See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/5677983.Major depressive disorder (invited review)
Article in New England Journal of Medicine · February 2008
DOI: 10.1056/NEJMra073096 · Source: PubMed

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Kurs “ Allgemeine und systematische Pharmakologie und Toxikologie”
Sommersemester 2011
Seminarthema II: Psychopharmaka
Der Inhalt bzw. die Gliederung der Referate ist frühzeitig mit der/dem zuständigen
Dozentin/en abzusprechen. Alle Referate sollten max. 15 Minuten dauern und den Einsatz
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Referat I:
Therapie der endogenen Depression
Belmaker, R.H. and G. Agam (2008): Major depressive disorder. N. Eng. J. Med
358: 55-68.
Bschor, T. and M. Adli (2008): Treatment of depressive disorders. Dtsch. Ärztebl. Int.
105: 782-792.
Lee, S., Jeong, J., Kwak, Y., and Park, S.K. (2010): Depression research: where are
we now? Mol. Brain 3: 8.
Ihr Referat sollte folgende Punkte umfassen:- Aminhypothese, Therapie der unipolaren Depression: trizyklische undheterozyklische Antidepressiva, MAO- und reuptake-Inhibitoren- Therapeutische Anwendung und Nebenwirkungen- neue Erkenntnisse zu den Mechanismen der Entstehung von Depressionen
Referat II: Therapie der bipolaren Affekterkrankung
Quiroz, J.A., Gould, T.D., and Manji, H.K. (2004): Molecular effects of lithium. Mol.
Interv. 4: 259-272.
Beaulieu, J.M. and Caron, M.G. (2008): Looking at lithium. Mol. Interv. 8: 230-241.
Schloesser, R.J., Huang, J., Klein, P.S., and Manji, H.K. (2008): Cellular plasticity
cascades in the pathophysiology and treatment of bipolar disorder. Neuropharmacol.
33: 110-133.
Ihr Referat sollte folgende Punkte umfassen:- Definition und Therapie der bipolaren Depression- Molekulare und zelluläre Mechanismen der Wirkung von Lithiumionen
sowie Pharmakokinetik und Pharmakodynamik von Lithium
Referat III: Therapie der Schizophrenie
Burlon, M. (2007): Pharmakotherapie der Schizophrenie-“state of the art”.
NeuroTransmitter 5, 59-70.
Tajima, K., H. Fernandez, J.J. Lopez-Ibor, J.L. Carrasco, and M. Diaz-Marsa (2009):
Schizophrenia treatment. Critical review on the drugs and mechanisms of action of
antipsychotics. Actas Esp. Psiquatr. 37: 330-342.
Tost, H., Alam, T., and Meyer-Lindenberg (2010): Dopamine and psychosis: theory,
pathomechanisms and intermediate phenotypes. Neurosci. Biobehav. Rev. 34: 689700.
Ihr Referat sollte folgende Punkte umfassen:- Pathogenese der Schizophrenie, Dopaminhypothese, neue Ansätze in der Therapie- Therapie:
niederpotente versus hochpotente Antipsychotika
typische (first) versus atypischen (second) Antipsychotika, NW

T h e n e w e ng l a n d j o u r na l o f m e dic i n ereview article
Mechanisms of Disease

Major Depressive Disorder
R.H. Belmaker, M.D., and Galila Agam, Ph.D.
epression is related to the normal emotions of sadness andbereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe statesof depression often have no external precipitating cause. It is difficult, however, todraw clear distinctions between depressions with and those without psychosocial
precipitating events.1 The diagnosis of major depressive disorder requires a distinct
change of mood, characterized by sadness or irritability and accompanied by at least
several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or withfriends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of 2 weeks and interfere considerably with work and family relations. On the basis of this broad definition, the lifetime incidence of depression in the United States is more than 12% in men and 20% in women.2 Some haveadvocated a much narrower definition of severe depression, which they call melancholia or vital depression.3
A small percentage of patients with major depression have had or will have manic
episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking.
Although some pathogenetic mechanisms in these cases and in cases of major depressive disorder overlap, a history of mania defines a distinct illness termed bipolar disorder.4
Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. This review presents the
major current approaches to understanding the biologic mechanisms of major depression.

D

From Ben Gurion University of the Negev,
Beersheba, Israel. Address reprint requests
to Dr. Belmaker at Beersheba Mental
Health Center, P.O. Box 4600, Beersheba,
Israel, or at belmaker@bgu.ac.il.
N Engl J Med 2008;358:55-68.
Copyright © 2008 Massachusetts Medical Society.

Gene t ic s
Studies comparing concordance rates for major depression between monozygotic anddizygotic twins suggest a heritability of about 37%,5 which is much lower than theheritability of bipolar disorder or schizophrenia. Some aspects of the normal personality, such as avoidance of harm, anxiousness, and pessimism, are also partly heritable.6
Kendler et al.7 showed that although depression is due in part to heritable depressionprone personality traits, it is also the result of heritable factors that are independentof personality. Early-onset, severe, and recurrent depression may have a higher heritability than other forms of depression.8 It is clear from studies of families that major
depression is not caused by any single gene but is a disease with complex genetic features. Studies of pedigrees with multiple cases of major depression have identified
chromosomal regions with linkage to the disorder, and some of these loci have been
replicated in more than one study, although no single chromosomal region has been
replicated in every family study of genetic linkage in depression. Holmans et al.9 foundn engl j med 358;1

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55

T h e n e w e ng l a n d j o u r na l o f m e dic i n eevidence of linkage of recurrent, early-onset depression to chromosome 15q25-q26, but the population attributable risk was small.
No specific molecular risk factor has been reliably identified. One common polymorphic variantof the serotonin-transporter–linked polymorphic
region (5-HTTLPR), which affects the promoter ofthe serotonin-transporter gene, causes reduced
uptake of the neurotransmitter serotonin into thepresynaptic cells in the brain.10 Some studies haveshown that this polymorphism confers a predisposition to depression,11 but it also confers a predisposition to an anxious and pessimistic personality.10 Brain imaging reveals functional differencesin emotion-related areas of the brain among carriers of the different common polymorphisms of
5-HTTLPR,12 although a direct relation to depression is unclear. In a large, prospective epidemiologic study, Caspi et al.13 found that 5-HTTLPR
predicted depression only in association with defined life stresses. Some environmental factors
could confer a predisposition to depression by affecting the genome epigenetically — for example,
increased maternal care in rodents causes an epigenetic change in the promoter region of the glucocorticoid-receptor gene.14

The Monoa mine-Deficienc y
H y p o the sis
The noradrenergic and serotonergic systems originate deep in the brain and fan out over almost
the entire brain, suggesting a system capable ofmodulating many areas of feeling, thinking, andbehaving. The early antidepressants blocked thereuptake of norepinephrine and serotonin by thepresynaptic neuron. The immediate effects of thispharmacologic action are to increase the availability of norepinephrine and serotonin in the synapse
and to increase stimulation of the postsynaptic
neuron. Inhibitors of the enzyme monoamine oxidase were also discovered to have antidepressant
properties. This enzyme catabolizes norepinephrine and serotonin in their respective presynaptic
neurons, and such inhibition could be expected toincrease the availability of neurotransmitters. These
discoveries led to a major theory of depression
known as the monoamine-deficiency hypothesis.
Numerous studies of norepinephrine and serotonin
metabolites in plasma, urine, and cerebrospinal
fluid, as well as postmortem studies of the brainsof patients with depression, have yet to identify the56

n engl j med 358;1

purported deficiency reliably. However, a newly discovered form of the enzyme tryptophan hydroxylase, designated TPH-2, is specific to the brain15
and could explain why previous postmortem studies of total enzyme activity did not show differences in tryptophan hydroxylase activity between
patients with depression and controls.16 A recent
positron-emission tomographic study using a ligand for brain monoamine oxidase showed a 30%
increase of the enzyme in a subgroup of patientswith depression.17 A study measuring differences
in monoamine metabolites between the internal
jugular vein and the brachial artery showed lower
production by the brain of norepinephrine metabolites in patients with depression than in controls.18
The monoamine-deficiency hypothesis continues
to stimulate research whenever a new technicalwindow into the brain is opened.
Serotonin and norepinephrine can be depleted
experimentally in humans by oral treatments.19
A drink containing all amino acids except tryptophan stimulates the liver to synthesize proteins
and rapidly depletes the plasma (and therefore thebrain) of tryptophan. Tryptophan is rate-limiting
for serotonin synthesis in the brain. Such oral
tryptophan depletion does not induce depression
in healthy subjects but will cause a relapse of depression in patients who have been successfully
treated with a serotonin-reuptake inhibitor.19 Similarly, α-methyl paratyrosine inhibits tyrosine hydroxylase, the rate-limiting step in catecholaminesynthesis. Treatment with α-methyl paratyrosine
does not induce depression in normal subjects but
will induce a relapse in patients who have beentreated successfully with a norepinephrine-reuptake inhibitor.19 These findings suggest that norepinephrine and serotonin have critical roles in themechanisms of these treatments of depression butthat additional neurochemical factors are necessary to cause depression.
Because direct measurements of monoamine
neurotransmission did not yield definitive findings
in relation to depression, the downstream effects
of monoamine neurotransmission were explored(Fig. 1). The serotonin-1B receptor is located presynaptically and regulates the release of serotoninby feedback inhibition. Postmortem studies showthat the levels of p11, a protein that enhances theefficiency of serotonin-1B receptor signaling, aredecreased in the brains of patients with depression.20 The serotonin-1A receptor is located bothpresynaptically and postsynaptically to regulate

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mechanisms of disease

serotonin function (Fig. 1). The receptor can beevaluated in patients with depression by injecting
specific agonists and measuring specific neuroendocrine responses, such as elevation of the prolactin level.21 Results suggest that the sensitivityof this receptor is reduced in patients with depression.21 The α2-noradrenergic receptor, which isusually presynaptic, modulates norepinephrine release by feedback inhibition (Fig. 1). Heightened
receptor sensitivity has been described in patientswith depression,22 which is consistent with reduced norepinephrine release.
It is conceivable that the second-messenger systems for serotonergic and noradrenergic neurotransmission malfunction in depression, and forthis reason the phosphatidylinositol and cyclic
AMP second-messenger systems have been extensively evaluated. Reduced inositol levels have beenfound in postmortem studies of the brains of persons who have died by suicide23 and in magnetic
resonance spectroscopic studies of the frontal cortex in patients with depression.24 A blunted cyclic
AMP response to stimulation was found in postmortem studies of the brains of patients with depression.25 These reductions in second-messengerfunction may impair neurotransmitter function
even without changes in monoamine levels or receptor numbers. These data indirectly support
elaborations of the original monoamine-deficiency
hypothesis of depression (Fig. 1).
G proteins that mediate signaling between receptors and second-messenger systems have also
been investigated in patients with depression, bothin postmortem studies of the brain26 and in studies of peripheral-blood cells.27 Although thesesystems are clearly affected, no consistent picture
has emerged because there are numerous formsof G proteins that vary in different areas of thebrain. The cyclic AMP response element–binding
protein (CREB) is a transcription factor affected bycyclic AMP in the cell. In an animal model of depression, rats with overexpression of CREB in thedentate gyrus behaved similarly to rats treatedwith antidepressants, but the opposite effect was
found when CREB was overexpressed in the nucleus accumbens.26,28 Thus, the role of CREB in
depression is specific to the region of the brain.
Most but not all studies show that long-term treatment with antidepressants stimulates CREB function, possibly depending on the type of drug andthe dosage.28 Levels of CREB and phospho-CREB
were reduced in postmortem studies of the cor-n engl j med 358;1

texes of patients who had a major depressive
disorder and had not taken antidepressants, ascompared with controls.26,28 Many studies of second-messenger systems and transcription factors
in depression were inspired by the belief that it
takes several weeks before antidepressant treatment has an effect; consequently, the studies were
designed to detect time-dependent biochemicalchanges in the cell. New meta-analyses suggestthat antidepressant effects begin rapidly, however,29 thereby supporting the classic monoaminedeficiency hypothesis.
A strong point of the monoamine theory has
been its predictive power. Almost every compoundthat has been synthesized for the purpose of inhibiting norepinephrine or serotonin reuptake has
been proved to be a clinically effective antidepressant. A behavioral model of depression has beendeveloped in which a rodent is placed in a glass
cylinder filled with water, the sheer wall offering
no chance of escape. The animal struggles for awhile and then floats passively (the forced swimtest). A single prior injection of antidepressant increases the struggling time; results in this model
have excellent predictive validity for new antidepressants. Other animal models have been developed by selective breeding of rats for depressionlike behavior, and these genetically susceptiblerodents also have a response to antidepressants.30
Still other models that can be studied biochemically induce depression with the use of long-term
mild stress or learned helplessness. However, noanimal model of depression captures the periodic
change of behavior into and out of depression thatis seen in patients with depression.
Molecular techniques such as gene knockout
partially support the monoamine theory of depression. The serotonin-reuptake–transporter knockout mouse is excessively anxious and characterized
by increased immobility in the forced swim test.31
This effect is similar to that of the low-activity
polymorphic variant of the serotonin receptor onhuman personality10 but is the opposite of the expected effects of serotonin-reuptake–inhibitor antidepressants. However, this inconsistency could
be explained by the difference between a chronic monoamine abnormality during brain development 31 and the hypothesized acute monoamine
depletion in an adult with depression. Table 1
shows the effects in mice of knocking out genes
related to monoamine neurotransmitters.
The effects of stimulants on mood indirectly

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57

T h e n e w e ng l a n d j o u r na l o f m e dic i n e

support the monoamine-deficiency hypothesis ofdepression and show that mood can be altered
rapidly. Cocaine and amphetamines are powerfulreleasers of monoamines into the synapse as wellas inhibitors of reuptake. Their mood-elevating
effects are immediate, but in patients with severe
depression they have often been reported to cause
agitation rather than relief of depression. Thisfinding could reflect the ability of these stimulants
to deplete the presynapse of monoamines and thus
cause a “crash” into depression. Recent studies
support the theory that an acute response to asingle dose of amphetamine predicts a patient’s
longer-term response to monoamine-reuptake inhibitors.46
The role of dopamine deficiency in depression
is suggested by the frequency of depression in patients with Parkinson’s disease and the effect ofreserpine, which depletes serotonin, norepinephrine, and dopamine, causing a hypoactive state inanimals. The antidepressant agent buproprion inhibits the reuptake of dopamine. Some direct dopamine-receptor agonists, such as pramipexole,
have been reported to be efficacious in the treatment of depression, even though they were developed for Parkinson’s disease.47
A major liability of the monoamine-deficiency
hypothesis is its derivation from the mechanismof currently available antidepressants. Approximately two thirds of patients have a clinical response to these agents, whereas one third have a
response to placebo.48 Perhaps the mechanism ofdepression is not related to monoamines in twoof three cases.

S t r e s s , the H y p o th a l a mic –Pi t ui ta r y– A dr ena l A x is ,a nd Grow th Fac t or s
Stress49 is perceived by the cortex of the brain andtransmitted to the hypothalamus, where corticotropin-releasing hormone (CRH) is released onto
pituitary receptors. This stimulus results in the secretion of corticotropin into plasma, stimulationof corticotropin receptors in the adrenal cortex,
and release of cortisol into the blood. Hypothalamic cortisol receptors respond by decreasing CRH
production to maintain homeostasis (Fig. 2).
There is considerable evidence that cortisol andits central releasing factor, CRH, are involved indepression.50,51 Patients with depression may haveelevated cortisol levels in plasma,38 elevated58

n engl j med 358;1

Figure 1 (facing page). The Monoamine-Deficiency
Hypothesis Extended.
The monoamine hypothesis of depression postulates
a deficiency in serotonin or norepinephrine neurotransmission in the brain. Monoaminergic neurotransmission is mediated by serotonin (5-hydroxytryptamine
1A [5-HT1A] and 5-hydroxytryptamine 1B [5-HT1B]) or
norepinephrine (noradrenaline) released from presynaptic neurons (serotonergic neuron, shown on the left
side, and noradrenergic neuron, shown on the rightside [condensed virtually]). Serotonin is synthesizedfrom tryptophan, with the first step in the synthetic
pathway catalyzed by tryptophan hydroxylase; norepinephrine is synthesized from tyrosine, with the firststep catalyzed by tyrosine hydroxylase. Both monoamine transmitters are stored in vesicles in the presynaptic neuron and released into the synaptic cleft, thereby affecting both presynaptic and postsynaptic
neurons. Cessation of the synaptic action of the neurotransmitters occurs by means of both reuptake
through the specific serotonin and norepinephrinetransporters and feedback control of release throughthe presynaptic 5-HT1A and 5-HT1B regulatory autoreceptors for serotonin and the α2-noradrenergic autoreceptors for norepinephrine. Monoamine oxidase A(MAO-A) catabolizes monoamines presynaptically andthereby indirectly regulates vesicular content. The protein p11, which interacts with 5-HT1B receptors, increases their function. Postsynaptically, both serotonin
and norepinephrine bind two kinds of guanine nucleotide triphosphate–binding protein (G protein)–coupled
receptors: cyclic AMP (cAMP)–coupled receptors,
which activate adenylate cyclase (AC) to generatecAMP, and phosphatidylinositol (PI)–coupled receptors, which activate phospholipase C (PLC). PLC generates inositol triphosphate (IP3) and diacylglycerol(DAG); cAMP activates protein kinase A (PKA), and IP3
and DAG activate protein kinase C (PKC). The two protein kinases affect the cAMP response element–binding protein (CREB). Findings in patients with depression that support the monoamine-deficiency
hypothesis include a relapse of depression with inhibition of tyrosine hydroxylase or depletion of dietarytryptophan, an increased frequency of a mutation affecting the brain-specific form of tryptophan hydroxylase (TPH-2), increased specific ligand binding to
MAO-A, subsensitive 5-HT1A receptors, malfunctioning 5-HT1B receptors, decreased levels of p11, polymorphisms of the serotonin-reuptake transporter associated with depression, an inadequate response of G
proteins to neurotransmitter signals, and reduced levels of cAMP, inositol, and CREB in postmortem brains.

CRH levels in cerebrospinal fluid,50 and increased
levels of CRH messenger RNA and protein in
limbic brain regions.50 In studies using dexamethasone to evaluate the sensitivity of the hypothalamus to feedback signals for the shutdown of
CRH release, the normal cortisol-suppression response is absent in about half of the most se-

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mechanisms of disease

verely depressed patients.52 Antidepressant-induced
clinical remission is accompanied by reversal ofsome of these abnormalities.52
Adults with a history of physical or sexual
abuse as children have increased levels of CRH in
cerebrospinal fluid.53 Adult rodents that were separated from their mothers or abused as pups show
increased immobility in the forced swim test,
which is reversed by antidepressant treatment.54
Mice with region-specific knockout of the glucocorticoid receptor at an adult age have increasedn engl j med 358;1

activity of the hypothalamic–pituitary–adrenal axis
and increased immobility in the forced swim test,
both of which are reversed by antidepressants.55
Increased levels of monoamines in the synapse
affect the hypothalamic–pituitary–adrenal axis56
and reverse some of the long-term effects ofstress.56 It is possible that antidepressants relieve
depression by reducing the secondary stress caused
by a painfully dispirited mood rather than by directly elevating mood. An antistress mechanism
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59

T h e n e w e ng l a n d j o u r na l o f m e dic i n eTable 1. Monoamine-Related Gene Knockouts That Affect Depression-Related Behavior in Mice.*

Gene or Protein

FunctionCorroborationof MonoamineDeficiency
Hypothesis

Depression-Related Changes

Other Behavior Elicited byKnockout of Gene

sert

Serotonin transporter

Increased depressive behavior, reduced serotonin level, desensitized postsynaptic
5-HT1AR, and reduced presynaptic
5-HT1AR function32

No

Excessive anxiety32

net

Norepinephrine transporter Reduced depressive behavior, prolonged
norepinephrine clearance, elevated extracellular norepinephrine levels33

Yes

Increased locomotion responseto amphetamines and cocaine33

5-ht1ar

Serotonergic 1A receptor(presynaptic autoreceptor and postsynaptic)

Reduced depressive behavior, normal serotonin level and release, impaired SSRIinduced neurogenesis32

No

Excessive anxiety,impaired hippocampal learning32

5-ht1br

Serotonergic 1B receptor(presynaptic autoreceptor and postsynaptic)

Reduced response to SSRI in forced swim
test, reduced serotonin level and increased serotonin release, increased
SSRI-induced serotonin release, decreased serotonin-transporter expression32

Yes

Increased aggressiveness, reduced anxiety, increased exploration, increased use of
cocaine32

p11 (protein)

Interacts with and enhances signaling efficiencyof 5-HT1BR

Increased depressive behavior, increased
serotonin turnover20

No

Not reported20

5-ht2ar

Serotonergic 2A receptor

No change34

No

Reduced inhibition in conflictanxiety paradigms34

5-ht7

Serotonergic 7 receptor(possibly presynaptic
autoreceptor and postsynaptic)

Reduced depressive behavior and REM
sleep duration35

No

Normal locomotion35

α2aar

α2A-Adrenergic receptors(presynaptic autoreceptor)

Reduced norepinephrine levels, presynaptic
inhibition of release,36 increased depressive behavior37

No

Altered sympathetic regulation,36 impaired motor coordination

α2car

α2c-Adrenergic receptors(presynaptic autoreceptor restricted to central
nervous system)

Reduced depressive behavior38

Yes

Increased aggressiveness,32
increased locomotion response to amphetamines36

mao-a

Monoamine oxidase A

Increased brain serotonin and epinephrine
levels39

No

Increased aggressiveness andresponse to stress,30 decreased exploration32

ac VII (heterozygotes)

Adenylyl cyclase type 7

Reduced depressive behavior40

No

Unchanged anxiety40

impa1

Inositol monophosphatase 1

Reduced depressive behavior, unalteredbrain inositol levels41

Yes

Increased hyperactivity andsensitivity to pilocarpineinduced seizures41

smit1

Sodium-myo-inositol transporter 1

Reduced depressive behavior and brain inositol levels42

Yes

Increased sensitivity to pilocarpine-induced seizures42

creb

Cyclic AMP–response element–binding protein

Reduced depressive behavior, normal antidepressant-induced behavior43

No

No increase in BDNF after longterm use of antidepressants43

Brain-derived neurotrophic
factorNo depressive behavior44

No

Increased aggressiveness, hyperphagia,45 hyperactivity44

Increased depressive behavior44

Yes

Increased aggressiveness, hyperphagia45

bdnf
Male miceFemale mice Brain-derived neurotrophic
factor* BDNF denotes brain-derived neurotrophic factor, 5-HT1AR 5-hydroxytryptamine 1A receptor, 5-HT1BR 5-hydroxytryptamine 1B receptor,
REM rapid eye movement, and SSRI selective serotonin-reuptake inhibitor.

60

n engl j med 358;1

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mechanisms of disease

Figure 2. The Hypothalamic–Pituitary–Cortisol System in Depression.
The hypothalamic–pituitary–cortisol hypothesis of depression postulates that abnormalities in the cortisol responseto stress may underlie depression. The black arrows show that in response to stress, which is perceived by the brain
cortex and the amygdala and transmitted to the hypothalamus, corticotropin-releasing hormone (CRH) is released,
inducing the anterior pituitary gland to secrete corticotropin into the bloodstream. Corticotropin stimulates the adrenal cortexes to secrete the glucocorticoid hormone cortisol. The red lines show that cortisol, in turn, induces feedback inhibition in the hypothalamus and the pituitary, suppressing the production of CRH and corticotropin, respectively. Findings in patients with depression that support the hypothalamic–pituitary–cortisol hypothesis include thefollowing: cortisol levels are sometimes increased in severe depression, the size of the anterior pituitary and adrenal
cortex is increased, and CRH levels in the cerebrospinal fluid and CRH expression in the limbic brain regions are increased. Hippocampal size and the numbers of neurons and glia are decreased, possibly reflecting reduced neurogenesis due to elevated cortisol levels or due to reduced brain-derived neurotrophic factor.

sants for a wide variety of psychiatric conditions,
including panic disorder, post-traumatic stressdisorder, bulimia, premenstrual syndrome, andobsessive–compulsive disorder. CRH-receptor antagonists show antidepressant activity in animalmodels,57 but the results of large clinical trials
have been disappointing. A compound that blocks
the glucocorticoid receptor has been reported ton engl j med 358;1

be efficacious in depression, but only the most
severe and psychotic type.58
A single test for the cortisol level in blood does
not contribute to the diagnosis of depression, sincelevels of cortisol vary markedly in a circadianrhythm38 and because the overlap between values
in patients and those in controls is considerable.
Mild stress induced in the laboratory, such as

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61

n engl j med 358;1

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Neurosteroids (neuroactive steroids in the brain that modulate neurotransmitter receptors) mostly affect memory and sleep

DHEA has antidepressant effects in patients with depression108

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Most studies are correlative116

Cytokines affect the hypothalamic–pituitary–adrenal axis and monoamines115

Antidepressants have antiinflammatory effects115

Substance P antagonists are not therapeutic in depression

Exposure to cytokines induces depressive symptoms, and cytokine secretion Cytokine-induced depressive symptoms are temporary and not replicated in
is increased in major depression115
all studies117

Many antidepressants are not anticholinergic

Depression is common in infectious and autoimmune diseases115

Mecamylamine, a nicotinic acetylcholine receptor antagonist, reduced symptoms of depression113

Nicotinic acetylcholine receptor antagonists potentiate antidepressants114

Monoamine–acetylcholine Depressed mood can be induced in humans by administration of physostigimbalancemine, an acetylcholinesterase inhibitor112

Capacity for cortical µ-opioid–receptor binding is decreased in response tosustained sadness111

Although early reports suggested that opiates may be effective in treating depression,110 data from large, controlled, randomized trials are lacking

The findings in schizophrenia are similar107

Cholesterol levels are low in plasma and the brain during depression106

Rodents active during the day become depressed when daylight is shortened105

Some patients with depression have circadian abnormalities of mood, sleep,
temperature, and neuroendocrine secretion104

Sleep deprivation and light therapy have antidepressant effects101,102

The association between clock-related genes and depression is inconsistent103

GABA neurotransmission may be related to symptoms of anxiety indepression

Antidepressants affect GABAergic function98

GABA neuron immunoreactivity is reduced in the prefrontal cortex

There is a lack of difference in prefrontal cortex GABA levels on MRS in depression99

GABA-modulating agents have effects in animal models of depression98

100

GABA occurs in more than 30% of brain synapses, suggesting nonspecificity

It is not clear whether antidepressants affect AMPA receptors in the brain97

Cortical messenger RNA levels of glutamate transporters and of the enzymethat converts glutamate to glutamine are reduced96

Levels of GABA in plasma, cerebrospinal fluid, the dorsolateral prefrontal
cortex, and the occipital cortex are reduced91-93

Ketamine binds to high-affinity-state D2 dopamine receptors95

Intravenous ketamine, an NMDA antagonist, induces rapid, sustained antidepressant effect 94

Contradictory Evidence
Glutamate levels in the occipital cortex are increased92,93

Supporting Evidence

Glutamate and glutamine levels in the prefrontal cortex are reduced91

Impaired endogenous opi- δ-Opioid–receptor agonists have antidepressant-like effects in rodents andoid function
up-regulate levels of BDNF in the brain109

Deficient neurosteroid
synthesis

Reduced GABAergic
neurotransmission

Altered glutamatergic
neurotransmission

Abnormal circadianrhythms

62

TheoryTable 2. Additional Biologic Theories of the Pathophysiology of Depression.*T h e n e w e ng l a n d j o u r na l o f m e dic i n e

* AMPA denotes alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, BDNF brain-derived neurotrophic factor, DHEA dehydroepiandrosterone, GABA γ-aminobutyric acid, MRS magnetic resonancespectroscopy, and NMDA N-methyl-D-aspartic acid.

Circuit dynamics in the hippocampus are altered in a rat model of depression127

Inconsistent findings with respect to blood flow, volumetric, glucose utilization, and postmortem methodologies63,124,126
Glucose use is reduced in the prefrontal cortex124 and subgenual prefrontal
cortex125

Hypothyroidism is not manifested in most patients with depression
Brain neurogenesis is decreased after the administration of thyroxine inadult rats with hypothyroidism120

Transcranial magnetic stimulation of the prefrontal cortex122 and deep-brain Implicated brain areas differ from study to study
stimulation of the anterior cingulate affect mood123

Thyroxine monotherapy is ineffective
Thyroid hormones modulate the serotonergic system in the brain119

Rate of response to triiodothyronine is increased during depression121

Dysfunction of specificbrain structures andcircuits

Thyroxine abnormalities

Levels of transthyretin are reduced in the cerebrospinal fluid in patients withdepression118

mechanisms of diseasen engl j med 358;1stress associated with mental arithmetic calculations or simulated public speaking, results ingreater changes in plasma cortisol levels thanmost reported differences between the values inpatients with depression and those in controls.38
It is possible that chronic mild elevations of cortisol, especially at night, when cortisol levels innormal subjects are very low, have a pathogenicrole in depression. It is also possible that peripheral cortisol elevations are only a reflection ofcentral disturbances in CRH signaling, which mediate the effects of environmental stress on mood.59
A major liability of the hypothalamic–pituitary–adrenal axis theory of depression is the difficultyof defining the relationship of stress to depression. Some patients have a single lifetime depressive episode, whereas a larger proportion have arecurrent or even chronic course. Various typesof acute stress, early childhood trauma, or longterm psychosocial problems may be involved andmay lead to different responses of the stress system. Stress may be causative in some cases andsecondary to depressed mood in others.
Severe stress in rodents does not necessarily
model the common stresses of childhood. The
association of abuse in childhood with psychopathologic disorders, including depression, in
adulthood could be due to common factors linking family perpetrators of abuse and their victims,
including not only shared genes but also a sharedenvironment of poverty, poor nutrition, and poorprenatal care. Depression is not uncommon inpeople with no psychosocial risk factors. Most
patients treated for depression have no evidenceof hypothalamic–pituitary–adrenal dysfunction,
just as most such patients have no direct evidenceof brain monoamine deficiency.
The classic teaching is that neurons do not divide in the adult mammalian brain, but studies
have shown that neurogenesis occurs in several
areas of the brain, especially the hippocampus.
Neurogenesis is more prominent in rodents thanin primates,60 and some have questioned whether
it occurs in the human cortex.61 Elevated levels of
glucocorticoids can reduce neurogenesis, and thishas been suggested as a mechanism for the decreased size of the hippocampus on magnetic
resonance images of the brain in many patientswith depression.62 In postmortem studies of patients with depression, cell loss in the subgenual
prefrontal cortex, atrophy in the dorsolateral prefrontal cortex and the orbitofrontal cortex, andwww.nejm.org

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63

T h e n e w e ng l a n d j o u r na l o f m e dic i n eincreased numbers of cells in the hypothalamus
and the dorsal raphe nucleus have been reported.63
These effects resemble the atrophic changes in thebrain in patients with Cushing’s disease64 and inrodents treated with glucocorticoids.65 However,cortisol elevations in depression are much lower
than in Cushing’s disease.
Restraint in a small container induces stress inrodents, suppressing neurogenesis, and this effectis countered by antidepressant treatment.66 Antidepressants also enhance neurogenesis in nonhuman primates.67 Santarelli et al.68 irradiated the
hippocampus in mice and abolished neurogenesis. They found that the radiation also abolished
the ability of the animals to respond behaviorally
to antidepressant treatment in the forced swim
test, but this phenomenon does not occur in every
mouse strain studied.69 Henn and Vollmayr summarized other studies providing evidence that decreased neurogenesis is a result of stress andanxiety but may not be behaviorally relevant.70 The
relevance of animal models of neurogenesis toclinical studies of depression has been questionedby analogy with studies of neuroprotection strategies in stroke, for which numerous findings inanimal models have not been replicated in human studies.71
Brain-derived neurotrophic factor (BDNF),
a neurotrophic peptide, is critical for axonal
growth, neuronal survival, and synaptic plasticity,72 and its levels are affected by stress73 andcortisol.74 A postmortem study of patients withdepression who had committed suicide showedthat BDNF was reduced in the hippocampus.75
Antidepressant drugs and electroconvulsive therapy up-regulate BDNF and other neurotrophic andgrowth factors75,76; a single bilateral infusion of
BDNF into the dentate gyrus has antidepressantlike effects.77 One study showed that the hippocampus was smaller than normal in patients withdepression who carried a met166 BDNF allele.78
In an animal model of depression, epigenetic histone methylation mediated down-regulation of
BDNF transcripts and antidepressant treatment
reversed this effect.79 These studies suggest that
BDNF is the link among stress, neurogenesis, andhippocampal atrophy in depression. However,a genetic association of the BDNF val166met polymorphism with depression has not been replicatedin most studies,74 and BDNF may be related not
only to depression but to multiple psychiatric disorders.74 BDNF-knockout mice have behaviors un64

n engl j med 358;1

related to depression.45 Reduced BDNF levels in
the peripheral blood of patients with depression
seem to derive almost entirely from blood platelets,80 and many artifacts must therefore be considered in interpreting these findings. Inflammation in the brain and some neurotoxins increase
brain BDNF levels, suggesting that the actions of
BDNF are not uniformly therapeutic.81 Castrén82
has proposed that antidepressant treatments may
increase synaptic sprouting and allow the brain
to use input from the environment more effectively to recover from depression. This hypothesis highlights the role that cognition may play indepression and suggests that biochemical mechanisms may be nonspecific.
Strong epidemiologic data point to an association between major depressive disorder and increased cardiovascular morbidity and mortality.83
In many patients, cardiovascular disorders precede
depression, and in others, depression precedes the
cardiovascular disorder. Both n−3 fatty acid deficiency84 and elevated plasma homocysteine levels85
have been implicated in cardiovascular disease andin depression. Elevated cortisol levels in depression could increase the risk of coronary arterydisease, since cortisol increases visceral fat.64,86
Antidepressant treatment increases the survival
rate among patients who become depressed after
coronary occlusion.86 Endothelial-cell signaling
plays a crucial role in brain neurogenesis,87 andthese cells secrete BDNF; thus, both depression
and cardiovascular disease could be examples ofan endothelial disorder. Signs of inflammatory
processes have been described in major depression88 and in cardiovascular disease. Some datasuggest that exercise has protective or therapeutic effects in depression.89 Rodent models support
this possibility.90

O ther P os sibl e Mech a nisms
Table 2 summarizes possible pathophysiologicalmechanisms of depression other than those basedon the monoamine-deficiency hypothesis or theroles of stress, cortisol, and neurogenesis. Manyof these other proposed mechanisms have also
been implicated in psychiatric and neurologic disorders other than depression. Since the components of the brain are highly interconnected, it is
not difficult to find possible integrative frameworks between two or more of the various theories. Testing the theories in a manner that can re-

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mechanisms of disease

ject the null hypothesis has been more difficult.
Research in depression has sometimes been sequentially imitative of dominant ideas in related
fields, such as neurogenesis, glutamate neurotransmission, and nicotinic receptors, instead of progressing on its own path.

Sum m a r y
It would be appealing to attempt to categorize depression in terms of monoamine-depletion forms
that are perhaps related to genes coding for enzymes involved in neurotransmission and cortisolrelated forms that are characterized by a more
long-term course, hippocampal atrophy, and a history of psychosocial stress. However, the clinicaldata do not fall into such neat categories, sincemonoamine-based antidepressants are most effective in patients with severe depression when cortisol levels remain high after the administrationof dexamethasone.
Major depressive disorder is likely to have anumber of causes. Middle-aged or elderly patients
presenting with depression may have a disorderrelated to cardiovascular disease and originating
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REVIEW

Open Access

Depression research: where are we now?
Saebom Lee, Jaehoon Jeong, Yongdo Kwak, Sang Ki Park*
Abstract
Extensive studies have led to a variety of hypotheses for the molecular basis of depression and related mood disorders, but a definite pathogenic mechanism has yet to be defined. The monoamine hypothesis, in conjunction withthe efficacy of antidepressants targeting monoamine systems, has long been the central topic of depression
research. While it is widely embraced that the initiation of antidepressant efficacy may involve acute changes inmonoamine systems, apparently, the focus of current research is moving toward molecular mechanisms that
underlie long-lasting downstream changes in the brain after chronic antidepressant treatment, thereby reaching fora detailed view of the pathophysiology of depression and related mood disorders. In this minireview, we briefly
summarize major themes in current approaches to understanding mood disorders focusing on molecular views ofdepression and antidepressant action.
Introduction
Mood disorders such as major depression and bipolar
disorders are the most common psychiatric disorders inmodern society. About 16% and 1% of the population
are estimated to be affected by major depression andbipolar disorder one or more times during their life
time, respectively [1]. The presence of the common
symptoms of these disorders are collectively called‘depressive syndrome’ and includes a long-lasting
depressed mood, feelings of guilt, anxiety, and recurrent
thoughts of death and suicide [2]. The genetic contribution to the manifestation of depression has been estimated as 40-50% [3]. However, combinations ofmultiple genetic factors may be involved in the development of depression, because a defect in a single geneusually fails to induce the expression of multifaceted
symptoms of depression [4]. Also, various non-genetic
factors such as stress, affective trauma, viral infection,and neurodevelopmental abnormalities increase thecomplexity of the pathogenesis of the disease. Thus,
extensive studies have led to a variety of hypotheses forthe molecular mechanism of depression, but a definite
pathogenic mechanism has yet to be defined.
The ‘monoamine hypothesis,’ which suggests a deficiency or imbalances in the monoamine neurotransmitters, such as serotonin, dopamine and norepinephrine,as the cause of depression has been the central topic of* Correspondence: skpark@postech.ac.kr
Department of Life Science, Division of Molecular and Life Science, Pohang
University of Science and Technology, Pohang, Republic of Korea

depression research for approximately the last 50 years.
This hypothesis has been initiated and supported by thefact that early versions of antidepressants including tricyclics and monoamine oxidase inhibitors have the common effect of acutely enhancing monoamine function[5-7]. Recent development of the selective serotonin
reuptake inhibitors (SSRIs) as effective antidepressantshas further strengthened the hypothesis [6,8]. However,unresolved complexity of the current antidepressantsremains. First, antidepressants are effective in less than
50% of patients, and recently discovered drugs havefailed to enlarge the extent of applicable patients [2].
Second, chronic treatment with antidepressants isrequired for clinical effects, and the reason for this is
unknown [9]. Third, depression medications as well asmood stabilizers show a wide spectrum of undesiredside effects.
In particular, because clinical effects of antidepressantsthat acutely modify monoamine systems are significantly
delayed, it is now believed that an adaptation of downstream events, including lasting changes in gene expression by chronic treatment, underlie the antidepressantefficacy [10]. This phenomenon suggests that there is
probably not a simple relationship between biogenic
amines and depression postulated by classical monoamine hypothesis. The complexity may be due to multiple factors, which is likely because depression is a groupof disorders with several underlying pathologies. Also,
expression of depression symptoms may require disturbances in certain neurotransmitter systems that are© 2010 Lee et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.

Lee et al. Molecular Brain 2010, 3:8
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functionally interconnected to each other at multiple
levels. Taken together, while it still has to be emphasized that the initiation of antidepressant efficacy may
be mediated by acute changes in monoamine systems,
apparently, the focus of current research is moving
toward molecular mechanisms that underlie long-lasting
downstream changes in the brain after chronic antidepressant treatment, thereby reaching for a detailed viewto the pathophysiology of depression and related mooddisorders. In this minireview, we summarize major
themes in current approaches to understanding depression and related mood disorders.
Gene-environment interactions

As a way to discovering genes predisposing to depression, geneticists have long been searching for gene variants that play a role in the response to life stresses, acritical environmental factor for the onset of depression,
which would be an example of ‘gene-environment interaction’: whereby an environmental factor is filteredthrough the activity of a gene to confer differential susceptibility to depression among individuals. To this end,
polymorphisms in the serotonin transporter (5-hydroxyltryptamine transporter, 5-HTT) gene have been extensively analyzed. It has been reported that the expression
level of 5-HTT from the 5-HTT gene is influenced bypolymorphisms in the 5’-flanking region (5-HTT genelinked polymorphic region, 5-HTTLPR) and in the variable number tandem repeat (VNTR) of the second
intron [11,12]. In particular, a short variant of 5HTTLPR appears to be associated with repressed transcriptional activity of the promoter, decreased 5-HTT
expression, and decreased 5-HT uptake when comparedwith a long variant of 5-HTTLPR [13]. Significantly,
genetic studies have shown that these polymorphisms
are associated with major depressive disorder in human[14]. Moreover, a longitudinal study with 847 New Zealanders has shown that a short allele of 5-HTTLPR variants is associated with an increase in susceptibility todepression in response to life stresses such as job losses
or divorces [15]. Strikingly, in this study, the polymorphism is influential only when the subjects are insignificant life stresses, suggesting that 5-HTT may be aconnecting point between individual’s genetic makeup
and environmental triggers of depression. These observations were further strengthened by study showing that
increased depression scores in maltreated children without social supports are associated the short allele of
5HTTLPR [16].
However, the insight from these studies does notappear to be fully supported by other studies. The association of allelic variation in VNTR of 5-HTT gene withthe susceptibility to depression was not consistently
detected in some analyses [17,18]. A meta-analysis

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showed that polymorphisms in 5-HTTLPR and the second intron are actually found in depressed patients but
the strength of association does not reach a statisticalsignificance [19]. An extensive study using 1206 twins
also failed to find a main effect of 5-HTTLPR, or aninteraction between the 5-HTTLPR genotype and stressful life events on major depression [20]. Moreover, a
recent meta-analysis using 14 comparable studies has
yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is
associated with an elevated risk of depression [21]. The
mixed results from these studies reveal the potential
weakness of the ‘candidate gene’ approach focusing on a
specific gene variant to elucidate gene-environment
interactions, and thus add importance on unbiased
whole-genome scan approach, especially when a disease
with polygenic nature, such as depression and relatedmood disorders, is concerned.
Stress response circuits

Chronic stress is an important component in depression
even though it does not seem to function as a necessaryor sufficient factor. From this point of view, thehypothalamic-pituitary-adrenal (HPA) axis, a core neuroendocrine circuit for managing stress in the body, hasbeen a topic of interest in depression research [22]. Corticotrophin-releasing factor (CRF) secreted from theparaventricular nucleus of the hypothalamus enhances
secretion of adrenocorticotrophin (ACTH) from thepituitary [22,23], and subsequently, glucocorticoid issecreted from the adrenal cortex, impacting neurobehavioral functions of various brain regions [2]. The HPA
axis forms a feedback loop via certain brain regions
such as the hippocampus and amygdala [24]. It wasreported that hypercortisolemia, a persistent upregulation of blood glucocorticoid levels, increases the excitotoxicity of CA3 pyramidal neurons in the hippocampus,
resulting in dendritic atrophy, reduction in spinogenesis,
apoptosis of neurons, and possibly inhibition of adultneurogenesis [25]. These functional abnormalities ofhippocampal neurons caused by chronic stress can
reduce the inhibitory tone on the HPA-axis, which
results in hyperactivity of the HPA-axis [23]. Notably,
hyperactivity of HPA-axis is evident in approximately
half of depressed patients and chronic treatment withantidepressants often reverses this phenomenon [23,26].
Furthermore, evidence from animal studies suggests thatchronic treatment with antidepressants appears to contribute to the recovery of the abnormal function of the
hippocampus by increasing neurogenesis [27,28].
In this regard, one research direction is to evaluate thetherapeutic potentials of weakening of the functions of
the HPA axis. The obvious targets are CRF receptors
expressed in the pituitary and glucocorticoid receptors

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expressed in the hippocampus and other brain regions,because those receptors are core components in the
HPA axis and the associated feedback loop [24,29-32].
In a similar context, vasopressin receptors have also
emerged as alternative targets [33,34]. Vasopressin is aneuropeptide that enhances CRF function and works
through vasopressin receptors expressed in the amygdala
and other parts of the limbic system. Also, a single
nucleotide polymorphism (SNP) of vasopressin 1b (V1b)receptor has protective effects against major depressive
disorder [35]. Intriguingly, antagonism of CRF receptors,
glucocorticoid receptors, and vasopressin receptors
appear to exhibit antidepressant effects in experimental
animals. The applicability to human patients remains to
be further refined.
Neurotrophic factors

Long-term stress appears to reduce the expression levelof brain derived neurotrophic factor (BDNF) in the
hippocampus [36]. Also, in a post-mortem study ofdepressed patients, a reduction in BDNF expression wasreported [37]. In addition, polymorphisms of BDNF
gene are associated with neuroticism, a personality trait
linked to increased susceptibility to depression [38].
A family-based association study showed that polymorphisms in BDNF genes are related to bipolar disorders [39]. Conversely, a chronic treatment withantidepressants not only enhances the BDNF level but
also increases the stress resistance in animals [40,41].
These observations provided a basis for ‘neurotrophism
theory’ stating that depression is caused by a deficit inneurotrophic factors, and antidepressants neutralize thisdeficit. This theory may be intimately related to neuronal damages in the hippocampal region caused byhyperactivity of stress response circuits aforementioned.
Because BDNF is known to enhance synaptic plasticity
in various brain regions [42,43], it is reasonable to postulate that improving BDNF function may be beneficial
to the hippocampal neurons that are susceptible tostress-induced damages. Supporting this idea, direct
injection of BDNF into the hippocampus of experimental animals induces behavioral changes similar to antidepressant treatment [41]. Thus, BDNF and its receptor
TrkB, have become promising targets of novel-type antidepression therapies.
Despite these observations, a possible causative relationship between BDNF function and the pathogenesisof depression or antidepressant efficacy requires further
clarification. For example, while the antidepressant efficacy is suppressed in experiments using inducible BDNF
knock-out mice, depression-related behaviors are only
seen in females, showing significant gender differences[36]. Moreover, forebrain-specific conditional TrkB
receptor knockout mice do not exhibit depression-

Page 3 of 10

related behaviors such as increased behavioral despair in
the forced swim test [44], whereas it has been demonstrated that activation of TrkB receptor is required for
antidepressant-induced behavioral effects [45]. Thus, therelationship between the loss of BDNF activity and theexpression of depressive symptoms is not in a simple
correlation. Nevertheless, the potential value of the neurotrophic theory as a basis for the design of new formof anti-depression therapies cannot be excluded by thecomplexity of the current experimental results.
Histone modifications

One poorly understood characteristic of antidepressantsis the long delay before the onset of positive effects inpatients [10]. This phenomenon is often attributed tothe slow development of adaptation in the relevant neurons that underlies the beneficial effect of the drugs.
The identity of the adaptation is not clear yet, but
enduring changes in the state of chromatin are thought
to be involved. Chronic electro-convulsive shocks thatare effective for some depressed patients also inducechanges in wide range of the histone modification patterns in experimental animals [46]. One locus with prominent changes is BDNF, and in conjunction with thesuggestion of BDNF as a potential target for design of
new antidepressants, the epigenetic control of BDNF
expression has been extensively analyzed in the context
of the expression of depression and chronic antidepressant treatments. In the rat hippocampus, chronic electro-convulsive shocks increase acetylated histone H3 atthe BDNF promoters 3 and 4, and these modifications
appear to be correlated with increased expression of
BDNF and CREB [46]. This upregulation has been
linked to the effects of antidepressants in animal studies[28,47]. Moreover, chronic defeat stress, an experimental
model for depression, elicits selective downregulation ofsome BDNF splice variants, in the hippocampus [28].
This downregulation appears to be due to induction of
H3-K27 dimethylation, a histone code for transcriptional
repression [28,48]. Conversely, an antidepressant treatment reverses repression of BDNF expression likely by
inducing H3 acetylation and H3-K4 methylation, acting
as histone codes for transcriptional activation, at the
BDNF promoter region [49]. During this whole process,roles for histone deacetylases (HDACs) seem to be crucial because chronic antidepressant treatment downregulates HDAC5, and overexpression of HDAC5 in the
hippocampus prevents its antidepressant effect [28].
HDAC inhibitors have thus received attention for theirpotentials as promising therapeutics for depression andrelated mood disorders. HDAC inhibitors are membersof four families: the short chain fatty acids (e.g. sodium
butyrate (SB), phenylbutyrate, and valproic acid (VPA)),the hyroxamic acids (e.g. TSA and suberoylanilideLee et al. Molecular Brain 2010, 3:8
http://www.molecularbrain.com/content/3/1/8

hydroxamic acid (SAHA)), the epoxyketones (e.g. trapoxin), and the benzamides. One of the most widelyused mood stabilizers is VPA. As VPA is known to havean inhibitory activity on HDAC1 and presumably other
HDACs [50], it has been proposed that its mood stabilizing efficacy may be mediated at least in part by histone modifications. Another study showed that HDAC
inhibitors such as VPA, SB, and TSA increase BDNF
expression in the brain [51]. Thus, epigenetic mechanisms, especially histone modification, seem to have thepotential to provide new mechanistic insights into theexpression of depression and novel treatments fordepression and related mood disorders.
Adult hippocampal neurogenesis

Brain imaging studies showing reduced hippocampal
volume in depressed patients have provided a platform
for investigating adult neurogenesis in the context of thepathogenesis of depression [52]. The hypothesis statesthat chronic stresses and other depression-inducing stimuli decrease neurogenesis [53-55], whereas antidepressant efficacy may rely on an increase in neurogenesis[54-56]. Adult neurogenesis is restricted to the subventricular zone and subgranular zone of the hippocampus[57], and this emphasizes the potential importance ofhippocampal neurogenesis during the onset as well as
during the treatment of depression. Supporting thisidea, various animal models of depression, such aslearned helplessness, chronic mild stress, and psychosocial stress, are associated with reductions in hippocampal neurogenesis [58-60]. Conversely, chronic
antidepressant treatment not only increases neurogenesis but also supports survival of newborn neurons [61].
It has also been shown that the antidepressant efficacyof tricyclics, imipramine, and SSRIs requires hippocampal neurogenesis in rodents [58,62,63]. Furthermore,chronic fluoxetine treatment appears to increase thenumber of synapses in the pyramidal cell layers andblock the decrease in spine density in the dentate gyrus
and other hippocampal cell layers [64]. Notably,enriched environments, which is known to enhance hippocampal neurogenesis [65], decrease depression-related
behaviors in rodents [66,67].
The expression level of BDNF deserves attention when
examining the molecular mechanisms underlying theantidepressant-mediated increase in neurogenesis. As
described above, in various animal models of depression,
the BDNF level is decreased [40], whereas chronic antidepressant medication and electro-convulsive shocks
increase the levels in the hippocampus [28,46]. A recent
study showed that CREB, a transcription factor that regulates expression of CRE-containing target genes including BDNF, is also upregulated and activated in
hippocampus by chronic antidepressant treatment

Page 4 of 10[2,53,68,69]. However, the cause and effect relationshipamong the induction of CREB and BDNF, the neurogenesis, and behavioral effects of antidepressants remains to
be further investigated.
Recent studies demonstrated that long-term administration of mood stabilizers such as lithium, valproic
acid, and carbamazepine also enhances adult hippocampal neurogenesis [70-72]. Lithium directly inhibits glycogen synthase kinase-3 (GSK-3) and inositol signaling[73]. VPA enhances gene expression likely by inhibiting
HDACs, indirectly blocks GSK-3 activity, and suppresses
inositol signaling [71,74-76]. Although it remains
unclear whether the GSK-3 and inositol signaling are
actually linked with clinical effects of mood stabilizers,
the data suggest a common molecular pathway constituting the pathophysiology of depression and relatedmood disorders that converges on adult hippocampal
neurogenesis.
Substance withdrawal

Various drugs such as alcohol, psychostimulants, opiates
and N-methyl-D-aspartate (NMDA) receptor antagonists
generate a physiological response called withdrawal
symptoms during abstinence in humans and experimental animals [77-80]. The characteristics of affective
symptoms caused by drug withdrawal and major depressive disorder are strikingly similar [80]. Depressed moodand anhedonia are commonly present with both drug
abstinence and depressive disorders [81]. Hyperphagia,
hypersomnia, feelings of fatigue, and suicidal ideation
are also observed in both conditions [82,83]. Disruptionsof the HPA axis are also seen during drug withdrawal,
and are accompanied by increased levels of cortisol andelevated cerebrospinal levels of CRF [84]. In addition,
elevated levels of cortisol, ACTH and b-endorphin during early cocaine withdrawal resemble those indepressed patients [85]. Brain-imaging studies using
positron emission tomography (PET) and functional
magnetic resonance imaging (fMRI) have revealed thatmethamphetamine withdrawal induces decreased glucose metabolism in the anterior cingulate cortex andinsula, and increased metabolic activity in the amygdala
and orbitofrontal cortex, all of which are frequently
observed in clinical depression [86].
Much evidence shows that depression and relatedmood disorders are accompanied by abnormalities in
dopaminergic transmission in the nucleus accumbens(NAc) and ventral tegmental area (VTA), regions thatare core parts of the brain reward circuit [87]. It is wellestablished that depressed patients have difficulties inthe expression of pleasure and acquisition of motivation,
which are mainly governed by a normal NAc-VTA
dopamine circuit [88]. Consistently, it has been shownthat a deregulation of dopamine D2 receptor signaling

Lee et al. Molecular Brain 2010, 3:8
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results in depression-like behaviors in experimental animals [89], and that neuronal nitric oxide synthase(nNOS) knockout mice with altered dopamine D1
receptor signaling exhibit decreased depression-related
behaviors [90]. Because nearly all drugs of abuse directly
or indirectly activate monoaminergic neurotransmission
in the limbic system, resulting in reward sensations[91,92], it has been postulated that counter-adaptations
may occur in opposition to the reward effects withchronic drug intake, generating cognitive, motivational,
and affective impairments, including depression-like
symptoms during the drug withdrawal period [93].
As described above, in many ways, depressive moodsubsequent to drug withdrawal shares common characteristics, such as neuro-hormonal changes, regional
brain activity, and pharmacological responses, with clinical depression. However, it needs to be emphasized thatthe onset, course, duration, and other factors such as
involvement of substances diagnostically distinguishes
substance-induced mood disorders from major depressive disorders [94,95]. Some experimental data also hint
at differences between these conditions at the molecularlevel, demanding cautions when interpreting the related
observations. For example, dopamine transporter densities are increased in the striatum in both cases [96], but
serotonin transporter densities are elevated in the brainstem during the early stage of cocaine abstinence [97],but not in clinical depression [98]. Also, some abstinent
drug addicts have been treated with antidepressantdrugs to reduce drug craving, but the positive effect ofthese drugs needs further validation [99]. Nonetheless,insights from these views not only tell us that brain
reward circuits composed of the mesolimbic system arepotentially important in understanding depression, butalso provide a useful behavioral readout for depressive
mood in experimental animals.
Circadian rhythms

Circadian rhythm is a roughly 24-hour cycle of biochemical, physiological, and behavioral processes undercontrol of internal clock [100-102]. From the clinicalpoint of view, a potential link between circadianrhythms and depression or related mood disorders haslong been postulated. For example, it is relatively wellknown that insufficient length of light phase to entrain
the circadian rhythm can be causative for the development of seasonal affective disorders [103,104]. Also,
abnormal regulation of sleep/wake cycles, body temperature, blood pressure, and various endocrine functions
under the control of circadian clock are prominent
symptoms of mood disorders [102,105-110]. However,molecular mechanisms underlying the link are still largely unknown.

Page 5 of 10

Recently, interesting observations have been made in
the mutant mouse that has a deletion of 19th exon of
Clock gene, a core component of molecular clock. The
mouse exhibits hyperactive VTA dopaminergic neurons
and behavioral phenotypes that are reminiscence ofmania seen in bipolar disorder patients [111,112]. Moreover, lithium, a mood stabilizer for bipolar depression
patients, effectively inhibits GSK3b, a core regulatorycomponent in the molecular clock. Lithium also has aneffect on the nuclear entry of Period-Cryptochrome heterodimers, a key process to form a negative loop in themolecular clock, likely through an inhibition of GSK3b
activity. Furthermore, lithium appears to regulate activity of Rev-erb a that links the negative loop to the positive loop in the biological clock [113-116].
Potential links between circadian rhythm and themonoamine system are also reported. The synthesis
and/or secretion of monoamine neurotransmitters andthe function of their receptors are under influence of
circadian rhythms. The circadian rhythmicity of dopamine transporter and tyrosine hydroxylase expression in
dopaminergic neurons is also disrupted when the suprachiasmatic nucleus of the hypothalamus, the central partof endogenous clock, is damaged [117]. Moreover,monoamine oxidase-A (MAO-A) expression is regulatedby dimer formation of Clock and Bmal1, and MAO-A
activity accordingly shows a circadian rhythmicity [118].
Conversely, the expression of circadian genes such as
Clock, Per1, and Bmal1 is stimulated when dopamine
D1 receptor is activated, and suppressed when dopamine D2 receptor is activated in the limbic area [119].
Collectively, the molecular clock appears to be tightlyinterconnected with monoamine systems, which might
explain symptomatic correlation between circadianrhythm and depression at the molecular level.
Although the relationship among the daily variationsof mood, endogenous molecular clock, and the expression of depressive symptoms is complicated, normalization of the biological rhythms of a depressive individual
could have a beneficial effect. In this regard, the recent
development of agomelatine as an antidepressant is ofgreat interest. Agomelatine is a potent agonist for melatonin receptors and has capacity to reset the internal
circadian clock [120,121]. Intriguingly, it also exhibits
antagonistic activity on 5-HT2C receptor, thereby indirectly enhancing the dopamine and norepinephrine neurotransmission [122-124]. Moreover, agomelatine affects
differentially various stages of neurogenesis in the dorsal
and ventral hippocampus [125]. Further understandingof the molecular basis of agomelatine action and its efficacy may provide interesting insight into the interface
between circadian rhythm and pathophysiology ofdepression.

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Page 6 of 10

Figure 1 Approaches to the development of antidepressants targeting non-monoaminergic components. Chronic stress can cause
hypercortisolemia which results in neuronal damages in the hippocampus, thereby weakening the feedback inhibition on HPA axis. Chronic
stress also can inhibit the expression of neurotrophic factors through epigenetic mechanisms. On the other hand, chronic treatment of
antidepressants and mood stabilizers can establish epigenomic environments that favor the expression of anti-depression genes. The targets may
include genes for neurotrophic factors which prevent neuronal damages and enhance hippocampal neurogenesis. Some of approaches to thedevelopment of antidepressants targeting non-monoaminergic components are also shown.

Functional anatomy

Information on brain regions and neural circuitry
responsible for the expression and progression of a disease is an important platform to better diagnose the disease and to properly interpret the observations obtained
from molecular, cellular, and tissue experiments in theclinically relevant context. While various brain regions
are known to be involved in regulation of mood or emotion, definite information on central neural circuits
responsible for mood disorders is still incomplete,
mainly because anatomical lesions in patients have beenless consistently found relative to other various neurological disorders such as some neurodegenerative diseases.
However, there are neuropathological and neuroradiological studies that have established interesting associations
between mood disorders and structural abnormalities inthe brain. For example, glial reduction was observed inanterior cingulate gyrus and neuronal abnormalities weredetected in the dorsolateral prefrontal cortex in postmortem neuropathological studies of mood disorderpatients [126,127]. Radiological studies using MRI also
revealed reduced volumes of orbitofrontal and subgenual

anterior cingulate cortex [128-130], electrical stimulation of which correlatively elicits an antidepressanteffect [131]. Most notably, reductions in hippocampal
volume in depressed elderly patients were reported[132,133].
Recent brain imaging studies mainly using fMRI are
adding information on brain regions that play importantroles in depressive symptoms at the functional level[134]. Functional changes in brain regions such as prefrontal/cingulate cortex, hippocampus, striatum, amygdala, and thalamus are correlated with depression [52].
The neocortex and hippocampus also appear to play critical roles in the symptoms related to the cognitive deficits that are prevalent in depressed patients [55], andthe nucleus accumbens and amygdala seem to be coreregions for anhedonia and emotional memory-related
symptoms [135,136]. The functional changes in the
hypothalamus are also linked to sleep- and appetiteassociated symptoms [137]. Research on these topics isnow being accelerated by fast advances in brain imaging
technologies, and the outcome, in combination with theinformation from the conventional anatomical studies, isLee et al. Molecular Brain 2010, 3:8
http://www.molecularbrain.com/content/3/1/8

driving the generation of a higher-resolution picture of
the neural circuitry relevant to depression.

Conclusion
A prerequisite for effective control of depression andrelated mood disorders is to understand their detailed
molecular pathways. Although the classical stress modelof depression and current understanding of antidepressant action appears to be partially linked via epigenetic
mechanisms and hippocampal neurogenesis (Figure 1),
obviously, the current picture of the pathophysiology ofdepression is largely incomplete, and thus many potential hypotheses are being generated and tested, forming
fragmented neurobiological views of depression andrelated mood disorders. One major task in the fieldmust be to integrate the relevant hypotheses to formulate a bigger picture of the pathophysiology of depression and related disorders. A key step may be to define
the high-resolution neural circuitry of depression, which
will provide a platform to better interpret the observations obtained from molecular, cellular, and tissue
experiments at the organism level. Another critical step
will be to identify ‘depression genes’ that are causativefor depression. This will help us generate genetic animalmodels that may not only be critical for clarifying many
issues in depression research using experimental animals, but may also be useful for assessing the potential
efficacy of candidate antidepressants. Finally, the mostchallenging task in the field is to overcome the limitations of current therapies, which are only effective in a
fraction of patients. It has long been expected that novel
antidepressants targeting non-monoamine systems
would enlarge the extent of treatable patients (Figure 1),
but the progress still falls short of expectations, thereby
leaving it as a pressing task in the field.
Acknowledgements
This work was supported by a grant (2009K001271) from Brain ResearchCenter of the 21st Century Frontier Research Program and by grants, 3312007-1-C00213, 3-200900000001605, and 20090076351, funded by the
Ministry of Education, Science, and Technology, the Republic of Korea.

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7.

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19.
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Authors’ contributions
SL, JJ, and YK collected information and participated in drafting themanuscript. SKP wrote the manuscript and coordinated the drafting process.
All authors read and approved the final form of the manuscript.

21.

Competing interests
The authors declare that they have no competing interests.

22.

Received: 22 January 2010 Accepted: 10 March 2010
Published: 10 March 2010
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doi:10.1186/1756-6606-3-8
Cite this article as: Lee et al.: Depression research: where are we now?.
Molecular Brain 2010 3:8.

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MEDICINE

CONTINUING MEDICAL EDUCATION

Treatment of Depressive Disorders
Tom Bschor, Mazda Adli

SUMMARY
Introduction: A confusing variety of options are available
for the treatment of depressive disorders.
Method: Selective literature review under consideration ofcurrent guidelines.
Results: The treatment of depression can be divided into
acute, maintenance and prophylactic phases. The basic
forms of treatment are pharmacotherapy, psychotherapy,
and supportive strategies. The approximately 30 antidepressants currently on the market differ mainly withrespect to their side effect profiles. Of the specific types ofpsychotherapy, cognitive behavioral therapy, psychodynamic therapy, and psychoanalysis are funded by thestatutory health insurance providers in Germany. All
treatment strategies (except for sleep deprivation) showa latency of onset of several weeks and a nonresponse rateof about 30% to 50%. In clinical practice it is essential tofollow a stepwise procedure and to perform a standardized
evaluation of response after the latency period. In theevent of nonresponse, the next step of treatment should beinitiated.
Discussion: Depressive disorders have a good prognosis
provided one takes best advantage of the available treatment
options. Preconditions are continuation of treatment for an
appropriate length of time (for antidepressants ca. 4 to 6
weeks, for psychotherapy ca. 4 to 12 weeks) andstandardized evaluation of response thereafter.
Dtsch Arztebl Int 2008; 105(45): 782–92
DOI: 10.3238/arztebl.2008.0782
Key words: depression, antidepressants, stepwise antidepressant treatment, treatment algorithm, psychotherapy

Jüdisches Krankenhaus, Abteilung für Psychiatrie und Psychotherapie, Berlin:
PD Dr. med. Bschor
Klinik für Psychiatrie und Psychotherapie, Charité – Universitätsmedizin Berlin,
Campus Mitte: Dr. med. Adli

he diagnostic evaluation of depressive disorders
and their classification as mild, moderate, orsevere was presented a short while ago in an earlier issueof Deutsches Ärzteblatt (1). If depression has been correctly diagnosed, numerous effective treatment options
are currently available. The prognosis of a depressive
disorder is good if it is treated appropriately and consistently.

T

The learning aims of this article arec knowing the fundamentals of the treatment ofdepressive disorders (indication, setting, treatment
phases, treatment steps)
c learning the principles of establishment of thephysician-patient relationshipc acquiring basic knowledge about pharmacotherapy
with antidepressantsc acquiring knowledge about treating depression
with different forms of psychotherapy.
This continuing medical education article is based ona selective review of the literature, combined with theauthors' own extensive experience in the ambulatory
and in-hospital treatment of depressed patients. It presents
the current state of the therapy of depressive disorders,with an emphasis on treatments that can be provided bygeneral practitioners and family physicians.
Evidence of a depressive episode requiring treatment,
as opposed to appropriate grief, can include the following:c Duration of the depressive syndrome > 2 weeks
c Persistently depressed affect that cannot be lightenedeven by positive experiencesc A sense of paucity of emotion (the patient does notconsider himself or herself to be sad, but rather
feels "turned to stone" or "dead within")c Typical circadian fluctuations, with a morning low
and improvement toward eveningc Somatic symptoms without any organic cause

Prognosis
Depressive disorders have a favorable prognosis
if the available treatments are applied consistently
and thoroughly.

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c Inappropriate feelings of guilt, or even depressive
delusionsc Suicidality
c Previous episodes of severe depressionc A family history of severe depressive disorders.

The treatment setting
Depression is a very common condition (1). Therefore,
its diagnosis and treatment, at least in uncomplicatedcases, are tasks not just for the psychiatrist, but for thegeneral practitioner and family physician as well.
c The indications for referral to a psychiatrist are– diagnostic uncertainty– psychiatric comorbidity (e.g., addiction, dementia,
personality disorder)– severe depressive manifestations– delusional depression– depression in the setting of a bipolar affective
disorder (bipolar depression)– suicidality– chronified depression– intractability, i.e., nonresponse to one or two treatments that have been carried out appropriately– need for psychotherapy or for an intensity of carethat cannot be delivered in the setting of a family
practice.
c The indications for referral for inpatient psychiatrictreatment are– acute suicidality or other type of self-endangerment (e.g., refusal of food)– severe delusional or other psychotic manifestations– depressive stupor– the inability, because of illness or other causes, toparticipate in outpatient treatment on a regularbasis (e.g., because of a lack of drive)– imminent neglect of oneself because of the lackof an adequately supportive social network– external living conditions that would impair the
success of outpatient treatment, e.g., severefamilial conflicts– lack of response to outpatient treatment.

Phases and objectives of treatment
The treatment of depression is divided into three phases(2, 3). The goal of acute therapy is complete or nearcomplete remission of the depressive manifestations.
Because the speed of response of depressive disorders to

Depression—a common disorder
The recognition and treatment of depression, atleast in cases with an uncomplicated course,
is a task not just for psychiatrists, but for generalpractitioners as well.

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treatment varies, acute therapy may need to be given for
no more than a few weeks or for many months.
After the acute phase, maintenance therapy is given,
with the main goal of preventing an early relapse. Its
duration varies from 6 to 12 months. Maintenance therapy
is indicated during this period because there is a high chanceof relapse regardless of the form of treatment that was used
to induce remission in the acute phase (4). In general, theform of treatment that led to remission is continued
unchanged into the maintenance phase. A further goal of
maintenance therapy is complete functional recovery, i.e.,
the patient's complete return to his or her premorbid levelof function at home, in the workplace, and elsewhere.
Prophylactic therapy is indicated only in patients
whose illness has taken a recurrent course, depending on
the likelihood of recurrence in the individual case. The
latter can best be judged from the number of priordepressive episodes and from the intervals of time
between them. If prophylactic therapy is thought to be
indicated, it should be started without any temporal endpoint in view (4). This review article will mainly deal
with acute therapy.

Principles of treatment
The three main types of treatment for depression arec pharmacotherapy,
c psychotherapy, andc supportive measures.
Because of the considerable rate of spontaneous
remission, particularly in milder cases of depression(untreated episodes last for an average of 6 to 8 months),
the physician and the patient may agree on a two- tofour-week period of "watchful waiting" before anytreatment is given (5).
The initial treatment of mild or moderate depression
should consist of monotherapy, either with a single
medication or with psychotherapy, depending on availability and on the patient's preference. In severe, recurrent,
or chronified depression, as well as for elderly depressed
patients, a primary combination of these two treatment
modalities may be advantageous.

Basic treatment strategy
The foundation of any treatment for depression, including
but not restricted to specific forms of psychotherapy, isconversation with an empathic and understanding physician in the framework of a stable therapeutic alliance.
The patient should sense the physician's acceptance of
his or her worries and fears and should feel relieved as a

The basis of treatment
The treatment of depression is based on conversation with an empathetic and understanding
physician and on a stable therapeutic alliance.

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result of the therapeutic interview, particularly with respect to feelings of guilt and inadequacy. The physician
should inspire optimism by assuring the patient that
depression is treatable and has a good prognosis. To thisend, it often helps to instruct patients with a biologicalmodel of their condition, making it possible for them—
particularly in the acute stage—to understand theirdepressive manifestations as the expression of an illness
and thus as a legitimate, temporary dispensation fromthe duties of everyday life. A biological explanation canoften also take away the inexplicable and threatening
character of depression. Chronically depressed patients,on the other hand, need stepwise activation and promotion of their individual responsibility and initiative.
Over-challenged family members often react withreproaches, trivializations ("everything will be OK soon
enough, it's not really so bad"), or exhortations to "pullyourself together." All of these are unhelpful, yet they
underscore the necessity of educating the patient's family,
too, about depression as a treatable illness and of enlisting them in the effort to bring about recovery. Patientsand their families can be motivated to participate in aself-help or family group (see German Internet addresses
listed at the end of this article). Written patient information can be useful as well (see Internet addresses).
A special danger of depressive disorders is suicidality.
3% to 15% of persons suffering from depression commit
suicide (e1), while 40% to 70% of suicide victims had
suffered from depression (6).
The issue of suicidality should always be addressed
repeatedly over the course of treatment. Patients almost
always feel relieved when this topic is discussed. For
concrete management, see the article by Rudolf et al.
(1). Most suicides are announced beforehand in someway, either directly or indirectly.
Important steps to be taken for suicidal patients are
the following:c The immediate commencement of a psychotherapeutic crisis intervention. A stable physician-patient
relationship is the most effective protective factor;
thus, the family physician plays a central role insuch situations.
c Referral to a specialized psychiatristc Short-term follow-up at close intervals and clear,
unambiguous agreement on the time and place ofthe next session—no vague offers such as, "give mea call if things are not going well."c A concrete, 24-hour offer of help: telephone numberof the psychiatric crisis service or rescue center

Suicidality
A special danger of depressive disorders issuicidality. 3% to 15% of persons suffering fromdepression commit suicide, while 40% to 70% of
suicide victims had suffered from depression.

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c Obtain the patient's agreement to put off any
thoughts of harming himself or herself and havethe patient commit to an anti-suicide pact. The
latter is an agreement between the physician andthe patient in which the patient promises not toharm himself or herself within a specified periodof time.
c Inpatient referral or involuntary commitment, if
necessary, in accordance with the relevant lawsc For acute suicidality, give benzodiazepine whenindicated.
Because there is no single treatment method towhich all patients will respond, depression is treated,
as a rule, in sequential therapeutic steps (7). The
duration of each step should be long enough to givethe method used a chance to be effective, yet also
short enough to avoid treating the patient ineffectively
for any longer than necessary. Four weeks (or six, forelderly patients) has generally been found to be an
appropriate period for treatment with antidepressant
medications, four to twelve weeks for specific formsof psychotherapy.
At the end of this period, the patient's response totreatment should be evaluated in a standardized fashion.
To this end, a detailed documentation of the patient's
disease manifestations at the outset of the treatment stepis essential. The established, easy-to-use depression
severity scales are also helpful—both external assessment scales (e.g., the Hamilton Depression Scale [8])and self-assessment scales (e.g., the Beck Depression
Inventory [9]). A "response" in terms of these scales isgenerally said to have occurred when the overall scorehas gone down by at least half during the treatment stepin question (10). If this is the case, further treatment
should be aimed at a complete remission of the disease
manifestations. In case of nonresponse, on the other
hand, a transition should be made to the next treatment
step.

Pharmacotherapy
Antidepressants
The antidepressants play a central role in the pharmacotherapy of depression. Approximately 30 substances inthis class are approved for use in Germany. All are about
equally effective (5), with a nonresponder rate of onethird to one-half. All antidepressants have a similar
latency until the onset of their therapeutic effect: forpractical clinical purposes, a latency of two to fourweeks can be assumed (EBM level A [Ia]).

The treatment of depression
As a rule, depression should be treated insuccessively applied therapeutic steps, because
not all patients respond to every kind of treatment.

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With very few exceptions, all available antidepressants
work mainly by raising the synaptic concentration ofserotonin and/or noradrenaline in the central nervous
system. They differ only in the precise mechanism bywhich they do this (11) (table 1).
Phytotherapy (St. John's wort)
Phytotherapy with St. John's wort preparations is very
popular in Germany in particular. The scientific evidencewith regard to the efficacy of this agent is mixed at present,with many studies fraught with severe methodologicaldeficiencies. A current meta-analysis (5) comes to theconclusion that St. John's wort is probably effective forthe treatment of mild and moderate depression. The morethan 40 St. John's wort preparations that are now available
on the German market contain extremely variable concentrations of more than 400 individual chemical
substances (5).
It is not widely known, yet highly clinically relevant,that St. John's wort carries with it a major risk of interactions with other medications: by inducing isoenzymesof the cytochrome P450 system, it can weaken the effectof many medications, including oral contraceptives,
anticoagulants, digoxin, theophylline, other antidepressants, cyclosporine, and anti-HIV agents. Likewise,
when a patient stops taking St. John's wort, the serum
concentrations of these drugs will rise.
Benzodiazepines
Benzodiazepines have no antidepressant effect in the strict
sense of the term, yet they have an acute sedative andanxiolytic effect and their use may thus be indicated forseverely depressed and suicidal patients for a period nolonger than 14 days. Such treatment is often needed
because of the long latency of effect of the antidepressants,
which was already mentioned above. The risks and contraindications of the benzodiazepines must, however, betaken into account. For instance, a history of addiction
may be a risk that contraindicates benzodiazepine use.

TABLE 1
The mechanism of action of antidepressantsMechanism

Pharmacological group

Inhibition of serotonin and/or
noradrenaline reuptake

c Tri- and tetracyclic
antidepressants (TCA)c Selective serotonin and noradrenaline
reuptake inhibitors (SNRI)c Selective serotonin reuptake
inhibitors (SSRI)
c Selective noradrenaline reuptake
inhibitors (reboxetine)

Inhibition of monoamine oxidasesc Reversible monoamine oxidase
inhibitorsc Irreversible monoamine oxidase
inhibitors

Inhibition of presynaptic autoreceptors

c Presynaptic receptor antagonists

Weekly injections of fluspirilene should not be given
because of the risk of tardive dyskinesia.
Lithium
So-called lithium augmentation plays a role in the acutetreatment of depression that has not responded to antidepressants (12). Furthermore, lithium as monotherapy
is effective for prophylactic treatment in recurrent
depression. Treatment with lithium requires special
knowledge and precautionary measures and should thus
be prescribed only by experienced physicians.

The course of pharmacotherapy

Neuroleptics
Neither the older nor the newer neuroleptics have beenshown to be effective as monotherapy for unipolar
depression. Neuroleptics are indicated only for the treatment of delusional depression and should only be prescribed by a psychiatrist. Studies have shown that someof the atypical neuroleptics are effective when given in
addition to an antidepressant (augmentation therapy),
but neuroleptics have not been approved for this indication.

Patient education and shared decision-making
Thorough patient instruction about the effect, duration,and possible side effects of treatment is an integral component of pharmacotherapy. Patients must also be informed that maintenance therapy will be needed after
the acute phase of treatment. When discussing thesematters with the patient, the physician must address
widespread misgivings and ungrounded fears, e.g., ofaddiction or a change of personality. Patient compliancewith psychiatric medication is often inadequate but canbe improved by informing the patient about the latencyof the antidepressant effect and by describing possible
side effects in advance. Shared decision-making (13)means that the well-informed patient should be able todecide for or against taking any proposed antidepressant
medication in tandem with the physician. Letting the

St. John's wort
St. John's wort is likely to be effective for thetreatment of mild or moderately severe depression.
The available preparations are, however, of variable
composition and can lower the effectiveness ofmany types of concomitantly taken medications.

Patient education and shared decision-making
A thorough orientation of the patient about the effect,
duration, and possible side effects of treatment is an
integral component of pharmacotherapy. Patients
must also be informed that maintenance therapy will
be necessary after the acute phase of treatment.

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TABLE 2
Antidepressants

Substance group,
substances

Initialdose(mg/d)

Tricyclic antidepressants:
amitriptyline, clomipramine,
desipramine, doxepine,
imipramine, lofepramine,
nortriptyline, trimipramine
Tetracyclic
antidepressant:maprotiline
MAO inhibitors:
Irreversible: tranylcypromine
Reversible: moclobemideStandard
dose(mg/d)

High
dose*1(mg/d)Side effect, risk, and interaction profile(selected)

Neurochemical
properties

Anticholinergic effects (dry mouth, constipation,
impaired accommodation, urinary retention, delirium,
cognitive impairment); orthostatic hypotension;
sedation, increased appetite, weight gain
(esp. with amitriptyline, doxepine, and trimipramine);heart block, cardiac arrhythmia;
potentially lethal toxicity with overdose:
beware of accidental (impaired memory)or suicidal overdoses

Inhibition of serotonin andnoradrenaline reuptake; also,
blockade of muscarinic
acetylcholine receptors,
histamine1 receptors,
and α1-adrenergic receptors

For tranylcypromine, pay close attention to drug
information (a low-tyramine diet is necessary—bewareof hypertensive crises! Danger of serotonin syndrome
when combined with serotonergic medications, or given
at too short an interval before or after them!). Side effects:
sleep disturbance, orthostatic hypotension, dry mouth.

Tranylcypromine: irreversible
MAO-A and MAO-B inhibition;
Moclobemide: reversible
MAO-A inhibition

Nausea, inner unrest, sleep disturbance, sexual
dysfunction, SIADH*2. With fluoxetine, paroxetine,
and fluvoxamine, beware of the major risk ofinteractions with many other drugs because
of inhibition of cytochrome P450 isoenzymes!

Selective inhibition of serotonin
reuptake

Nausea, inner unrest, sexual dysfunction,rise in blood pressure (esp. venlafaxine),
SIADH*2, dry mouth, diaphoresis

Selective inhibition of serotonin
and noradrenaline reuptake

Sedation, increased appetite, weight gain; mianserin:risk of changes in blood count (check periodically!)

Blockade of presynaptic
autoreceptors and thus inhibitionof negative feedback

Sedation, sleep disturbance, increased appetite,weight gain, orthostatic hypotension, priapism(inform patient!)

Blockade of serotonin2 receptors
and presynaptic autoreceptors,
moderate inhibition of serotonin
reuptake
Inhibition of dopamine andnoradrenaline reuptake

25–50

150

300

10
150

10–30
300–600

80
900

SSRI:
Citalopram, fluoxetine,paroxetine
Escitalopram
Fluvoxamine, sertraline

20
10
50

20–40
10–20
50–150not
indicated

SNRI:
Venlafaxine
Duloxetine

75
60

150–225
60

375
120

Autoreceptor blockers:
Mianserine
Mirtazapine30
15

60–120
15–45

180
80

Other:
Trazodone

50–100

200–400

600

Bupropion

150

150–300

450

Unrest, sleep disturbance, headache,rise in blood pressure, dry mouth

Reboxetine

8

8

10

Tachycardia, orthostatic hypotension, inner unrest, sleep Selective inhibition of
disturbance, dry mouth, diaphoresis, urinary retention
noradrenaline reuptake*1High-dose treatment requires more frequent monitoring, sometimes on an inpatient basis, and will predictably result in a higher rate of undesired effects.
*2SIADH, syndrome of inappropriate ADH secretion

patient's family take part in this process also improvescompliance.
The choice of antidepressant
The choice of an antidepressant for acute treatment islargely based on the side-effect profile, as the agentsused for acute treatment are all comparably effective(table 2). If a particular antidepressant has already been

The choice of antidepressant
The choice of an antidepressant for acutetreatment is largely based on the side-effectprofile, as the agents used for acute treatment are
all comparably effective.

786

used effectively to treat a previous episode, then thisagent should be preferred.
Sedation is a side effect that may be either undesiredor beneficial if the patient suffers from sleep disturbance.
Tricyclic antidepressants should be avoided in a number of situations (5):c In prostatic hyperplasia, glaucoma, cognitive impairment/dementia, constipation, and co-medication

EffectivenessThe effectiveness of antidepressants can only beassessed after they have been given for two tofour weeks in standard doses.

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with other anticholinergically active substances,because of their anticholinergic side effects;
c In patients with pre-existing heart disease, because
they may cause cardiac conduction abnormalities
or arrhythmias;c In suicidal or cognitively impaired patients (risk ofdeliberate or accidental overdose), because of theirgreater overdose toxicity compared to other antidepressants.
A reasonable and well-established practice is to give,
during the maintenance phase, the same antidepressantthat led to remission in the acute phase (4), even thoughvenlafaxine is the only substance officially approved inGermany for maintenance pharmacotherapy. Either
antidepressants or, alternatively, lithium can be used forprophylactic therapy in recurrent depression.
DosingEach antidepressant has a minimal effective dose; thesestandard doses are listed in table 2, as are the differing
starting doses of preparations that must be given initially in a slowly increasing dose. For elderly patients,
but for no others, lower than standard doses may
already be effective and may, indeed, be indicatedbecause they cause fewer complications. The sameantidepressant dose should be prescribed in the maintenance phase of treatment that induced a remission in
the acute phase (4). It is very difficult to recommend
specific doses for prophylactic treatment at present
because of the limited data that are currently available.
For prophylactic treatment, too, the standard doseused for acute treatment is probably more effective
than a lower dose.
Monitoring
In the first four weeks of acute therapy, the patient
should be seen in follow-up at least once a week. At eachfollow-up appointment, the patient's toleration of the
medication should be evaluated, and any concerns on
the patient's part should be addressed. The response
should be evaluated after four weeks of treatment.
The following tests are recommended for follow-up:
c Before treatment with an antidepressant, complete
blood count and transaminases
c If a tricyclic antidepressant (TCA) is used, an ECG
as wellc If a TCA or selective serotonin and noradrenaline
reuptake inhibitor (SNRI) is used, blood pressure
measurement

For acute therapy
In the first four weeks of acute therapy,
the patient should be clinically reassessedat least once per week.

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c Over the course of treatment, repeated complete
blood count and transaminases, as well as (in thesituations mentioned above) ECG and bloodpressure measurement, particularly if the dose israisedc If selective serotonin reuptake inhibitors (SSRI) areused, then the serum electrolytes should be measured
over the course of treatment because of the risk ofhyponatremia, particularly in elderly patients.

What to do in case of nonresponse
If the patient's disease manifestations do not respond totreatment with antidepressants in adequate doses for anadequately long trial period, the treatment strategy
should be changed. In this situation, a number of options
are available.
A reasonable first step consists of measuring theserum concentration of the antidepressant being used.
This is called therapeutic drug monitoring (TDM) and isa helpful check on patient compliance as well as a meansof detecting any metabolic particularities that may cause
an inadequate serum level in the individual patient when
taking a standard dose. Blood must be drawn before themedication is taken. For many newer antidepressants,
however, there is still no reliably established connection
between a therapeutic serum level and a clinical response;
thus, TDM is mainly recommended if the agent being
used is either a tricyclic antidepressant or venlafaxine.
More information on therapeutic levels, the degree of
evidence upon which they are based, and the laboratories
that measure them can be found on the Internet (please
see list of German-language websites at the end of thisarticle).
A common strategy after nonresponse to initial antidepressant treatment is to switch to another antidepressant; choosing an agent from another antidepressantclass is usually recommended. There is, however, no
scientific evidence for the effectiveness of this strategy(14). Thus, the antidepressant should not be changed
more than once in the acute phase, and, if the second
antidepressant also fails to bring about a response, another strategy should be used.
High-dose antidepressant treatment (table 2) is asensible option for most antidepressants (15). The
SSRIs are an exception: these agents have no clear
dose-response relationship, so dose escalation of
SSRIs lacks a theoretical basis (15). Antidepressantsgiven in high doses can be expected to produce more
severe side effects. ECG checks at closer intervals are

In case of resistance to treatmentc measure the serum concentration ofantidepressantc change the antidepressant (no more than once)c give the antidepressant in a high dose(exception: SSRI)

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obligatory when tricyclic antidepressants are given inhigh doses; with venlafaxine, the blood pressuremust be checked at close intervals. The possible
response to high-dose therapy should be evaluated no
sooner than about four weeks after it has been initiatedbecause of the known latency until the treatment
effect sets in.
A further reasonable treatment strategy after nonresponse to antidepressant monotherapy is combination
therapy with two antidepressants. The effectiveness of
combination therapy, however, has only been documented
for one specific type of combination, namely that of a
reuptake inhibitor (tricyclic antidepressant or SSRI)
together with a presynaptic autoreceptor blocker (mirtazapine, mianserin, or trazodone) (16).
Lithium augmentation is the administration of lithiumin addition to an antidepressant that has been usedhitherto for monotherapy without effect. Adding onlithium can bring about a response in a considerable
number of patients, as has been shown in numerous
studies and meta-analyses (12).

FIGURE

Psychotherapy
The effectiveness of various forms of psychotherapy indepression has been well documented. Most of thetherapeutic effect seems to be due to common, nonspecific factors that may also be at work in medical careoutside the specifically psychotherapeutic setting. The
most important among these factors is a systematicallyestablished therapeutic relationship with an accepting,actively listening, and empathetic physician. The physician himself or herself thereby becomes a potent "therapeutic agent," whose importance can scarcely be underestimated.
Most psychotherapeutic approaches to the treatment
of depression involve the following strategies:c Resource activation (identification and reinforcement of the patient's current abilities)
c Problem actualization (directed addressing of particular areas of conflict)c Problem coping (supporting the patient with emotional, cognitive, or active solution strategies)c Motivational clarification (recognition of problematic modes of perception and behavior and dysfunctional cognitions).
As in pharmacotherapy, patients should be regularly
re-evaluated for the possible emergence of side effects,
and therapeutic efficacy should be assessed after anadequate period of treatment.

Psychotherapy in the treatment
of depressionc Resource activationc Problem actualizationc Problem copingc Motivational clarification

788

Algorithm-based flowchart for stepwise treatment of depression. The flowchart shows thethree arms of the algorithm study of the German Competence Network on Depression, because
neither the result of the study (supported by the German Federal Ministry of Education andResearch) nor the relevant literature permits any definite recommendation to be made.
Whether the patient goes on to the next step in any of the three algorithms is a function of thedecision procedure. The severity of depression is assessed at the end of each step with the
Hamilton Depression Rating Scale (HAM-D, 21-item version).
T3, triiodothyronine• HAM-D < 9: remission Þ clinical reassessment in 2 weeks to confirm remission, if confirmedÞ transition to maintenance therapy, if not confirmed Þ next step
• HAM-D decreased by at least 8 points (and overall score > 9): partial response Þ prolongation of the current step by 2 weeks (no more than once per step)• HAM-D decreased by less than 8 points: non-response Þ next step

Algorithm-based stepwise treatment
There are a number of different stepwise algorithms
for the treatment of depression. The current stateof the data does not permit any definite
recommendation to be made.

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Specific psychotherapeutic techniques
Psychotherapy for depression can be carried out in an
outpatient or inpatient setting, individually or in groups,
and with or without the participation of the patient's
family. In Germany, the statutory health insurance carriers
currently reimburse ambulatory behavioral therapy anddeep psychology–based and analytic psychotherapy as
so-called guideline techniques.
Cognitive behavioral therapy
Cognitive behavioral therapy (CBT) is based on theassumption that dysfunctional cognitions can lead to
disturbed emotions and behavior, and vice versa. A lackof positive reinforcement owing to depression worsens
the patient's depressive manifestations. CBT thus involves
both cognitive and behavioral approaches. Its treatment
strategies aim at overcoming the patient's lack of positive
reinforcement, social withdrawal, and conviction of hisor her own helplessness. The "cognitive errors" that areoften identified among depressed patients include inappropriate generalizations, personalization, emotional
thinking, and black-and-white thinking. Etiologicalimportance is also attached to "depressiogenic" cognitive
schemata that are learned early on in life and may bereactivated by critical life events; a typical example isthe so-called "cognitive triad" of automatic negative
assumptions about oneself, the environment, and thefuture. Cognitive therapy aims to correct these dysfunctional cognitions with structured and directed shortterm therapy consisting of an average of 20 sessions.
The efficacy of ambulatory CBT against depression has
been very well studied and has also been confirmed bymeta-analyses (17, e2–e4).
Deep psychology–based and psychoanalytic psychotherapy
Classical psychoanalytic treatment is performed withthe patient lying on a couch, several times weekly, overa long period of time. Deep psychology–based psychotherapy is based on central fundamental assumptions
and principles of psychoanalysis, but it is usually performed with the patient sitting in a chair, only once per
week, and over a shorter period of time. Both of thesetypes of psychotherapy are based on the assumption that
depressive disorders are largely due to unconscious processes whose roots typically lie in the patient's childhood. Depressed persons, in particular, often suffer fromuncertainties in their relationships and a negative bondingstyle with increased vulnerability to losses and affronts.
More than in other types of psychotherapy, the therapist-

Cognitive behavioral therapy
The effectiveness of cognitive behavioral therapy
in the outpatient setting has been very wellstudied and has also been confirmed by metaanalyses.

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patient relationship itself becomes an object of treatment,
because the patient's typical relationship pattern andanxieties are reproduced in this relationship and can beaddressed within it.
The currently available data from controlled studies
of efficacy are less extensive than for CBT. More structured, short-term deep psychological psychotherapy inmildly or moderately depressed patients has been the typemost frequently studied (e5). Other studies and metaanalyses have involved patients with a mixture of diagnoses, so that it is difficult to draw any specific conclusions about the effectiveness of these types of treatment
for depression (e6, 18).
Interpersonal psychotherapy (IPT)
IPT is a type of short-term psychotherapy that wasdeveloped specifically for the treatment of depression. It
consists of 12 to 20 hours of semi-structured psychotherapy, generally in weekly sessions, and focuses on
the psychosocial and interpersonal aspects of depressive
disorders. Thus, it places particular emphasis on copingwith grief, role switching, life changes, and interpersonal
conflicts.
Although much evidence for the efficacy of IPT isavailable from controlled studies and meta-analyses(19), in which it was used alone or in combination withantidepressants, IPT is currently not reimbursed by thestatutory health insurance carriers in Germany.

Supportive measures
The importance of involving the patient's family has
already been mentioned more than once. The only
treatment for depression that has an immediate
therapeutic effect is sleep deprivation, which can bedone on an inpatient or outpatient basis. The patient isrequired either to do without sleep for an entire night(complete sleep withdrawal) or simply to get up
between 1 a.m. and 2 a.m. (partial sleep deprivation),
without making up for the missed sleep either inadvance or afterward. It is crucial for the success of
this treatment that the patient should not take even a
short nap during periods of wakefulness. About 60%
of patients so treated have a marked improvement ofmood the day after.
The main disadvantage of sleep deprivation treatment is that its beneficial effect lasts no more than 1 or 2days in about 80% of patients. If the treatment is effective, it can be repeated once every 3 to 4 days. An absolutecontraindication is a history of epileptic seizures; relative

Supportive measures
Roughly 60% of patients undergoing sleep
withdrawal therapy experience a marked
improvement of mood for 1 to 2 days thereafter.

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contraindications include bipolar or psychotic forms ofdepression.
The effectiveness of light therapy with special apparatus has been unequivocally documented only forseasonal depression (winter depression) (e7). Physicalactivity probably has a beneficial effect on the resolutionof depression and can be recommended as a supplementary treatment, even though the scientific data to support
this are as yet inadequate (e8). Treatments that are currently under investigation include aerobic training andendurance training (treadmill running) (20).
The most effective of all treatments for depression isprobably electroconvulsive therapy (ECT), for which
the current main indication is treatment-resistantdepression (21, 22). Because of the specialized personnel
and apparatus that this form of treatment requires, andalso because of persistent, widespread misgivings about
it, ECT is used only when multiple previous therapeuticattempts have failed, or when the patient explicitly
requests it. Its beneficial effect typically appears after
one to three weeks of treatment with three ECT sessions
per week. Its major clinical drawback is the high rate ofearly recurrences in the first 16 weeks—up to 75% of
patients who are not subjected to continuing treatment.
With good maintenance therapy, the percentage of earlyrecurrences can be reduced to about 35%, but suchrecurrences cannot be eliminated.

Conclusion
Depression can be treated effectively at present because
multiple forms of treatment are available that complement
each other or can be given in combination. Most of them
have been well documented as effective in properly
designed, controlled studies. No single form of treatment can be considered superior to all of the others, anda relatively high nonresponder rate is a common featureof all of them. Thus, the art of treating depression consists of a methodical and exhaustive use of the available
therapeutic options within the framework of an algorithm-based stepwise treatment regimen (figure), in
which each sequential step of treatment is carried out foran adequate length of time and is then evaluated for
effectiveness in standardized fashion. Randomized
comparative studies have shown that stepwise treatment
leads to more frequent and more rapid treatment responses
than unstructured treatment, while simultaneously reducing the amount of psychoactive medication thatmust be prescribed as well as the frequency of changes
in treatment strategy (7).

Conflict of interest statement
Dr. Adli has received research grants from the German Federal Ministry of
Education and Research and from the following companies: Pharmacia, Pfizer,
Lilly, Janssen Cilag, and Wyeth as well as honoraria from Astra Zeneca, Lilly,
Boehringer Ingelheim, GlaxoSmithKline, Pfizer, Sanofi Aventis, Wyeth, andCyberonics. PD Dr. Bschor has received lecture honoraria from Sanofi Aventis,
Lilly, esparma, GlaxoSmithKline, Pfizer, and Astra Zeneca.
Manuscript received on 4 June 2006; revised version accepted on 20 August
2008.
Translated from the original German by Ethan Taub, M.D.

REFERENCES
1. Rudolf S, Bermejo I, Schweiger U, Hohagen F, Härter M: Zertifizierte
medizinische Fortbildung: Diagnostik depressiver Störungen. Dtsch
Arztebl 2006; 103(25): A 1754–62.
2. Pöldinger W: Kompendium der Psychopharmakotherapie. Grenzach/Baden: Hoffmann-La Roche AG 1971: 116.
3. Kupfer DJ: Management of recurrent depression. J Clin Psychiatry
1993; 54 (suppl. 2): 29–33.
4. Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M,
Möller HJ, WFSBP Task Force on Unipolar Depressive Disorders:World Federation of Societies of Biological Psychiatry (WFSBP)
Guidelines for Biological Treatment of Unipolar Depressive Disordersin Primary Care. World J Biol Psychiatry 2007; 8: 67–104.
5. AkdÄ – Arzneimittelkommission der deutschen Ärzteschaft: Empfehlungen zur Therapie der Depression. 2. Auflage. Arzneiverordnung in der Praxis (Therapieempfehlungen), Juli 2006;
Band 33, Sonderheft 1.
6. Wolfersdorf M, Mäulen B: Suizidprävention bei psychich Kranken.
In: Wedler H, Wolfersdorf M, Welz R, Hrsg.: Therapie bei Suizidgefährdung. Ein Handbuch. Regensburg Roderer 1992: 175–97.
7. Adli M, Bauer M, Rush AJ: Algorithms and collaborative-care systems
for depression: are they effective and why? A systematic review. Biol
Psychiatry 2006; 59: 1029–38.
8. Hamilton M: A rating scale for depression. J Neurol Neurosurg
Psychiatry 1960; 23: 56–62.
9. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J: An inventory formeasuring depression. Arch Gen Psychiatry 1961; 4: 561–71.
10. Bschor T: Definition, klinisches Bild und Epidemiologie therapieresistenter Depressionen. In: Bschor T, Hrsg.: Behandlungsmanual
therapieresistente Depression. Pharmakotherapie -somatische
Therapieverfahren – Psychotherapie. Stuttgart: Kohlhammer 2008:
11–6.
11. Bschor T: Behandlung mit Antidepressiva. Pharmakologie, Therapieabschnitte. In: Bschor T, Hrsg.: Behandlungsmanual therapieresistente
Depression. Pharmakotherapie – somatische Therapieverfahren –Psychotherapie. Stuttgart: Kohlhammer 2008: 28–39.
12. Bschor T, Bauer M: Efficacy and mechanisms of action of lithium augmentation in refractory major depression. Curr Pharm Des 2006; 12:2985–92.
13. Loh A, Simon D, Kriston L, Härter M: Shared Decision-Making in Medicine. Dtsch Arztebl Int 2007; 104(21): A 1483–8.
14. Bschor T, Baethge C: Wechsel des Antidepressivums. In: Bschor T,
Hrsg.: Behandlungsmanual therapieresistente Depression. Pharmakotherapie – somatische Therapieverfahren – Psychotherapie. Stuttgart:
Kohlhammer 2008: 48–56.

High nonresponder rate
The treatment of depression must make thoroughuse of all of the currently available therapeutic
options in accordance with a stepwise treatment
algorithm.

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15. Adli M, Baethge C, Heinz A, Langlitz N, Bauer M: Is dose escalation ofantidepressants a rational strategy after a medium-dose treatment has
failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005;
255: 387–400.
16. Bschor T, Hartung HD: Antidepressiva-Kombinationsbehandlung. In:
Bschor T, Hrsg.: Behandlungsmanual therapieresistente Depression.
Pharmakotherapie -somatische Therapieverfahren – Psychotherapie.
Stuttgart: Kohlhammer 2008: 86–101.
17. Gloaguen V, Cottraux J, Cucherat M, Blackburn IM: A meta-analysis of
the effects of cognitive therapy in depressed patients. J Affect Disord
1998; 49: 59–72.
18. Leichsenring F: Are psychodynamic and psychoanalytic therapies effective? A review of empirical data. Int J Psychoanal 2005; 86: 841–68.
19. de Mello MF, de Jesus Mari J, Bacaltchuk J, Verdeli H, Neugebauer R: A
systematic review of research findings on the efficacy of interpersonal
therapy for depressive disorders. Eur Arch Psychiatry Clin Neurosci
2005; 255: 75–82.
20. Knubben K, Reischies FM, Adli M, Schlattmann P, Bauer M, Dimeo F: A
randomized, controlled study on the effects of a short-term endurance
training programme in patients with major depression. Br J Sports Med
2007; 41: 29–33.
21. UK ECT Review Group: Efficacy and safety of electroconvulsive therapy
in depressive disorders: a systematic review and meta-analysis. Lancet
2003; 361:799–808.
22. Folkerts H, Remschmidt H, Saß H, Sauer H, Schäfer M, Sewing K-Fr:
Stellungnahme zur Elektrokrampftherapie (EKT) als psychiatrische Behandlungsmaßnahme. Dtsch Arztebl 2003; 100(8): A 504–6.
Corresponding author
PD Dr. med. Tom Bschor
Jüdisches Krankenhaus Berlin
Abteilung für Psychiatrie und Psychotherapie
Heinz-Galinski-Str. 1
13347 Berlin, Germanybschor@jkb-online.de@

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For e-references please see:www.aerzteblatt-international.de/ref4508
For a case illustration relating to this article,
see the following website:www.aerzteblatt-international.de/0812
German-language websites for further information:– Self-help and family groups:
www.nakos.de– Written information for patients:
www.akdae.de/45/Depression.pdf
www.kompetenznetz-depression.de– Information about therapeutic serum levels of antidepressants and grades of supportive evidence:www.agnp.de ÞArbeitsgruppen ÞAG Therapeutisches
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Please answer the following questions to participate in our certified Continuing Medical Education
program. Only one answer is possible per question. Please select the answer that is most appropriate.
Question 1
What is the objective of maintenance therapy for depressive
disorders?
(a) Phase prophylaxis(b) Remission(c) Response(d) Relief of symptoms(e) The prevention of an early relapse

Question 2
In what respect do the roughly 30 antidepressants that are currently
available in Germany differ from one another most markedly?
(a) Their side-effect profiles(b) Their nonresponder rates(c) Their addictive potential(d) Their latency of onset(e) Their potency

Question 3
A 68-year-old woman in whom you have diagnosed moderately
severe depression will only accept St. John's wort as the sole
pharmacotherapeutic agent against depression. What should be
your particular concern if you prescribe her a preparation
containing this substance?
(a) The potential for morbid obesity(b) The ECG(c) Any medications she is concomitantly taking(d) Renal function(e) Possible addiction

Question 4
A 59-year-old bus driver presents to you with a history of depressionthat began two months ago. You are considering treatment witha tricyclic antidepressant. Which of the following comorbidities
would lead you not to prescribe a drug of this type?
(a) Bronchial asthma(b) Gout(c) Prostatic hyperplasia(d) Psoriasis(e) Rheumatoid arthritis

Question 5
What is the most rapidly acting treatment for depression?
(a) Depression-specific psychotherapy(b) Electroconvulsive therapy (ECT)(c) Light therapy(d) Pharmacotherapy with antidepressants(e) Sleep deprivation

Question 6
According to the theory underlying psychotherapy based on deep
psychology, what psychological phenomenon is more common in
depressed people?
(a) Borderline personality structure(b) Latent homosexuality in a parent

792(c) Penis envy(d) Increased vulnerability to loss(e) Documented above-average intelligence

Question 7
Which of the following antidepressive treatments has been
well documented to be effective by multiple controlled
studies and meta-analyses?
(a) Physical activity(b) Neuroleptic monotherapy(c) High-dose SSRI treatment(d) Outpatient cognitive behavioral therapy(e) Changing the antidepressant in case of nonresponse

Question 8
What is meant by an algorithm-based stepwise treatment
regimen for depression?
(a) Alternation between psycho- and pharmacotherapeutictechniques until a remission occurs(b) Choice of treatment according to the classification of thepatient's depression as mild, moderate, or severe, on the basisof a systematic evaluation(c) Treatment of depression with monotherapy or with a combinationof two, three, or four therapeutic methods, depending on thesystematically assessed degree of resistance to treatment(d) Determination of the treatment plan with the aid of treatment
software that processes the data of the individual patient on
the basis of a response probability matrix(e) Determination of a multi-step treatment plan at the beginningof treatment with a standardized response evaluation at theend of each step, whose results determine the transition to thenext treatment step

Question 9
Which of the following is a basic assumption of cognitive
behavioral therapy?
(a) Placing the overwhelming emphasis on cognition, rather thanemotion, is a central element in the pathogenesis of depression.
(b) Depressive disorders are based to a large extent on
unconscious processes.
(c) Dysfunctional cognitions lead to disturbed emotions andbehavior.
(d) Cognitive ego-splitting lies at the heart of depressive disorders.
(e) Excessive positive reinforcement in the consumer society is themain cause of depression.

Question 10
What tests are advisable before the beginning of treatment
for depression and regularly over the course of treatment?
(a) Stress ECG for sertraline treatment(b) Blood pressure checks for venlafaxine treatment(c) EEG for citalopram treatment(d) Metabolizer status checks for amitriptyline treatment(e) Serum level determinations for treatment with reboxetine Dtsch Arztebl Int 2008; 105(45): 782–92
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CONTINUING MEDICAL EDUCATION

Treatment of Depressive Disorders
Tom Bschor, Mazda Adli

E-REFERENCES
e1. Bostwick JM, Pankratz VS: Affective disorders and suicide risk:
A reexamination. Am J Psychiatry 2000; 157: 1925–32.
e2. Dobson KS: A meta-analysis of the efficacy of cognitive therapy for
depression. J Consult Clin Psychol 1989; 57: 414–9.
e3. Gaffan EA, Tsaousis I, Kemp-Wheeler SM: Researcher allegianceand meta-analysis: the case of cognitive therapy for depression.
J Consult Clin Psychol 1995; 63: 966–80.
e4. DeRubeis RJ, Gelfand LA, Tang TZ, Simons AD: Medications versus
cognitive behavior therapy for severely depressed outpatients: megaanalysis of four randomized comparisons. Am J Psychiatry 1999;
156: 1007–13.
e5. Leichsenring F: Comparative effects of short-term psychodynamic
psychotherapy and cognitive-behavioral therapy in depression: ameta-analytic approach. Clin Psychol Rev 2001; 21: 401–19.
e6. Crits-Christoph P: The efficacy of brief dynamic psychotherapy: ameta-analysis. Am J Psychiatry 1992; 149: 151–8.
e7. Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen FM,
Suppes T, Wisner KL, Nemeroff CB: The efficacy of light therapy inthe treatment of mood disorders: A review and meta-analysis of theevidence. Am J Psychiatry 2005; 162: 656–62.
e8. Lawlor DA, Hopker SW: The effectiveness of exercise as an intervention in the management of depression: systematic review and metaregression analysis of randomised controlled trials. BMJ 2001; 322:
763–7.

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CONTINUING MEDICAL EDUCATION

Treatment of Depressive Disorders
Tom Bschor, Mazda Adli

Case

now continually worried about the possible implications of his current three-day absence for his job security and the family's financial future.

Treatment of Depressive Disorders

The addiction history and past psychiatric history
were negative. There was, however, a positive family
history: the patient's paternal grandfather hadcommitted suicide, for unknown reasons.

A 46-year-old office worker went to his family physician, accompanied by his wife, complaining of
persistent headaches. When questioned more closely,
he described a dull pressure in the entire head that
had been present continuously, though at varying
intensity, for approximately the past four weeks. His
chronic back pain had worsened in the same period.
Because of these problems, he had first stopped
attending his weekly chess night and then stopped
going on his usual weekend excursions with hisfamily. Over the course of time, he had stopped performing any tasks at all for his family and household.
He had stayed home from work for the past threedays. A thorough physical examination revealed noabnormality.
Only on directed questioning did the patient statethat he had felt exhausted and bereft of energy all thetime for the past few weeks, that he had lost interest in
his usual activities, and that he no longer enjoyed thethings that used to give him pleasure. His food nolonger tasted good to him, and he had already lost 2.5
kg of weight. Most recently, he had begun to havedifficulty falling asleep and to wake up every morning
between 4 and 5 a.m.; he attributed this to the headaches. His wife, on directed questioning, said that her
husband often seemed sad and that she had seen tears
in his eyes for no apparent reason on multiple occasions. Nor could she understand why her husband,
who was normally very conscientious about his work, Dtsch Arztebl Int 2008; 105(45)
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The family physician diagnosed a first depressive
episode, informed the patient and his wife of her
diagnosis in two separate interviews, and stressedboth the nature of the symptoms as a disease and thegood prognosis for recovery.
She declared him unable to work for two weeks andurged him to take a one- to two-hour walk each morning, but to take on no further tasks or activities. The
patient was able to accept the temporary, passive roleof an ill person only when acute depression was
explained to him through an analogy to acute pneumonia. The patient and his family physician agreed that hewould take antidepressive medication; she prescribed
nortriptyline (150 mg/day), an agent with both serotonergic and noradrenergic properties, because suchagents can be expected to have an additional beneficial
effect in pain. Other than dry mouth, the medication
was well tolerated. The patient and his family physician
saw each other weekly. Three weeks after the onset oftreatment, the patient came for the first time without
his wife accompanying him and reported that he hadjust begun working in the garden again on his own
initiative. After a total of five weeks of treatment, he
was practically free of symptoms and returned towork. The patient and his family physician agreed that
he would continue taking nortriptyline for six
months as maintenance therapy.

I