10
Peripheral changes in cortisol levels and inflammatory mechanisms induce 11
depressive symptoms by ultimately affecting brain function at a cellular level, 12
primarily by disrupting neuroplasticity. Lower levels of the neurotrophin, brain-derived 13
neurotrophic factor (BDNF), have been found in the serum and in the leukocytes 14
mRNA of depressed patients, and pharmacological and non-pharmacological 15
antidepressant therapies have been found to normalize BDNF levels90. BDNF and 16
other components of the neuroplasticity network, affect behavior also by regulating 17
neurogenesis, the process by which new neurons are generated in the adult brain 18
from pluripotent stem cells. The role of neurogenesis in MDD has been amply 19
debated91. For example, reducing experimentally adult neurogenesis in rodents in the 20
absence of stress does not induce depressive-like behavior. However, reduced 21
neurogenesis can precipitate depression-like symptoms in the context of stress, 22
probably because it impairs the ability to respond to stress. For example, at a 23
biological level, adult neurogenesis promotes resilience to stress by enhancing 24
glucocorticoid-mediated negative feedback on the HPA axis, and at a cognitive level 25
it influences whether events are perceived as stressful and, therefore, whether a 26
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stress response is elicited. According to the latter notion, reduced neurogenesis 1
results in “overgeneralization”, so that even innocuous stimuli are associated with 2
negative memories and become emotionally charged. This results in a stress 3
response, which is further unrestrained by the lack of the aforementioned 4
neurogenesis-related enhancement of glucocorticoid-mediated negative feedback. In 5
contrast, an effective adult neurogenesis, as occurring following antidepressant 6
treatment, reduces stress responsiveness and maintains resilience91. 7
8
[H2] Monoamines 9 10 The monoamine hypothesis of MDD was initially developed based on findings that 11
substances such as the antihypertensive drug reserpine that reduce monoamines 12
such as serotonin (5-hydroxytryptamine, 5-HT), norepinephrine, or dopamine in the 13
synaptic cleft, led to MDD in a subgroup of patients. Furthermore, the first 14
antidepressant drugs were developed in the 1950s, when the antidepressant 15
properties of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors 16
(MAOIs) were discovered by serendipity. Both TCAs and MAOIs were subsequently 17
shown to have robust effects on monoamine neurotransmission. These findings 18
stimulated the development of a long series of monoamine-based compounds, which 19
have dominated the field of modern psychopharmacology of MDD thus far. For 20
example, the newer selective serotonin reuptake inhibitors (SSRI) strongly bind to the 21
serotonin transporter (5-HTT) with little or no impact on post-synaptic monoamine 22
receptor activity. 23
24
However, a plethora of studies that have measured norepinephrine and serotonin 25
metabolites in plasma, urine, and cerebrospinal fluid, as well as postmortem studies 26
of the brains of depressed patients have yielded inconsistent results92. Furthermore, 27
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drugs that target monoamines affect these neurotransmitter systems within hours 1
after administration. However, antidepressant effects only occur with a delayed onset 2
of action that can last up to several weeks. Presumably, changes in brain gene 3
expression that occur after continuous treatment with monoaminergic 4
antidepressants might underlie their therapeutic effects93. 5
6
[H2] Structural brain alterations 7 8 Many cross-sectional studies using structural brain imaging have investigated 9
regional brain volumes in patients with MDD, which have been summarized in meta-10
analyses. A meta-analysis of 143 studies94 confirmed smaller volumes in patients 11
with MDD than in healthy controls in the basal ganglia, thalamus, hippocampus and 12
several frontal regions (Figure 5). A meta-analysis of MRI data from more than a 13
dozen independent research samples by the ENIGMA working group detected 14
significantly lower volumes in the hippocampus (but no other subcortical structures) 15
95 as well as cortical thinning in the orbitofrontal cortex, anterior and posterior 16
cingulate, insula and temporal lobes in MDD patients 96. Furthermore, a large scale 17
trans-diagnostic voxel-based morphometry meta-analysis of 193 studies comprising 18
15,892 individuals also suggested that the hippocampus might be selectively affected 19
in MDD compared to other psychiatric disorders such as schizophrenia, bipolar 20
disorder, addiction, obsessive-compulsive disorder, and anxiety97. While an earlier 21
meta-analysis suggested that smaller hippocampal volumes might already be present 22
in patients with first episode MDD98 this could not be confirmed in the most recent 23
meta-analysis of MRI data by the ENIGMA working group 95. Thus, it remains unclear 24
whether smaller volumes of the hippocampus seen in MDD are an early 25
manifestation or develop later in the course of the disorder. 26
27
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1 [H2] Functional brain circuits 2
Neuroimaging studies in MDD have identified abnormalities in either activation or 3
connectivity within the affective-salience circuit, the medial prefrontal-medial parietal 4
default mode network and the fronto-parietal cognitive control circuit. 5
6
[H3] Affective-salience circuit. 7
One of the most frequently reported neuroimaging findings in MDD is abnormally 8
increased connectivity and heightened activation of the amygdala99-101. Much like the 9
amygdala, the dorsal anterior cingulate and anterior insula are hyperactive in MDD, 10
which may reflect the increased salience of negative information and self-directed 11
thoughts in MDD101. By contrast, decreased activity and connectivity of the ventral 12
striatum and other reward-related regions has been found in MDD, leading to 13
decreased recruitment of saliency processing areas like the dorsal cingulate and 14
anterior insula102-106. 15
16
[H3] Default mode network. 17
The default mode network is characterized by greater activity during “resting” 18
states where most mental activity is internal or self-directed. Difficulties in dynamic 19
modulation of the default mode network in MDD has been proposed to underlie 20
excessive self-focus and rumination100,107-111. Indeed, the default mode is 21
hyperconnected in MDD112-114, which correlates positively with measures of 22
rumination115,116. In contrast, the dynamic coupling between frontoparietal activation 23
(which increases with task-directed attention) and default mode deactivation is 24
perturbed in MDD111,117. 25
26
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18
[H3] The fronto-parietal cognitive control circuit. 1
The fronto-parietal cognitive control network is engaged across many cognitive 2
tasks118. A recent meta-analysis found evidence for frontoparietal hypo-connectivity 3
in MDD, especially of the dorsolateral prefrontal cortex, implicating it in goal-directed 4
attention deficits in MDD119. Moreover, decreased frontoparietal connectivity has 5
been found both at rest and in response to negative stimuli, but not in response to 6
positive stimuli, suggesting that this network may contribute to inappropriate cognitive 7
appraisals of negative events more specifically100,105. 8
9
[H1] Diagnosis, screening and prevention 10
[H2] Differential diagnosis 11
According to DSM 5 (Box 1), MDD is demarcated from normal sadness or 12
bereavement; however, in patients who are mourning who develop symptoms severe 13
enough and persistent beyond the acute grieving period, an MDD diagnosis can be 14
given. While it is possible to diagnose MDD based on a single depressive episode, 15
MDD is recurrent in the majority of cases1. 16
17
The key differential diagnosis of MDD is with bipolar depression and with persistent 18
depressive disorder. The differential diagnosis of MDD from bipolar depression rests 19
entirely with the presence of a history of hypomania or mania, which is characterized 20
by a clear period of elevated mood or irritability and with at least three of the following 21
symptoms presently overtly: inflated self-esteem; reduced need for sleep; increased 22
speech; flight of ideas; distractibility; increased activity in goal-directed tasks; and 23
involvement in risky behavior. 24
25
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19
Persistent depressive disorder is a chronic disorder and describes patients who have 1
been depressed for >2 years. Apart from depressed mood, only two of six symptoms 2
(appetite disturbance; sleep disturbance; loss of energy; decreased self-esteem; poor 3
concentration; or hopelessness) are required for the diagnosis. Thus, it is possible to 4
meet criteria for persistent depressive disorder without having MDD. If a patient 5
meets criteria for MDD, then the patient would receive two diagnoses — MDD and 6
persistent depressive disorder. 7
8
[H2] Specifiers of MDD 9
Once a diagnosis of MDD is made, the condition can be further characterized using a 10
variety of modifiers or specifiers (Box 1). 11
12
Severity of episode is rated from mild to moderate to severe. Severe symptoms have 13
a major impact on function. The specifier “with anxious distress” was introduced 14
because depressed patients with considerable co-occurring anxiety are more likely to 15
report suicidal thoughts and be less responsive to traditional antidepressants. 16
The specifier requires prominent symptoms of anxiety present most of the days the 17
patient experiences an episode of MDD. Patients are also required to experience at 18
least two of the following: a sense of being keyed up or tense, unusual restlessness, 19
trouble concentrating secondary to worry, fearing awful things will happen, and worry 20
about losing self-control. 21
22
The specifier “with mixed features” reflects a notion that MDD lies on a continuum 23
with bipolar disorder and that patients with either can demonstrate features of the 24
other during an index episode1. This hypothesis is based on the observation that 25
some depressed patients show rapid thinking and reduced need for sleep. The 26
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20
criteria include experiencing at least three of the following symptoms during the 1
depressive episode: elevated, expansive mood, heightened self-esteem or 2
grandiosity, increased speech or pressure of speech, racing thoughts, increased 3
energy or directed activity, excessive activity in behavior with possibly negative 4
consequences, or lessened need for sleep. 5
6
“With melancholic features” refers to the presence of what has often been called 7
endogenous features. The criteria include anhedonia, lack of pleasure, loss of 8
reactivity to positive stimuli, distinct quality of depressed mood such as despair, 9
depression worse in the morning, waking early in the morning, psychomotor 10
disturbance, weight loss, and excessive guilty thoughts. 11
The specifier “with atypical features” refers to a set of symptoms that are common in 12
MDD. The criterion in mood reactivity in atypical depression requires that mood 13
brightens in response to actual or potential positive events, which is in contrast to 14
“with melancholic features”. Other criteria include at least two out of: significant 15
increase in weight or appetite; increased sleep; a sense of leaden paralysis; and 16
interpersonal sensitivity. 17
Previously, the “with psychotic features” specifier in DSM-IV was included as part of 18
the severity continuum from mild to severe with psychotic features. In DSM-5, 19
psychotic features were separated from the severity specifier because the two were 20
not always highly correlated (that is, mild MDD can also present with psychotic 21
features)120. 22
The specifier “with catatonic features” refers to “marked psychomotor disturbance 23
that may involve decreased motor activity, decreased engagement during interview 24
or physical examination, or excessive and peculiar motor activity (DSM 5). These 25
patients are often psychotic. 26
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21
1
[H2] Research Domain Criteria (RDoC) 2
In addition to DSM-5, the National Institute of Mental Health (NIMH) developed 3
research domain criteria (RDoC), which are not meant to be a diagnostic system but 4
a framework for organizing research. The RDoC approach consists of a matrix where 5
the rows represent specified functional constructs characterized by genes, 6
molecules, cells, circuits, physiology, self-report, and paradigms used to measure it 7
(https://www.nimh.nih.gov/research-priorities/rdoc/development-and-definitions-of-8
the-rdoc-domains-and-constructs.shtml.). Constructs are in turn grouped into five 9
higher-level domains of functioning (negative valence systems, positive valence 10
systems, cognitive systems, systems for social processes, and arousal/regulatory 11
systems). The ultimate goal of RDoC is to develop a deeper understanding of the 12
biological and psychosocial basis of psychiatric disorders, which might help to 13
improve current classification systems 121. 14
15
[H2] Screening 16
Screening is discussed controversially in the MDD field. Many experts argue that 17
screening for depression is of obvious benefit since MDD is often overlooked in 18
medical settings122,123. In contrast, other authors state that it is impractical to 19
implement universal screening and argue that there is a lack of evidence supporting 20
screening124. A recent systematic review included 71 studies and assessed benefits 21
and harms of screening for depression in primary care125. The authors concluded that 22
the overall evidence of health benefit of depression screening in primary care is 23
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22
weak. However, the existing data do suggest that screening programs generally 1
increase the likelihood of remission and treatment response in general adult 2
populations but only in the presence of subsequent treatment offers. 3
4
[H2] Prevention 5
Given the high prevalence of depression, effective prevention strategies such as 6
strengthening protective factors (such as increasing social support or problem-7
solving skills) or diminishing prodromal disease stages (such as reducing depressive 8
symptoms that do not fulfill criteria for MDD yet) might have an enormous public 9
health impact in reducing disease burden. The effects of preventive psychological 10
interventions on the incidence of MDD have been systematically examined in a meta-11
analysis of 32 randomized controlled trials. The meta-analysis included studies 12
examining universal prevention (in a whole population group regardless of risk 13
status), selective prevention (in individuals or subgroups that are at higher risk of 14
developing depression) and indicated prevention (in individuals who are identified as 15
having prodromal symptoms of depression, but who do not yet meet the diagnostic 16
criteria for a full-blown MDD diagnosis). 17
The results indicated a 21% decrease in incidence in prevention groups in 18
comparison with control groups126. The authors concluded that prevention of 19
depression seems feasible and may be an effective way to reduce the numbers of 20
incident MDD cases. 21
22
[H1] Management 23
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23
[H2] Psychotherapy 1
Psychotherapy for depression comes in many different forms, the most common of 2
which are described in Box 4. These different paradigms rely on different conceptual 3
models and prescribe techniques that vary to some degree in their focus and 4
methods. A large number of randomized controlled trials and meta-analyses 5
consistently show that psychotherapy is effective at treating depression, and that 6
there are no consistent or clinically meaningful differences between different types of 7
psychotherapy127-129 . 8
This conclusion130 has led to two broad hypotheses. The first, the non-specific 9
or common factors explanation, argues that the primary agents for change in 10
psychotherapy are largely those that are common to all psychotherapies, such as the 11
therapeutic alliance (a positive, warm, caring and genuine stance)131 and therapist 12
factors132, which are common to all forms of psychotherapy. The common factors 13
approach would suggest that focusing training and quality assurance on these 14
common factors can optimize treatment outcomes. 15
By contrast, proponents of the specific-factors explanation argue that 16
treatment-specific strategies produce change via different pathways, such as 17
cognitive restructuring, behavioral activation, or improved interpersonal 18
functioning133. Accordingly, head-to-head comparisons of different psychotherapeutic 19
treatment models, which are grossly underpowered to detect treatment 20
differences134, hide patient variables such as severity of depression, social 21
dysfunction, cognitive dysfunction, which have been shown to differentially predict 22
outcomes to different treatment modalities135,136. To the degree that the specific 23
factors hypothesis is true, treatment outcomes may be optimized by tailoring specific 24
interventions to patient characteristics. 25
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24
Psychotherapy produces effects that are largely equivalent to 1
pharmacotherapy although effect sizes from pharmacological and psychotherapeutic 2
trials cannot be readily compared due to methodological issues (e.g. blinding)137. A 3
recent individual patient data meta-analysis, combining the data across 16 trials 4
comparing individual psychotherapy to antidepressant medication, found no 5
meaningful differences in outcomes on self-reported depression, or rates of response 6
or remission138. The beneficial effects of cognitive therapy have been shown to 7
persist for at least one year post-treatment, similar to keeping people on 8
antidepressant medications, and with lower relapse rates compared to patients who 9
withdraw from medications 139. 10
Although psychotherapy is clearly effective, large numbers of people 11
have access barriers, including time constraints, lack of available services, and cost 12
140,141. Providing psychotherapy over the telephone has been repeatedly shown to be 13
an effective medium for delivering psychotherapy142, producing outcomes that are 14
equivalent to face-to-face therapy and reducing dropout143. Furthermore, group 15
therapy is often recommended as a less-costly way of providing treatment, 16
particularly for patients with mild to moderate levels of symptoms144. Trials comparing 17
individual to group psychotherapy have shown individual treatment to be moderately 18
superior to group at post-treatment, however these differences disappear at 3-month 19
follow-up145. 20
21
[H2] Behavioral intervention technologies 22
Behavioral intervention technologies, which use computers, tablets, and 23
phones to teach self-management skills146, are effective at reducing symptoms of 24
depression, when applied correctly. While standalone technology-based interventions 25
have not shown consistent benefits, primarily because people with depression do not 26
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25
adhere to them, internet-based tools, combined with low-intensity coaching via phone 1
or messaging, are highly effective at reducing symptoms of depression147,148. 2
Evidence for the efficacy and cost-effectiveness of these coached intervention 3
technologies has led to their being integrated into national mental health services in a 4
number of countries, including England149 and Australia150. 5
However, well-designed head-to-head comparisons of technology-supported 6
care and more traditional forms of psychotherapy and pharmacotherapy have yet to 7
be conducted. It is unclear if there are differences in who might respond to 8
technology-based treatments relative to traditional treatments, and indeed, as 9
attitudes and expectations about the role of technology in daily life change, the 10
populations that are responsive to such treatments will likely change. The rapid rate 11
at which technology advances means that technology-based interventions will 12
continue to proliferate and evolve rapidly151. 13
An emerging area of technology is digital phenotyping, which harnesses the 14
growing availability of data generated continuously in the course of daily lives to 15
create behavioral markers related to depression. For example, mobile phones, with a 16
growing complement of sensors, have become personal sensing systems. Because 17
people tend to keep their phones with them, phone sensors can continuously 18
estimate severity of depression in real time152. This opens the possibility of 19
intervention tools that can detect and react to sensed states and behaviors, allowing 20
just-in-time prompting and reinforcement of treatment congruent behaviors 153, as 21
well as tools that can passively monitor risk of depression. Harnessing personal 22
sensing platforms such as mobile phones and wearables has the potential to shift our 23
treatment tools from episodic to continuous, from reactive to proactive, and from 24
provider-centered to patient-centered 154. 25
26
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1 [H2] Pharmacotherapy 2
Three decades after the “monoamine hypothesis of depression” emerged, it became 3
clear that this hypothesis was overly simplistic and that the modulation of 4
monoamines by antidepressants was only an initiating event155. 5
6
[H3] Mechanisms of action 7
The actual therapeutic actions of monoamine-based antidepressant drugs are 8
thought to result from slower adaptive neuronal responses to these initial biochemical 9
perturbations. Downstream intracellular signal changes pathway as well as changes 10
in gene expression and neural and synaptic plasticity including hippocampal 11
neurogenesis may actually play a critical role in antidepressant drug action156,157 158. 12
13
All these research findings put into question the usefulness of the standard 14
classification of antidepressant drugs, typically based on the specific effects on 15
monoamines. However, such classification, often reflecting the affinity of drugs for 16
pre- and post-synaptic monoamine receptors and/or monoamine transporters, has 17
been useful in understanding some of their side effects. Recently, a new initiative 18
from five international scientific organizations with focus and expertise in 19
neuropsychopharmacology developed a “neuroscience-based nomenclature”159,160 of 20
psychotropic drugs that organizes medications based on their known pharmacologic 21
actions as opposed to grouping them according to indications (“antidepressants”, 22
“antipsychotics”, etc.). 23
24
The selective serotonin reuptake inhibitors (SSRIs) (such as fluoxetine, sertraline, 25
paroxetine, citalopram, escitalopram and fluvoxamine) have shown at therapeutically 26
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27
relevant doses to have significant binding to the serotonin transporter (5-HTT) and 1
are typically devoid of post-synaptic monoamine receptor activity. Vilazodone, has 2
significant affinity for serotonin 5-HT1A receptors as well as for the 5-HTT. The 3
relatively selective norepinephrine reuptake inhibitors (NRIs) (such as reboxetine) 4
have also shown at therapeutically relevant doses to have significant binding to the 5
norepinephrine transporter without any significant post-synaptic monoamine receptor 6
activity. The TCAs and other cyclic antidepressants, as well as the serotonin 7
norepinephrine reuptake inhibitors (SNRIs) block the reuptake of norepinephrine 8
serotonin by binding to their transporter in varying ratios. All the available SNRIs 9
(venlafaxine, duloxetine, desvenlafaxine, milnacipran and levomilnacipran) share the 10
property of being potent inhibitors of serotonin and norepinephrine uptake, with 11
minimal or no affinity for postsynaptic receptors, with the exception of venlafaxine, 12
which acts as a mild antagonist of nicotinic acetylcholinergic receptors. 13
By contrast, TCAs, to varying degrees, are potent blockers of histamine H-1 14
receptors, serotonin 5-HT2 receptors, muscarinic acetylcholine receptors, and α1-15
adrenergic receptors. These effects account for the higher degree of side-effect 16
burden of the TCAs compared to the other classes of antidepressants. The 17
norepinephrine dopamine reuptake inhibitors (NDRIs) such as bupropion primarily 18
block the reuptake of dopamine and norepinephrine and have minimal or no affinity 19
for post-synaptic receptors. The α2-adrenergic receptor antagonists (such as 20
mirtazapine and mianserin) seem to enhance the release of both serotonin and 21
norepinephrine by blocking auto- and hetero-α2 receptors. Given mirtazapine’s 22
antagonism of serotonin 5HT2 and 5HT3 receptors, it has been argued that its 23
overall effect is an enhancement of 5HT1A-mediated serotonergic transmission and 24
of norepinephrine release, in addition to blocking histaminergic H-1 receptors. The 25
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latter effect is thought to be responsible for significant sedation. Mianserin is also a 1
5HT2 antagonist. More selective serotonin receptor antagonists/agonists (such as 2
nefazodone and trazodone) primarily bind to serotonin 5-HT2 receptors. Vortioxetine, 3
has significant affinity for serotonin 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 4
receptors as well as for the 5-HTT. Agomelatine is a melatonin receptor (MT1 and 5
MT2) agonist and a 5-HT2c antagonist without anticholinergic or antihistaminergic 6
properties. 7
Most currently used MAOIs (such as isocarboxazid, phenelzine, 8
tranylcypromine, and selegiline) are irreversible inhibitors of both MAOA, 9
preferentially oxidizing serotonin, and MAOB, preferentially oxidizing 10
phenylethylamine (PEA) and benzylamine, with dopamine, tyramine, and tryptamine 11
being substrates for both forms of MAO. Moclobemide is a selective and reversible 12
MAOA inhibitor. 13
14
[H3] Tolerability and efficacy 15
The success of the SSRIs and SNRIs in displacing tricyclic drugs as first-choice 16
agents is not based on established differences in efficacy, but rather on a generally 17
more favorable side effect profile such as lack of anticholinergic and cardiac side 18
effects, a high therapeutic index (ratio of lethal dose: therapeutic dose), combined 19
with ease of administration. However, all the monoamine-based antidepressant 20
drugs, regardless of their pharmacological class, have fundamentally comparable 21
modest efficacy, with response rates hovering around 50%, and exhibiting a 22
characteristic delayed (typically over several weeks) response to treatment16,161. 23
24
Drugs such as the SSRIs and SNRIs are also not devoid of significant tolerability 25
issues: common acute treatment side effects are nausea, insomnia, headaches, 26
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29
dizziness, gastrointestinal symptoms, and sexual dysfunction, whereas their common 1
long-term side effects include weight gain, sexual dysfunction, and sleep 2
disturbances162. In the past two decades, there have been significant efforts to 3
develop antidepressant drugs that are not monoamine-based, that are devoid of 4
some of the untoward side-effects of these drugs, and that are capable to induce 5
clinical changes in a much more rapid fashion. Compounds that are under 6
development include neurokinin NK-1 antagonists163, glutamatergic system 7
modulators164, anti-inflammatory agents165, opioid tone modulators and opioid kappa 8
antagonists166, hippocampal neurogenesis-stimulating treatments167, and 9
antiglucocorticoid therapies168. The degree of advancement in the development 10
process varies across these different mechanisms, although all of these types of 11
compounds have shown some degree of promise in the treatment of MDD. 12
13
[H2] Combined pharmacotherapy and psychotherapy 14
A number of studies have shown that initiating treatment with both psychotherapy 15
and pharmacotherapy produces significantly better outcomes than either treatment 16
alone169,170. Similarly, augmenting psychotherapy or antidepressant medications with 17
the treatment not received when the monotherapy has not achieved satisfactory 18
results is also effective at increasing the response rate171. 19
20
[H2] Treatment-resistant depression 21
The term treatment-resistant depression (TRD) is typically used to describe a form of 22
MDD that has not responded adequately to at least one antidepressant trial of 23
adequate doses and duration172 although varying definitions of treatment resistance 24
exist173. TRD is frequently observed in clinical practice, with up to 50%-60% of 25
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30
patients not obtaining adequate response following antidepressant drug treatment172. 1
A careful diagnostic re-assessment is considered critical to the proper management 2
of TRD patients (Figure 6). More specifically, it is important to evaluate the potential 3
role of several contributing factors, such as medical and psychiatric comorbidity. The 4
degree of resistance to treatment can vary greatly among TRD patients and some 5
staging methods to classify TRD based on different levels of treatment resistance 6
have shown to be of utility clinically174. A recent meta-analysis found several 7
variables to be associated with treatment resistance including older age, marital 8
status, longer duration of current depressive episode, moderate to high suicidal risk, 9
anxious comorbidity, higher number of hospitalization, and comorbid personality 10
disorders175. 11
There are multiple general approaches to TRD. The most established strategies 12
include psychopharmacological approaches, psychotherapy and electroconvulsive 13
therapy. 14
[H3] Psychopharmacological strategies. 15
The term optimization/high dose refers to a psychopharmacological strategy involving 16
the significant increase of the dose of the antidepressant in the face of non-response 17
(e.g., doubling or tripling the dose), strategy that has been shown to lead to 18
significant improvements, particularly in the event of partial response176. This has 19
recently been confirmed in two meta-analyses for SSRI177,178. 20
The psychopharmacological strategy of switching involves changing the primary 21
antidepressant drug to another of the same class or of a different class. In the 22
STAR*D study, this strategy has been shown to lead to remission in one of four 23
patients in citalopram non-responders (both within the same class or with a different 24
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31
class), but its success in patients who have not responded to two antidepressant 1
trials is extremely modest, with remission only in one of ten patients16. 2
The psychopharmacological strategy of augmentation refers to the addition to 3
ongoing antidepressant drug treatment of drugs that are not antidepressant agents 4
themselves. Initially well-studied augmentation strategies such as lithium or L-5
triiodothyronine (T3)179 have become somewhat less common in practice, while 6
augmentation with atypical antipsychotic drugs such as quetiapine or aripiprazole is 7
increasingly established180. 8
Combination treatment generally refers to the prescribing of more than one 9
antidepressant simultaneously. The array and number of combinatory possibilities 10
has dramatically increased with the introduction of newer antidepressant agents. The 11
two best studied combination strategies, studied in STAR*D as well, are 12
SSRIs/SNRIs with bupropion or mirtazapine16. 13
14
[H3] Psychotherapy. 15
In TRD, the most commonly used form of psychotherapy studied is cognitive 16
behavioral therapy. A systematic review of the pertinent literature concluded that the 17
current evidence examining the effect of psychotherapy as augmentation or 18
substitute therapy in TRD is sparse and reveals mixed results181. However, the use of 19
cognitive behavioral therapy in citalopram non-responders of the STAR*D study was 20
associated with comparable efficacy to pharmacotherapy17. Furthermore, a recent 21
large-scale randomized controlled study has demonstrated both efficacy and long-22
term effectiveness of cognitive behavioral therapy as adjunct to pharmacotherapy in 23
treatment-resistant depression182,183. Finally, a recent meta-analysis has 24
demonstrated efficacy for the cognitive behavioral analysis system of 25
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psychotherapy (CBASP), a specific psychotherapy for chronic depression including 1
treatment resistant depression184. 2
[H3] Electroconvulsive therapy. 3
Electroconvulsive therapy (ECT) is considered to be the most widely used and 4
effective non-pharmacological biological treatment for TRD185. It is commonly used 5
when a rapid antidepressant response is required, such as in very severely 6
depressed and/or highly suicidal patients. The main tolerability issues of ECT are its 7
cognitive side effects, especially anterograde and retrograde amnesia. It appears that 8
right unilateral ECT is as effective as bilateral treatment, albeit bilateral treatment 9
may lead to more rapid clinical response. Another approach is to use ultra-brief 10
pulse-width (UBP) stimulation in order to minimize cognitive side effects. However, a 11
systematic review found that, UBP ECT may yield lower efficacy as well as lower 12
speed of remission186 . 13
[H3] Emerging treatments. 14
Newer treatments for TRD include numerous approaches, ranging from repetitive 15
transcranial magnetic stimulation (rTMS) and deep TMS (dTMS) to magnetic seizure 16
therapy (MST) and transcranial direct current stimulation (tDCS), to low field 17
magnetic stimulation (LFMS), vagus nerve stimulation (VNS), deep brain stimulation 18
(DBS), to parenteral/intranasal ketamine and esketamine as well as other 19
pharmacological approaches. 20
A recent review of 18 TRD studies of rTMS concluded that, for MDD patients with 2 21
or more antidepressant treatment failures, rTMS is a reasonable, effective 22
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33
consideration187. However, a meta-analysis has shown that rTMS is inferior to ECT 1
with regard to efficacy in TRD188. 2
In contrast to standard TMS, deep TMS (dTMS) modulates neuronal activity in 3
deeper regions of the brain.. A recent review concluded that dTMS in TRD patients is 4
effective both as a monotherapy and as an add-on treatment189. 5
Magnetic seizure therapy (MST) combines elements of both rTMS and ECT. In MST, 6
a rTMS device is used to induce a seizure, with the procedure being otherwise 7
conducted as ECT using a general anaesthetic and a muscle relaxant. A review of 8
eight MST studies reported remission rates ranging from 30% to 40%, and no 9
significant cognitive side effects related to MST190. 10
Transcranial direct current stimulation (tDCS) typically applies a weak direct current 11
via scalp electrodes overlying targeted cortical areas191. A recent review concluded 12
that the data do not support the use of tDCS in TRD192. 13
Low field magnetic stimulation (LFMS) refers to a form of brain stimulation delivered 14
in a magnetic field waveform inducing a low, pulsed electric field in the brain. Two 15
sham-controlled pilot studies of LFMS have shown a rapid antidepressant effect in 16
mood disorder patients193. 17
Vagus nerve stimulation (VNS) involves the surgical implantation of a pacemaker-18
like pulse generator in the chest, connected to a stimulating electrode attached to the 19
vagus nerve in the neck. VNS results in activation of a variety of subcortical brain 20
structures and the stimulation of hippocampal neurogenesis194. Despite the fact that 21
the only controlled trial in TRD of VNS using a sham control did not achieve the pre-22
specified statistical significance and reported modest response rates in the acute 23
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34
phase, long-term, extension phases of VNS treatment have been associated with an 1
increased therapeutic effect over time, with a sustained response rate of 40% and a 2
remission rate of 29% after a 9 month follow-up194. 3
Deep brain stimulation (DBS) involves the implantation of a pulse generator 4
connected to two stimulating electrode wires, surgically placed in specific brain 5
regions. As pointed out by Fitzgerald195, DBS is typically reserved for patients with 6
the most severe forms of TRD, and requires further evaluation of both administration 7
methods and its role in MDD therapy. 8
A novel pharmacological approach to the treatment of TRD involves parenteral or 9
intranasal administration of the glutamergic drugs ketamine and esketamine. A 10
review of 21 studies found that single ketamine intravenous infusions elicit a 11
significant antidepressant effect from 4 h to 7 days in TRD patients196. Similar results 12
were reported in a trial of a single intravenous infusion of esketamine197. Other drugs 13
with NMDA receptor antagonism properties have been associated with relatively 14
more modest antidepressant effects compared with ketamine; however, they have 15
shown other potentially favorable characteristics, such as decreased dissociative or 16
psychotomimetic effects198. Other emerging pharmacological augmentation 17
strategies use compounds such as s-adenosyl-methionine199, l-methylfolate200, 18
omega-3 fatty acids201, i.v. scopolamine202 and the opioid modulator ALKS 5461203, 19
but their efficacy is not well established yet. 20
21
[H1] Quality of life 22
[H2] Impact on work and family life 23
Much of the burden of disease associated with MDD is related to the dramatic effect 24
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35
of MDD on ability to work and the significant strain on family life. In a large survey 1
conducted in the United States, MDD was associated with 27.2 workdays lost per 2
affected worker per year204. 3
Epidemiological studies have indicated that low socioeconomic status is linked to 4
MDD205. Of particular concern is that MDD has been linked to lower educational 5
attainment 205. The cause-effect of this association, however, is unclear and a large 6
recent study with 25.000 subjects suggested that it might in part be due to shared 7
genetics206. 8
9
[H2] Cognitive impairment 10
Considerable literature has supported the presence of objectively measured cognitive 11
deficits in patients with MDD. These deficits affect a wide range of cognitive domains 12
including both “hot” (i.e. emotion-laden) and “cold” (non-emotional) cognition. One 13
meta-analysis identified executive function, memory, and attention as the 14
predominantly affected domains207. An attentional bias towards negative information 15
has also been meta-analytically confirmed208. Impairments in psychomotor speed, 16
attention, visual learning and memory as well as executive function can already be 17
detected with small to medium effect sizes during a first episode of MDD.209 18
19
Although the cognitive deficits are more modest after remission (i.e. in euthymic 20
patients with MDD), slight impairments in executive control207,210 and memory207 may 21
remain, suggesting that these deficits are not simply an epiphenomenon of 22
decreased motivation during episodes of low mood. 23
Cognitive impairment in MDD in part depends on the patient subgroup studied. MDD 24
severity, for example, has been shown to be a significant predictor of cognitive 25
dysfunction211. In addition, patients with psychotic depression have been shown to 26
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36
perform significantly worse than patients with non-psychotic MDD on tests of verbal 1
learning, visual learning, and processing speed212. Neurocognitive impairment is a 2
relevant factor in patients’ quality of life as it is negatively associated with 3
psychosocial functioning in MDD213. Overall, antidepressant pharmacotherapy 4
appears to significantly improve cognitive function214. 5
6
[H2] Suicide risk 7
The most immediate clinical concern with MDD is its strong relation to suicidal intent 8
and completed suicide215. Patients with MDD have a 1.8 fold increased overall 9
mortality and MDD patients lose an estimated 10.6 life years lost for men and 7.2 10
years for women7. This is due – in part – to the elevated risk of suicide in this 11
population. In a meta review, the risk of suicide in MDD was almost 20 fold higher 12
than in the general population7. 13
The effectiveness of behavioral and psychosocial interventions to prevent suicide 14
and suicide attempts has been supported by a recent meta-analysis, particularly for 15
interventions that directly address suicidal thoughts216. There are also strategies to 16
reduce suicides at “suicide hotspots” (i.e. public areas often used for suicides) that 17
aim at restricting access to means and encouraging help seeking that might be 18
effective according to one meta analysis217. 19
It should be noted that recent meta-analyses of randomized controlled trials have not 20
found a beneficial effect of antidepressants to reduce suicide risk in MDD218,219. 21
Importantly, risk and benefit of antidepressants use and suicidality appear to be 22
strongly age dependent220,221. Meta-analyses revealed that suicidal ideation or 23
behavior associated with antidepressants was non-significantly increased in patients 24
< 25 years, non-significantly decreased in patients 25 – 64 years and highly 25
significantly decreased in patients > 64 years (OR 0.37, 95% CI 0.18 to 0.76). In 26
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any event, clinicians should pay special attention to suicidal ideation and suicidality in 1
patients with MDD in general and during antidepressant pharmacotherapy222. 2
3
4
[H1] Outlook 5
A pivotal task in the future of MDD research will be to break down the heterogeneous 6
clinical picture of MDD as a broad DSM-5 category into more narrowly defined 7
disease entities with a more specific biology. The initial goal of DSM-5 was to define 8
psychiatric diagnoses including MDD by genetics, neuroimaging, and other biological 9
measures. However, this knowledge has not sufficiently evolved yet to reliably base 10
psychiatric diagnoses on biological measures. Nevertheless, DSM still provides 11
clinicians and researchers with the opportunity of defining subtypes of MDD by 12
grouping patients according to distinct clinical characteristics (for example, 13
melancholic versus atypical depression). Importantly, these subtypes have already 14
been associated with different neurobiological signatures43. Furthermore, the 15
concepts of “vascular depression” 223, „metabolic depression“ 224,225, or „inflammatory 16
depression“ 226 that all imply a specific etiology and potentially specific treatments 17
warrant further validation. 18
19
Once valid MDD subtypes have been found, it is hoped that these will lead to more 20
specific treatments with better outcomes. There are now several studies that were 21
able to predict response to specific psychological or pharmacological treatment by 22
clinical criteria such as history of childhood trauma227, neuroimaging markers such as 23
insula hypometabolism228, or inflammatory markers such as C-reactive protein229,230. 24
However, clinical subtypes (melancholic, atypical, anxious) did not predict treatment 25
response in the iSPOT-D and STAR*D trial231. Ideally, precision psychiatry will allow 26
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to categorize MDD subtypes in the future analogue to the field of oncology that has 1
started to define different forms of cancer in the same organ into separate disease 2
entities requiring different treatment232. It remains to be seen whether the 3
dimensional approach of the RDoC using concepts from genetics as well as from 4
cognitive, affective, and social neuroscience will achieve this goal. It has been 5
argued that the RDoC approach disregards the distinction between “sick” and “well” 6
and that RDoC might introduce a gap between clinicians using DSM-5 and 7
researchers using RDoC233. In any event, further research should test the validity of 8
the new DSM 5 specifier with mixed features. A pressing clinical question is whether 9
MDD with mixed features requires a different therapy than MDD without mixed 10
features. 11
12
Clearly, MDD is not just a phenomenon in industrialized countries but will affect one 13
out of six individuals worldwide. Therefore, to improve the outcome of MDD treatment 14
worldwide, one of the highest priorities in the field should be to implement effective 15
treatment in low-income countries in which <10% of depressed patients get adequate 16
treatment234,235. The currently ongoing mental health Gap Action Programma 17
(mhGAP)236 of the World Health Organization is aiming to scale up services for 18
mental disorders for countries with low and lower middle incomes. An 19
epidemiological phenomenon consists in the repeatedly described sex differences in 20
prevalence rates of MDD2 and it will be important to examine the mechanisms that 21
are responsible for the increased MDD prevalence in women. 22
23
Given the fact that MDD is a strong risk factor for developing metabolic and 24
cardiovascular diseases and for a worse course and outcome in these diseases5, it 25
will be important to learn more about the mechanisms of association between MDD 26
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39
and other medical diseases such as diabetes or coronary heart disease. Future 1
research should also examine whether treatment of comorbid MDD reduce morbidity 2
and mortality in medical patients. 3
4
In terms of the etiology and pathophysiology of MDD, many questions remain 5
unresolved. For example, how exactly is the immune system dysregulated in MDD 6
(i.e. which immune compartment (innate vs. adaptive immunity) is affected? Again, 7
are immunological alterations present in MDD in general or only in specific subtypes? 8
Furthermore, there is a lack of replicated findings in both GWAS and G×E studies8. 9
Thus, a crucial question remains how exactly environmental influences interact with 10
the genome leading to MDD. Furthermore, how stable are epigenetic alterations of 11
genomic read-out and are they reversible with successful therapy? 12
13
Better treatment for patients is the ultimate goal of all biomedical research and 14
obviously this is true for MDD research as well. In terms of new psychotherapeutic 15
approaches, the technological revolution with its fast evolving developments will 16
allow technology-supported diagnostic and treatment options. This might include 17
intervention tools that can detect and react to sensed states and behaviors, allowing 18
just-in-time prompting and reinforcement of treatment congruent behaviors153, as well 19
as tools that can passively monitor risk of MDD. 20
Within pharmacological research, antidepressants within the glutamatergic system 21
such as ketamine are currently under intense scientific scrutiny. An almost 22
revolutionary approach might consist in substances that stimulate neurogenesis in 23
humans. A first phase 1b clinical study has been published in depressed patients 24
demonstrating efficacy compared to placebo in two out of four MDD outcome 25
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measures167. However, future studies are necessary to determine safety and efficacy 1
of substances that stimulate neurogenesis in depressed patients. 2
Perhaps, MDD affects the “conditio humana” more than every other medical disease 3
and its etiology and pathophysiology remains a complex puzzle. Consistent with 4
Winston Churchill’s famous quote “ Success is not final, failure is not fatal: it is the 5
courage to continue that counts“, it will be worth every effort to relieve the enormous 6
burden of MDD. 7
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41
Box 1. Definition of Major Depressive Disorder according to DSM5 1 • Five (or more) of the following symptoms have been present during the same 2
2- week period and represent a change from previous functioning: 3 o Depressed mood 4 o Markedly diminished interest or pleasure in all, or almost all, activities 5 o Significant weight loss when not dieting or weight gain or decrease or 6
increase in appetite nearly every day. 7 o Insomnia or hypersomnia nearly every day. 8 o Psychomotor agitation or retardation nearly every day 9 o Fatigue or loss of energy nearly every day. 10 o Feelings of worthlessness or excessive or inappropriate guilt (which 11
may be delusional) nearly every day (not merely self-reproach or guilt 12 about being sick). 13
o Diminished ability to think or concentrate, or indecisiveness, nearly 14 every day (either by subjective account or as observed by others). 15
o Recurrent thoughts of death (not just fear of dying), recurrent suicidal 16 ideation without a specific plan, or a suicide attempt or a specific plan 17 for committing suicide. 18
19 • The symptoms cause clinically significant distress or impairment in social, 20
occupational or other important areas of functioning. 21 22
• The episode is not attributable to the physiological effects of a substance or to 23 another medical condition 24
25 • The occurrence of the major depressive episode is not better explained by 26
schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional 27 disorder, or other specified and unspecified schizophrenia spectrum and other 28 psychotic disorders. 29
30 • There has never been a manic episode or a hypomanic episode. 31
32 33 Specifiers of MDD according to DSM-5 are: 34
o Severity 35 o With anxious distress 36 o With mixed features 37 o With melancholic features 38 o With psychotic features 39 o With peripartum onset 40 o With seasonal pattern 41
42 43
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Box 2. Pathophysiology: from mice to man 1
Research into the underlying mechanisms of human disorders can be facilitated by 2
model systems that allow reduction and molecular dissection of specific pathways. 3
Finding the appropriate model systems for a given human disease is always 4
challenging. This is particularly true for psychiatric disorders (see 237 for a review). 5
Developing animal models is further complicated by the lack of consistently identified 6
genetic cause of depression in humans. Moreover, many of the symptoms typically 7
seen in patients with MDD are highly subjective (e.g. depressed mood) and only few 8
can be observed and assessed in animals. 9
Despite these challenges, animal models have allowed the discovery of many 10
exciting target pathways that may contribute to the etiopathogenesis of depression 11
and carefully unraveled the molecular processes involved. These include 12
13
• neuroendocrine and -immune mechanisms (see 238-240), 14
• epigenetics241, 15
• molecular networks and the transcriptome242, 16
• the microbiome and the gut-brain axis243, 17
• synaptic dysfunction and plasticity244, 18
• neurogenesis245, 19
20
Surely, this is a fascinating and highly active area of investigation that has the 21
potential to discover novel targets for therapy and ultimately to bring about better 22
treatments for patients. However, to review all of these in detail would be beyond the 23
scope of this review and reviewing them briefly would not do them justice. Moreover, 24
at present, the clinical relevance of any of these mechanisms for MDD remains 25
uncertain and no newly developed, hypothesis-driven therapeutic approaches for 26
depression have made it to the clinic (yet). 27
28
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43
1
Box 3. Social determinants of MDD (modified after234) 2
3
Several types of social determinants are associated with the risk and outcome of 4
MDD246. They can be categorized as follows: 5
6
• Demographic factors: e.g. age, sex, and ethnicity 7
• Socioeconomic status: e.g. poverty, unemployment, income inequality, low 8
education 9
• Neighborhood factors: e.g. inadequate housing, overcrowding, neighborhood 10
violence and safety 11
• Socio-environmental events: e.g. natural disasters, war, conflict, migration, 12
discrimination, difficulties in work, low social support, trauma, negative life 13
events 14
15
There is a bidirectional association between these social determinants and MDD: 16
certain social variables such as low socioeconomic status or lack of social support 17
may contribute to the risk for MDD („social causation“). On the other hand, patients 18
with MDD, especially those with a chronic course of the disease, often deteriorate in 19
their social functioning leading to work and family problems („social drift“), which may 20
eventually lead to poverty234,246 21
22
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Box 4. Psychotherapy for MDD 1
Cognitive therapy 2
Cognitive therapy teaches the patient to identify negative, distorted thinking patterns 3
that contribute to depression and provides skills to test and challenge these negative 4
thoughts, replacing them with more accurate, positive ones. 5
Behavioral activation therapy 6
Behavioral activation therapy focuses on increasing the patient’s positive activities 7
that provide a sense of pleasure or mastery. This treatment also frequently focuses 8
on identifying and confronting avoidance processes. 9
Psychodynamic therapy 10
Psychodynamic therapy helps the patient explore and gain insight into how emotions, 11
thoughts, and earlier-life experiences have created patterns that contribute to current 12
problems. Recognizing these patterns can help a person cope and change those 13
patterns. 14
Problem solving therapy 15
Problem solving therapy teaches patients a structured set of skills to generate 16
creative methods of addressing problems, identifying and overcoming potential 17
barriers to goals, and making effective decisions. 18
Interpersonal therapy 19
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Interpersonal therapy focuses on helping people identify and resolve problems in 1
relationships and social roles, including interpersonal conflicts, role transitions, and 2
diminished or impoverished relationships. 3
Mindfulness-Based Therapy 4
Mindfulness has its origins in contemplative practices, primarily Bhuddism, and 5
involves regular meditative practice in which one pays attention to thoughts, feelings, 6
and experiences in a nonjudgemental manner, learning to accept things as they are 7
without trying to change them. 8
9
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46
Figure 1. Average 12-month prevalence of major depressive disorder. Although 1
considerable variation in inter-country prevalence is noted, the overall estimates in 2
high-income countries (5.5%) and low- and middle-income countries (LMICs; 5.9%) 3
are not different. Data derived from the World Mental Health Survey3. 4
5
Figure 2. The somatic consequences of major depressive disorder. Evidence 6
from meta-analyses43 of longitudinal studies have revealed the relative risk (RR) of 7
various diseases is increased in those with major depressive disorder (MDD) 8
compared with those who do not have MDD. The mechanisms contributing to the 9
diverse somatic consequences of MDD are diverse and together may explain the 10
unfavorable health outcomes in depressed patients. They include unhealthy lifestyle, 11
poorer (self)care adherence, medication side effects, shared pathophysiology 12
including e.g. upregulation of immune-endocrine stress systems and genetic 13
pleiotropy (see 39, 247 for a review that gives more details). 14
15
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47
1
Figure 3: Neurobiological systems involved in MDD pathology. Biological 2
alterations associated with MDD have been described in the central nervous system 3
(CNS), the major stress responses systems such as the hypothalamic-pituitary-4
adrenal (HPA) axis, the autonomic nervous system and the immune system. While 5
the sequence of events leading to these changes and their exact interrelation is not 6
known, it is assumed that a combination of vulnerability factors and environmental 7
triggers are the primary event. Psychological stressors set off responses in the HPA 8
axis, which over time show a diminished feedback inhibition capacity resulting in 9
chronically elevated levels of stress hormones such as cortisol and CRH. Chronically 10
elevated stress hormones can also contribute to pathology in cardiovascular and 11
metabolic systems, which often co-occur with MDD. In addition, chronic activation of 12
innate immune responses and elevated circulating levels of inflammatory mediators 13
such as cytokines have been described in MDD; which may be related to a higher 14
incidence of infections in this population. While the cause-effect relationship between 15
these biological correlates is often unclear in clinical studies, mechanistic studies in 16
animals have shown that stress response systems as well as immune activation can 17
directly and indirectly impact on the CNS. Here, they contribute to altered plasticity, 18
connectivity and neurotransmission and may even exacerbate tissue loss. Ultimately, 19
these may underlie abnormal structural and functional connectivity of relevant brain 20
circuits and regional brain volume changes seen in neuroimaging studies. 21
22
Abbreviations: ACTH: adrenocorticotropin; CRH: corticotropin releasing hormone; 23
CNS: central nervous system; HPA: hypothalamic-pituitary-adrenal axis; MDD: major 24
depressive disorder; NK: natural killer; IL-6: interleukin 6; IL 1ß: interleukin 1ß. 25
26
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48
Figure 4. Model of gene × environment interactions leading to major depressive 1
disorder. The schematic depicts a model of MDD that is based on predisposing 2
genetic vulnerability that interacts with aversive and protective environmental factors 3
in the development of MDD. At least some of the environmental effects are mediated 4
through epigenetic mechanisms to produce the phenotype of MDD, which is 5
characterized by alterations on a molecular level, on a brain network level, and on a 6
behavioral level. 7
8
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49
Figure 5. Structural brain alterations in MDD. Regional brain volumes as 1
determined by structural MRI have been investigated in patients with MDD compared 2
to healthy controls in numerous cross-sectional studies. Brain areas with smaller 3
volumes in MDD compared to healthy controls as confirmed in a meta-analysis 4
include the basal ganglia, the thalamus as well as the hippocampus and frontal 5
regions, typically with moderate effect sizes (left panel) and volume differences 6
between 3,5-15.5% (right panel) (based on Kempton et al. 94). Smaller volumes in the 7
basal ganglia and the hippocampus were also found when comparing patients with 8
MDD and bipolar disorder (based on Kempton et al. 94), suggesting some specificity 9
for these areas for depressive symptoms occurring in the context of unipolar MDD. 10
Finally, in an independent meta-analysis of structural MRI studies using voxel-based 11
morphometry, only smaller volumes in the hippocampus were specific to patients with 12
MDD when compared to other psychiatric disorders such as bipolar disorder (BPD), 13
schizophrenia (SCZ), anxiety disorders (ANX), obsessive-compulsive disorder (OCD) 14
and substance abuse. *Volume group differences, effect sizes and confidence 15
intervals of MDD compared to healthy controls taken from Kempton et al. 94). a 16
Smaller volumes detected in MDD compared to patients with bipolar disorder. b 17
Smaller volumes detected in MDD compared to patients with other psychiatric 18
disorders (SCZ, BPD, substance abuse, OCD, ANX). 19
20
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50
1 Figure 6. Treatment recommendations after a first antidepressant has failed. 2
In patients not responding to an initial treatment with an antidepressant, one or 3
several of the following strategies should be used in parallel including reassessing 4
the comorbid psychiatric and/or medical diagnoses, discussing potential problems 5
with adherence and considering several additional treatment options. The latter can 6
be added at all treatment levels. If still no response occurs, one out of three different 7
pharmacological strategies are recommended: switching the antidepressant, 8
combining two antidepressants, or augmenting the antidepressant with an atypical 9
antipsychotic or lithium. If all of these strategies have failed, electroconvulsive 10
therapy (ECT) is recommended. In a next step, more experimental treatment options 11
with less evidence can be considered such as pharmacological treatment with 12
ketamine or stimulatory treatment with repetitive transcranial magnetic stimulation 13
among other more experimental options (see text). 14
These are modified recommendations based on three different guidelines: the 15
revised 2015 German national treatment guideline248 the revised 2015 British 16
Association for Psychopharmacology guideline78, and the 2010 practice guideline for 17
the treatment of MDD by the American Psychiatric Association249. AD = 18
antidepressant; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin and 19
noradrenaline reuptake inhibitor. 20
21
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35
Figure 1
12-Month prevalence (%)
0 2 4 6 8 10 12
Japan
Germany
Italy
PRC (Shenzhen)
Mexico
Spain
India (Pondicherry)
Netherlands
South Africa
Belgium
Lebanon
France
Israel
Colombia
New Zealand
United States
Ukraine
Brazil (Sao Paulo)
High-income country
Low- or middle-income country
Mortality
Diabetes
Disability Cognitive impairment
Obesity
Heart disease
Cancer
RR=1.6
R R
= 1 .8
R R
= 1 .8
Figure 2
ACTH
Blood pressure ↑ Glucose ↑ Insulin resistance ↑
Cortisol ↑
CRH Locus coeruleus
Prefrontal
Cortex Hippocampus
Amygdala Reduced plasticity
Impaired neurogenesis?
Altered connectivity Tissue
loss?
T cell
NK cell
Impaired function
Activation
Humoral or neural route
Immune system Cardiovascular and
metabolic systems
Cytokines
TNF IL-6 IL-1b
Monocyte
Endocrine systems
Central nervous system
Adrenaline,
Noradrenaline ↑
Figure 3
Altered monoamine system
+
Aversive • Prenatal factors • Childhood trauma • Stress • Medical illness • Drug abuse Protective • Social support • Coping • Exercise
Depressed phenotype Epigenetic mechanisms Genome
MOLECULAR LEVEL • Monoamines • Hypothalamic-pituitary-
adrenal axis • Immune system • Neuroplasticity
BRAIN NETWORK LEVEL • Regional brain volume
reductions • Default network • Cognitive control network • Affective salience network
BEHAVIOURAL LEVEL • Cognition • Mood • Anxiety • Sleep • Appetite
Environment Figure 4
Figure 5 Data for Fig 5: Structural brain alterations in MDD
Brain volumes 1 Effect size* 95% CI
(upper; lower)* Average volume difference to healthy controls*
Caudate a 0.22 0.30; 0.06 -3,5%
Putamen a 0.25 0.43; 0.06 -4.1%
Globus Pallidus a 0.31 0.61; 0.02 -4.5%
Thalamus 0.34 0.60; 0.07 -6.7%
Hippocampus a,b
0.47 0.62; 0.32 -5.5%
Frontal lobe 0.29 0.53; 0.05 -3.8%
Orbitofrontal cortex 0.38 0.64; 0.11 -7.5%
Gyrus rectus 0.72 1.03; 0.41 -15.5%
DRAFT FIGURE 5
Non-response to first antidepressant
Parallel use of one or more of these strategies:
Discuss
• Medication adherence including potential adverse effects
Reassess
• Psychiatric (comorbid) diagnoses including substance abuse • Medical diagnoses including medication and potential drug-drug interactions
Consider
• Increasing the dose of antidepressant
• State-of-the art psychotherapy • Exercise therapy • Light therapy • Sleep deprivation
No response
Switch Antidepressant
(preferably to AD with different mechanism of action)
Combination of antidepressants:
• SSRI/SNRI + mirtazapine • SSRI + bupropion
Augmentation with either:
• AD + atypical antipsychotics • AD + lithium
No response
Electroconvulsive therapy (ECT)
No response
Consider more experimental treatments*
Alternative use of one of these strategies:
F
i
g
u
r
e
6
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