major depressive disorder- new clinical, neurobiological, and treatment perspectives

8/2/2019 Major Depressive Disorder- New Clinical, Neurobiological, And Treatment Perspectives

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www.thelancet.com Vol 379 March 17, 2012 1045

Lancet 2012; 379: 104555

Published Online

December 20, 2011

DOI:10.1016/S0140-

6736(11)60602-8

University of Pittsburgh

Medical Center, Western

Psychiatric Institute and Clinic,

Pittsburgh, PA, USA

(Prof D J Kupfer MD, E Frank PhD,

M L Phillips MD)

Correspondence to:

Prof David J Kupfer, University

of Pittsburgh Medical Center,

Western Psychiatric Institute and

Clinic, 3811 OHara Street,

Pittsburgh, PA 15213, USA

[email protected]

Major depressive disorder: new clinical, neurobiological, and

treatment perspectivesDavid J Kupfer, Ellen Frank, Mary L Phillips

In this Seminar we discuss developments from the past 5 years in the diagnosis, neurobiology, and treatment ofmajor depressive disorder. For diagnosis, psychiatric and medical comorbidity have been emphasised as importantfactors in improving the appropriate assessment and management of depression. Advances in neurobiology have alsoincreased, and we aim to indicate genetic, molecular, and neuroimaging studies that are relevant for assessment andtreatment selection of this disorder. Further studies of depression-specific psychotherapies, the continued applicationof antidepressants, the development of new treatment compounds, and the status of new somatic treatments are alsodiscussed. We address two treatment-related issues: suicide risk with selective serotonin reuptake inhibitors, and thesafety of antidepressants in pregnancy. Although clear advances have been made, no fully satisfactory treatments formajor depression are available.

Epidemiology, comorbidity, and diagnosisWorldwide, depression is a seriously disabling publichealth problem of very high prevalence.1 Major depressivedisorder has a 12-month prevalence of 66% and alifetime prevalence of 162%, is twice as common inwomen as in men, and causes considerable impairment.Age-of-onset distributions suggest that depression isprevalent for the entire lifespan.2 The disorder not onlyproduces decrements in health that are equivalent tothose of other chronic diseases (eg, angina, arthritis,asthma, and diabetes), but also worsens mean healthscores substantially more when comorbid with these

diseases, than when the diseases occur alone.

3

A crucialimplication is that primary care providers should notignore the presence of depression when patients have achronic physical disorder.

Overdetection and underdetection are important factorsthat should be considered to ensure the appropriatediagnosis and management of clinical depression.4Although a meta-analysis5 concluded that generalpractitioners correctly exclude depression in mostindividuals who are not depressed, overdetections (falsepositives) can outnumber missed cases. The presence ofanxiety with depression can increase diffi culties indiagnosis. Some researchers have argued that theestablishment of anxious depression as a specific

diagnosis would substantially improve identification ofdepression in primary care settings, and such a categoryhas been proposed for the fifth edition of the diagnosticand statistical manual of mental disorders (DSM-5) andfor the 11th revision of the international classification ofdiseases (ICD-11).6

Although in this Seminar we focus on major depres-sive disorder (bipolar disorder has been addressed inother Seminars in The Lancet7), studies that betterelucidate the boundaries and phenotypical description ofthe disorder are highly relevant. In up to 40% of patients,major depression is associated with lifetime occur-rences of isolated manic or hypomanic symptoms that donot cluster in a way that is consistent with a diagnosisof hypomania. Furthermore, such symptoms can be

concurrent with syndromal-level major depressive dis-order.8,9 Further investigation is needed to examine thetreatment and prognosis of major depression that isassociated either concurrently, or at other points in thepatients history, with hypomanic symptoms.10 Thisinvestigation could be facilitated by proposed changes inDSM-5, which include the possibility of a mixed specifierindicating the presence of sub-threshold hypomanicsymptoms in those with unipolar disorder.

Major depressive disorder was assumed to precedegeneralised anxiety disorder until a 32-year prospectivefollow-up study11 challenged this notion. Indeed, the

reverse pattern seems to be frequently present, and thecombination of generalised anxiety disorder and majordepression might represent an additional burden. Socialanxiety disorder (social phobia) is now also regarded asan important and consistent risk factor for the develop-ment of severe depression.12 Furthermore, comorbidpersonality disorder seems to confer a worse prognosisand poorer treatment response than does majordepression alone.13 Some of the risk factors for themetabolic syndrome (eg, obesity), might also increasethe risk of depression and, in turn, depression increasesthe risk for development of obesity.14 These two-wayrelations might be the reason for the increased associationbetween depression and coronary artery disease.

Kendler and colleagues15 have shown a major relationbetween depression and coronary artery disease, mainlyin acute states. A high severity of depression within

Search strategy and selection criteria

We searched PubMed from June, 2005, to June, 2010, for the

terms depression, antidepressants, and depression

treatment. Although the search was updated in

December 2010, publications were mainly selected from the

past 5 years. Other bibliographies of selected articles were

reviewed to obtain additional relevant references, especially

for neurobiology, genetics, and neuroimaging in depression.

We excluded non-English publications.

For the DSM-5 website see

http://www.dsm5.org/Pages/

Default.aspx


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several weeks of admission to hospital for an acute

coronary syndrome, or an inadequate treatment responsein depression, can double cardiac mortality in 67 yearsof follow-up.16 Studies examining depression and anxietyas predictors of 2-year cardiac events in patients withstable coronary artery disease have shown a high likeli-hood of major adverse cardiac events in those withdepression.17These results have led to the recommendationthat all patients with coronary artery disease be screenedfor depression;18 however, this recommendation issomewhat controversial.19 Studies of the relation betweendepression and diabetes have led to new conclusionseg, that clinical depression is associated with a 65%increased risk of diabetes in elderly people.20 Major andminor depressions seem to be implicated in this relation.21

These studies22 emphasise the importance of identificationand treatment of depression in the physically ill.

Advances in neurobiologyGenetic studiesGenetic, molecular, and neuroimaging studies continueto contribute to advances in our understanding of theneurobiological basis of major depressive disorder.However, the extent to which findings from neuro-biological studies can help improve the clinical andfunctional outcome of individuals with the disorder isstill uncertain. Thus, in the past 5 years, neurobiologicalresearch of depression has become two-tiered to:(1) understand the pathophysiology of the illness; and(2) identify the neurobiological measures for guidingtreatment choice.

The identification of single candidate genes associatedwith major depression has been diffi cult because of thelikelihood that complex psychiatric illnesses are underpolygenic influence and are associated with interactionsbetween genetic variants and environmental exposures.23One approach has been to go beyond the conventionalfocus on monoamines in the search for a geneticassociation.24 For example, major depressive disorder hasbeen associated with polymorphisms in the glucocorticoidreceptor gene NR3C1,25 the monoamine oxidase A gene,26the gene for glycogen synthase kinase-3 (which has a

key role in the phosphorylation and regulation ofmetabolic enzymes and many transcription factors27),and a group-2 metabotropic glutamate receptor gene(GRM3).28 Success has been greater in the identificationof candidate genes that are associated with knownbiological mechanisms and metabolic pathways forantidepressant drugs and, that in turn, can help predictthe response from antidepressant treatment.

Many studies have focused on the functional insertion-deletion promoter variant (serotonin transporter-linkedpolymorphic region [5HTTLPR]) in the serotonin trans-porter gene (SLC6A4). A meta-analysis29 showed twoassociations, first between the 5HTTLPR long alleleand increased response to selective serotonin reuptakeinhibitor (SSRI) antidepressant drugs (although not to

nortriptyline30), and reduced side-effects to SSRIs;31 and

second between the 5HTTLPR short allele and increasedparoxetine-induced, but decreased mirtazapine-inducedadverse effects.32 Several single-nucleotide polymorphisms(SNPs) in the gene for the serotonin type-2a receptor areassociated with outcomes of SSRI treatment.31,3335

Studies3638 of candidate genes associated with otherbiological mechanisms have emphasised associationsbetween glutamatergic genes (eg, GRIK4) and citalo-pram response and adverse effects; between the Metallele of the functional Val/Met polymorphism (rs6265)in brain-derived neurotrophic factor (BDNF) and SSRIresponse;39 and between several other BDNF SNPs anddesipramine response.31 Genetic variation in FKBP5a protein that helps to regulate cortisol binding to

the glucocorticoid receptor40is associated with anti-depressant response;41,42 whereas genetic variants inTREK1a potassium channel mediating SSRI mech-anism of actionare associated with non-response toseveral antidepressants.43 Genetic variation in thecatechol-O-methyltransferase (COMT) gene, whichalters COMT activity, is associated with response totreatment with several antidepressants.44,45

Genome-wide association studies further suggest thateffectiveness of antidepressants can be predicted bygenetic markers other than traditional candidate genes.These genes include those for the corticotrophin-releasinghormone (CRH) receptor-1 (CRHR1) and CRH bindingprotein (CRHBP), which predict SSRI response in anxiousdepression,46,47 and genes for uronyl-2 sulphotransferaseand interleukin-11, which predict response to nortriptylineand escitalopram oxalate, respectively.48

Molecular studiesAt least three main categories of peripheral hormone-type factors, for which genetic variants are associatedwith major depressive disorder, are implicated in thepathophysiology of the illness: (1) neurotrophic factorsand other growth factors, including BDNF, vascularendothelial growth factor, and insulin-like growthfactor-1; (2) proinflammatory cytokines, includinginterleukin-1, interleukin-6, and tumour necrosis

factor-; and (3) impaired regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. For example, serumBDNF is decreased in individuals with major depression,and antidepressant treatment reverses this decrease.49,50

The secretion and production of proinflammatorycytokines are increased in individuals who are stressedand depressed,51,52 and, in major depression, antidepres-sant drugs can return concentrations of these cytokinesto normal or suppress their synthesis.53 Impaired regu-lation of the HPA axis in an acute episode of depres-sion has long been documented,54 and published workhas indicated attenuation of neuroendocrine responseto the combined dexamethasone-corticotrophin-releasinghormone testa sensitive measure of altered regulationof the HPA systemduring antidepressant treatment.55


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Neuroimaging studies

Neural systems that are important to understand majordepressive disorder include those that support emotionprocessing, reward seeking, and regulate emotion, all ofwhich are dysfunctional in the disorder. These systemsinclude subcortical systems involved in emotion andreward processing (eg, amygdala, ventral striatum);medial prefrontal and anterior cingulate cortical regionsinvolved in processing emotion and automatic or implicitregulation of emotion; and lateral prefrontal corticalsystems (eg, ventrolateral prefrontal cortex and dorso-lateral prefrontal cortex) involved in cognitive control andvoluntary or effortful regulation of emotion.56 Thesesystems can be conceptualised as a medial prefrontal-limbic network, including amygdala, anterior cingulate

cortex, and medial prefrontal cortex that is modulated byserotonin neurotransmission,5759 and a reward networkcentred on ventral striatum and interconnected orbito-frontal and medial prefrontal cortices that is modulatedby dopamine (figure 1).60

Neuroimaging studies of major depressive disorder6165have provided evidence for specific functional abnor-malities in these neural systems in adults. Convergingfindings from these studies suggest abnormally increasedamygdala, ventral striatal, and medial prefrontal cortexactivity, mostly to negative emotional stimuli, such asfearful faces. Abnormally reduced ventral striatal activityto positive emotional stimuli,61,66 and during receipt andanticipation of reward in adults67 and adolescents68 withdepression have also been reported. These findingssupport a bias of attention towards negative emotionalstimuli, and away from positive emotional and reward-related stimuli in individuals with major depression.Further studies are needed to examine neural activity inthe prefrontal cortical regions that are implicated involuntary and implicit regulation of emotion. Thesefunctional neuroimaging studies are complemented byincreased findings suggesting reductions in grey matterin key regions of these neural systems (includingamygdala69), age-related decreases in volume of theanterior cingulate cortex,70 and post-mortem findingsindicating neural-cell and glial-cell pathology in prefrontal

cortical regions.71Additional evidence for abnormalities in neural systems

for emotion and reward processing and regulation ofemotion in major depressive disorder has come fromneuroimaging studies of emotion processing, whichused measures of functional connectivity, includingeffective connectivityie, the effect that activity in oneregion exerts over that in another. For example, onestudy72 reported abnormal-inverse effective connectivityin medial prefrontal cortical-amygdala during emotionlabelling of happy faces in individuals with majordepression. These findings suggest abnormally increasedtop-down regulation of the amygdala by medial prefrontalcortex in these individuals, which again suggests a biasaway from attendance to positive emotional stimuli.

Other studies73 have applied diffusion tensor imaging,which uses measures of the diffusivity of water in differ-ent directionseither parallel or perpendicular to thedirection of white-matter fibresto construct whole-brain measures of patterns of white-matter connectivitybetween different neural regions. Findings from thesestudies, have shown abnormal prefrontal cortico-sub-cortical white-matter connectivity between regions sup-porting emotion regulation in adults with depression.73

Examination of brain activity during rest can providevaluable insights into how the brain functions duringself-reflection, which could be abnormal in individualswith major depression. Studies have provided evidencefor a malfunction of the default mode network.74 Thisnetwork includes several midline regions, including the

inferior (ventral) part of the medial prefrontal cortex(vmPFC). Anterior parts of this network (eg, vmPFC) areinvolved in self-referential processing74 and tend todeactivate during cognitive tasks as cognitive resourcesare redirected. The normal decrease in vmPFC activityduring diffi cult tasks might indicate intact emotionalgating and, conversely, absence of this deactivation mightindicate impaired gating. Findings from analysis of task-independent deactivations suggest an abnormality of thedefault mode network in vmPFC in major depressivedisorder. A method to examine resting-state-related neuralactivity is measurement of the correlation of low-frequency blood oxygen level-dependent temporalfluctuations (LFBF) in steady-state functional MRI databetween different neural regions. One study75 showed

Voluntary regulation of emotion Automatic regulation of emotion

Emotion and reward processing

DLPFC

Amygdalaventral striatum

mPFCACCOFC

VLPFC

Figure 1: Neural systems of relevance to major depressive dis order

Key neural regions implicated in emotion and reward processing, and voluntary and automatic regulation of

emotion are shown superimposed on a greyscale depiction of the human brain. DLPFC=dorsolateral prefrontal

cortex. mPFC=medial prefrontal cortex. ACC=anterior cingulate cortex. OFC=orbitofrontal cortex.

VLPFC=ventrolateral prefrontal cortex. Adapted with permission from reference 56.


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that individuals with depression had increased resting-state connectivity in medial prefrontal cortex regions inthe default mode network, including the anterior cingulatecortex and the vmPFC.

A meta-analysis76 of several neuroimaging studies ofmajor depressive disorder identified two neural systemsof importance to the illness. One network that centred onthe dorsolateral prefrontal cortex and more dorsal regionsof the anterior cingulate cortex, but that also includedother regions implicated in cognitive control, wascharacterised by reduced activity in the resting state,which returned to normal with treatment. A secondnetwork, centred on medial prefrontal cortex andsubcortical regions, was hyperactive to emotional stimuliin the depressed state, but returned to normal afterantidepressant treatment. This meta-analysis76 providesfurther evidence of increased activity in neural systemssupporting emotion processing (amygdala and medialprefrontal cortex), and reduced activity in neural systemssupporting regulation of emotion (eg, dorsolateral

prefrontal cortex).Neuroimaging studies have also examined neural

predictors of outcome and neuroimaging measures thatchange with response to different antidepressanttreatments. These studies have focused mainly on therole of the serotonergically-mediated medial prefrontal-limbic network. In major depression, SSRI drugsmodulate emotion-induced activity in this network, andresponse to SSRIs is predicted by activity in this region.77LFBF correlations between subcortical regions and theanterior cingulate cortex can also increase after SSRItreatment in individuals with depression.78,79 However,less is known about the effects of non-serotonergic drugson the medial prefrontal-limbic network, and the extentto which pretreatment activity in this region predicts

subsequent response to non-serotonergic antidepressantsneeds to be examined. Desynchronisation of the anteriorcingulate cortex, and its functional connectivity with theamygdala predicts rapid antidepressant response toketamine,80 but response to cognitive behavioural therapyis predicted by reduced medial prefrontal activity, andincreased amygdala activation.81 Response to deep-brainstimulation correlates with reduced activity in ventral(subgenual) regions of the anterior cingulate cortex,82,83and increased metabolism in ventral striatum.83

Integration of measuresStudies examining a combination of genetic, molecular,and neuroimaging measures to identify relations amonggenes, molecules, neural systems, and behaviour inmajor depressive disorder could increase our under-standing of the underlying pathophysiological processesand prediction of treatment response (figure 2). Relationsbetween genetic variation in neutrophic factors, andvariation in concentrations of these factors, such as

BDNF and vascular endothelial growth factor, andstructural and functional variation in neural regionssupporting mood regulation and associated behavioursand neurocognitive function, are well documented.8488This variation might in turn reduce the ability to respondto treatments dependent on intact neurocognition, suchas cognitive behavioural therapy.

Reports8993 have emphasised associations betweengenetic variation in function of the HPA axis, geneticvariation betweenand variation in concentrations ofinflammatory cytokines, and functional and structuralvariation in key neural regions supporting mood regu-lation. Studies have also indicated how neuroimagingtechniques can be applied to diagnosis and how specificneuroimaging measures might help to distinguish major

Neuroimaging measuresAbnormalities in anatomically-defined neural systems Subcortical neural systems for emotion and

reward processing Medial prefrontal regions involved in processing

and implicit regulation of emotion Lateral prefrontal cortical systems involved in cognitive

control and voluntary or effortful regulation of emotionAbnormalities in neurotransmitter-defined neural systems Medial prefrontal-limbic network, modulated by serotonin

Reward network, centred on ventral striatum andmedial prefrontal cortices, modulated by dopamine

Newer neuroimaging methodologies to study MDD Measurement of brain activity during restNeuroimaging and antidepressant treatment response

Molecular measures Neurotrophic factors and

other growth factors Proinflammatory cytokines Impaired regulation of the

hypothalamic-pituitary-adrenocortical axis

Genetic measures Candidate genes associated with MDD

(ie, beyond the conventionalmonoamine focus)

Candidate genes associated with

biological mechanisms and metabolicpathways for antidepressant medications

Serotonergic mechanisms Other mechanisms Genome-wide association studies

Genes Molecules Neural systems

Figure 2: Advances in neurobiology of MDD

MDD=major depressive disorder.


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depressive disorder from bipolar depression.72,94,95 In turn,

these measures can facilitate early diagnosis and caninform treatment choice (figure 3). Computerisedmachine learning and techniques for pattern recognitionin combination with neuroimaging techniques can beused to classify individuals, case-by-case, into diagnosticgroups on the basis of neuroimaging measures.64,96

Advances in treatmentDepression-specific psychotherapiesPharmacotherapy and manual-driven depression-specific psychotherapy are both effective treatments forunipolar depression, either as monotherapies, or incombination. 97,98 Although similar results are reportedfor depression-specific psychotherapy in primary-care

samples, fewer published works are available in thisarea than in psychiatric samples.99,100 These studiessuggest that interpersonal psychotherapy alone, or incombination with pharmacotherapy, is effective for theacute treatment of depression.

In a clinical trial of inpatients with depression, 101response rates of patients receiving a combination ofinterpersonal psychotherapy (modified for inpatients) andpharmacotherapy were higher than those of patientsreceiving pharmacotherapy alone. The effects of acuteinterpersonal psychotherapy can be sustained even afterremission.101,102 Similarly, several trials in the USA andEurope continue to support the acute effi cacy of cognitivetherapy and its usefulness as an intervention to achievefull remission and reduce the risk of recurrence.103,104Research has also indicated that cognitive behaviouraltherapy can be effectively implemented in non-traditionalwayseg, via telephone and the internetthat accom-modate the unique needs of primary care practice. 105,106 Arandomised clinical trial comparing cognitive behaviouraltherapy and interpersonal psychotherapy in participantswith major depression found that, on average, thetreatments were equally effective. However, for a subset ofpatients with severe depression (Montgomery-sbergDepression Rating Scale [MADRS] score >30), thoseallocated to cognitive behaviour therapy had a greaterpercentage improvement in MADRS score and also had a

greater likelihood of response than did those receivinginterpersonal psychotherapy. No difference between thetwo treatments was noted for individuals with melancholicdepression.107 For patients with three or more previousdepressive episodes, mindfulness-based cognitive therapyhas an additive benefit to usual care. Problem-solvingtherapy might be as effective as alternative psychotherapiesand pharmacotherapies for the treatment of depression,and more effective than control treatments, and might beparticularly well-suited for use in primary care.108,109

Antidepressant pharmacotherapyAlthough expansion of antidepressant treatment in theUSA has been substantial, low rates persist in racialand ethnic minorities. Antidepressants were the most

commonly prescribed class of drugs in offi ce-based andhospital outpatient-based medical practice in 2005.110 Thetable lists the antidepressants that have been approved bythe US Food and Drug Administration (FDA), and theproposed mechanisms of action for the various classes ofantidepressants. A complete assessment of their use canbe found in the American Psychiatric Association guide-lines for depression.111

Since the latest update on depression in The Lancet,112 the

results of the sequenced treatment alternatives to relievedepression (STAR*D) study113the largest depressionstudy ever done outside the pharmaceutical industryhave been reported. This study was a practical clinical trialwith broad inclusion criteria, resulting in a highlyrepresentative sample of the US population. Undertakenin both psychiatric and primary care settings, STAR*Dused up to four successive treatment steps, including aswitch to and augmentation with additional drug orcognitive therapy in an equipoise randomisation design.The goal was for full remission, rather than just response.Remission rates in steps one to four were disappointing at368%, 306%, 137%, and 130%, respectively, with acumulative remission rate of 67% after all four steps.114These rates were low compared with effi cacy trials of

A B

C

Bipolardisorder

Unipolardisorder

Healthycontrols

0

010

020

030

040

050

060

Leftsuperiorlongitudinalfasciculus

(inferiortemporalcortex)

*

Figure 3: Distinguishing bipolar and unipolar depression with measures of white-matter connectivity

Fractional anisotropy (FA) maps showing three orthogonal ([A] coronal, [B] sagittal, and [C] axial) views of the main

effect of group on FA in the region of the left superior longitudinal fasciculus for adults with bipolar depression,

unipolar depression, and for healthy controls. MNI152 brain and white-matter skeleton (green) used for randomised

analysis. The images represent findings (in red-yellow) projected onto the white-matter skeleton (green). The

red-yellow spectrum represents a significance rangeie, 2


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antidepressants, which suggests that, in actual practice,most patients need several sequential treatment steps toachieve remission. The STAR*D trial showed no clearadvantage of one strategy of drug over another for patientswho did not achieve remission after one or more acutetreatments. Furthermore, because there was no placebocontrol in this hybrid (effi cacy-effectiveness) trial, there isno way to know whether any of the strategies were betterthan maintenance of the original treatment for anadditional period. Too few patients received psychotherapy,either as an augmentation or a switch strategy, to makefirm conclusions about its role.115 Neither sociodemographicnor clinical (anxious, atypical, and melancholic) featuresmoderated the effect of various switching options after thefirst non-successful attempt at acute treatment. No dif-ferences in outcomes were found between primary careand psychiatric settings in the first two stages of acutetreatment, suggesting that primary care physicians canbe reasonable providers of care for patients with lesscomplex depression.116

Although switching of antidepressants is a commonstrategy for management of depression, whether effec-tiveness can be improved remains controversial.117 Manycombination treatment trials of antidepressant drugs orantidepressant and antipsychotic combinations havebeen done, but caution is warranted for the recom-mendation of such combinations as first-step treat-ments.118 One review119 also emphasises the dis crepancybetween practice patterns and evidence for combinationtherapy. Lithium carbonate continues to be used as anaugmentation strategy, and second-generation anti-psychotics have been intensively studied.120,121 Drugsrecommended for treatment-resistant depression arearipiprazole, quetiapine fumurate, and the combinationof olanzapine with fluoxetine.

The notion of sequential combinations of pharma-cotherapy or psychotherapy represents a shift in thetreatment of mood disorders. Such two-stage approachesare based on awareness that one treatment strategyalone is unlikely to treat the varied symptoms ofdepression. Because the switch to a different treatmentis dependent on the patients response to the firsttreatment, reassessment of design and methodologicalapproaches is needed.122

Treatment of psychotic depressionPatients with psychotic depression (presence of delusionsor hallucinations) are often diffi cult to treat and needseveral interventions. Although new pharmacologicalstrategies are being tested, electroconvulsive therapy isimportant as a frequently used and effective treatment.Antipsychotics and antidepressants are being used moreoften to treat psychotic depression. In two studies,123,124 thecombination of an antidepressant with an antipsychoticshowed greater effi cacy than did the antidepressant alone.

Drug developmentIn the past 5 years, several strategies have been developedto improve depression outcomes, including the use ofnew compounds and several older drugs. An example isa report showing the benefit of ademetionine (S-adenosylmethionine [SAMe]) augmentation in major depressivedisorder.125,126 One strategy focuses on the use of N-methyl-D-aspartate glutamate-receptor antagonists providing thepromise of rapid antidepressant action,127 includingclinically significant effects from one dose that weresustained for up to 1 week.128 Another study129 hassuggested the use of repeated dose intravenous ketaminefor the acute treatment of treatment-resistant depres-sion. Although the effect of glutamate on depression is

Drugs Proposed mechanism of action

Sel ective se rotonin reup ta ke inhibitors Cital op ram, escitalopr am,

fluoxetine, fluvoxamine,

paroxetine, sertraline

Selectively inhibits the reuptake of serotonin

Tricyclic antidepressants Amitriptyline, desipramine,

doxepin, imipramine,

maprotiline, nortriptyline,

protriptyline, trimipramine

Nonselectively inhibits the reuptake of monoamines, including

serotonin, dopamine, and norepinephrine

Norepinephrine-dopamine reuptake inhibitor Bupropion Inhibits the reuptake of norepinephrine and dopamine

Serotonin modulator Nefazodone, trazodone Primarily antagonises 5-HT2 receptors

Serotonin-norepinephrine reuptake inhibitors Desvenlafaxine, duloxetine,

venlafaxine

Inhibits the reuptake of serotonin and norepinephrine

Noradrenergic and specific serot onergic modulat or Mirtazapine Primari ly antagonises - 2 and 5- HT 2C recept ors

Serotonin reuptake inhibitor and 5-HT1A-receptor

partial agonist

Vilazodone Po tent ly and selectively inh ibits seroto nin reu pt ake and act s as a partial

agonist at the 5-HT1A receptor

MAO inhibitors Isocarboxazid, phenylzine,

tranylcypromine;Selegiline

Nonselectively inhibits enzymes (MAO-A and MAO-B) involved in the

breakdown of monoamines, including serotonin, dopamine, andnorepinephrine

MAO-B selective inhibitor

FDA=US Food and Drug Administration. MAO=monoamine oxidase. 5-HT=serotonin.

Table: Antidepressants approved by the FDA


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promising, this has not necessarily been the case for

other novel pharmacological mechanisms. The failuresof CRF1 antagonist compounds and substance-P antagon-ists have continually been noted. Another advance is theintroduction of agomelatinea melatonin (MT1 andMT2) agonist and a 5-HT2C-receptor antagonist. Ago-melatine has shown a generally favourable tolerabilityand effi cacy, therefore providing a promising alternativefor patients who do not respond to existing pharmaco-therapies, or who cannot tolerate their side-effects.130Placebo-controlled research provides evidence for theeffectiveness of agomelatine as both an acute and acontinuation treatment for major depression.131133

Suicide risk with SSRIs

The safety of SSRIs has been debated because of theirpotential association with suicidal ideation and behaviouras noted from studies of adolescents with depression.134Some work suggests that adults treated with antidepressantdrugs, including SSRIs, are no more likely to attempt orcomplete suicide than those not treated with anantidepressant. 134,135 However, other research suggests areduced risk of suicide attempt in adults after start ofSSRI treatment, particularly with sertraline,135 and inmen.134 In 226 866 male veterans with depression, rates ofsuicide attempt were lower after the start of SSRItreatment than before, and compared with treatment withother antidepressants or no antidepressant.135 Similarly, astudy of county-level data in the USA showed that adecrease in suicide rate was associated with SSRIs whenprescribed in combination with non-SSRIs or non-tricyclic antidepressants.136 Despite these findings, cautionis needed against strong conclusions being made on thebasis of limited ecological analyses.137

Safety in pregnancyData before 2000 provided weak evidence for an associationbetween SSRIs and major fetal malformation. Since then,data have shown that paroxetine might be associated withmajor malformations, especially cardiac defects.138 Someevidence is available of an association between a neonatalbehavioural syndrome and exposure to SSRIs in utero

during the last trimester. This syndrome can be managedwith supportive treatment in a special-care nursery.139Presence of persistent pulmonary hypertension in theneonate can also be associated with SSRIs taken late inpregnancy.138 Infants with continuous exposure to mothersdepression and continuous exposure to SSRIs throughoutgestation were more likely to be born preterm than wereinfants with partial or no exposure.140 Guidelines suggestthat SSRIs should be used with caution during pregnancy,and that paroxetine be avoided.141,142

Status of new somatic treatmentsAlthough deep brain stimulation is still in the earlyinvestigational stages and not approved by the FDA or theEuropean Medicines Agency, it is promising as a treatment

for treatment-resistant depression.143,144 In deep brain

stimulation, electrodes are implanted bilaterally in thebrain and are connected to an internal pulse generator.145This procedure is fully reversible and the stimulation itprovides can be adjusted on the basis of the patientsneeds.145,146 The treatment might exert its effect by modu-lating neurotransmission in the cortico-striatal-thalamic-cortical circuit.143 Work has shown the antidepressanteffect of deep brain stimulation when used within thesubgenual cingulate white matter (Cg25WM), the nucleusaccumbens,83,147 the subcollosal cingulated gyrus,148 and theventral capsule or ventral stiatum.149 This treatment hasalso been discussed for use in the anterior limb of theinternal capsule, globus pallidus internus, inferiorthalamic peduncle, rostral cingulated cortex, and lateral

haenula.144,145 Although deep brain stimulation seems to bewell tolerated, the possibility of suicide should bemonitored.147149 One study149 notes that although stableremission can be achieved with deep brain stimulation,the affective instability induced by the treatment meritsspecific attention.

Transcranial magnetic stimulation (TMS) has beenapproved by the FDA for the treatment of majordepressive disorder, especially for those who have notresponded to a course of one antidepressant drug.150Although this treatment is regarded as safe and well-tolerated, seizures can be a rare side-effect. 150,151 TMSproduces a magnetic field around the brain; the left andright dorsolateral prefrontal cortex (DLPFC) are commontarget areas for TMS in depression.150 Several meta-analyses150,152 support the use of DLPFC TMS or repetitiveTMS to treat depression, because they were more effectivethan placebo or sham. Some studies150 suggest that thesizes of these effects are comparable to treatment withantidepressants; however, the sizes are moderate150,152 andrepetitive TMS seems to be less effective than electro-convulsive therapy.151 A multisite sham-controlled study153of repetitive TMS, which included an open-label extensionfor patients who did not improve, provided the oppor-tunity to examine predictors of acute outcome. In thissample, low degree of previous drug resistance in thecurrent episode, short duration of current episode,

absence of anxiety disorder, high severity of baselinedepression, and female sex, were associated withimproved outcome in one or both parts of this trial.153

ConclusionsIncreased data for imaging and genetics in major depres-sive disorder, and other neurobiological data, providepotential biomarkers for the assessment of treatmentoutcomes. If a description of precise subgroups based onsuch data were to emerge, short-term and long-term bene-fits of treatment might be improved. Although new reportsabout treatment response in multisite studies have emer-ged in the past 5 years, treatment advances are somewhatlagging because of an inability to undertake adequatestudies with the appropriate predictors of response.


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Contributors

EF, DK, and MP wrote and revised the first and final versions of the

Seminar, did the literature searches, and interpreted the data.

Conflicts of interest

EF serves on an advisory board for Servier. DK and MP declare that theyhave no conflicts of interest.

Acknowledgments

DK and EF were supported by a grant from the National Institute ofMental Health (MH081003). EF was supported by a grant from theNational Institute of Mental Health (MH065376). MP was supportedby a grant from the National Institute of Mental Health (MH076971).We thank Tanya Fabian, Jessica Levenson, and Meredith Lotz for theirassistance with the literature search for the section about advancesin treatment.

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major depressive disorder- new clinical, neurobiological, and treatment perspectives

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