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True Remission in Depression: The Ultimate Goal

Editorial

• DEFINING REMISSION IN DEPRESSION: THE CHALLENGE OF COMPLETE RECOVERY. DÉFINIR LA RÉMISSION DANS LA DÉPRESSION : LE DÉFI DE LA GUÉRISON COMPLÈTE
  J. MENDLEWICZ, BELGIUM

Themed articles

• TIME COURSE OF RESPONSE AND REMISSION DURING ANTIDEPRESSANT TREATMENT
  H.-J. MÖLLER, F. H. SEEMÜLLER, AND M. RIEDEL, GERMANY
• THE INFLUENCE OF COMORBID ANXIETY DISORDERS ON OUTCOME IN MAJOR DEPRESSIVE DISORDER
  D. S. BALDWIN AND A. T. V. LOPES, UNITED KINGDOM
• CIRCADIAN RHYTHM DISTURBANCES IN DEPRESSION: IMPLICATIONS FOR TREATMENT AND QUALITY OF REMISSION
  P. MONTELEONE AND M. MAJ, ITALY
• IMPROVEMENT OF THE SLEEP-WAKE CYCLE AS A TARGET FOR REMISSION IN DEPRESSION
  C. R. SOLDATOS AND C. G. THELERITIS, GREECE
• SEXUAL FUNCTIONING AND QUALITY OF LIFE IN PATIENTS IN REMISSION FROM DEPRESSION
  S. H. KENNEDY AND S. RIZVI, CANADA
• EMOTIONAL BLUNTING OR REDUCED REACTIVITY FOLLOWING REMISSION OF MAJOR DEPRESSION
  J. PRICE AND G. M. GOODWIN, UNITED KINGDOM
• RESIDUAL SYMPTOMS AND RELAPSE IN DEPRESSION
  E. S. PAYKEL, UNITED KINGDOM

Controversal Question

• IS THE PATIENT REALLY THE SAME AFTER A MAJOR DEPRESSIVE EPISODE?
  M. JAREMA, POLAND / M. BAUER, GERMANY / E. SACCHETTI, ITALY / P. A. SCHMIDT DO PRADO-LIMA, BRAZIL / H. ÅGREN, SWEDEN / J. PYO HONG, KOREA / R. MAHENDRAN, SINGAPORE / A. HATIM SULAIMAN, MALAYSIA / F. CAÑAS, SPAIN / F. T. ANTUN, LEBANON

Valdoxan

• BETTER QUALITY REMISSION IN DEPRESSION: VALDOXAN, THE FIRST MELATONERGIC ANTIDEPRESSANT
  C. MUÑOZ, FRANCE

Interview

• CLINICAL MANAGEMENT OF PATIENTS FOLLOWING REMISSION FROM DEPRESSION
  W. CHOUCHA AND J.-F. ALLILAIRE, FRANCE

Focus

• INCREASING THE LEVEL OF REMISSION IN DEPRESSION BY THE SEQUENTIAL USE OF PHARMACOTHERAPY AND PSYCHOTHERAPY
  G. A. FAVA AND D. VISANI, ITALY

Update

• MEASURING REMISSION IN DEPRESSION
  J. D. GUELFI, FRANCE

A Touch of France

• RUIJIN HOSPITAL. FROM 19TH-CENTURY FRENCH JESUIT HOSPITAL TO PRESENT-DAY STATE-OF-THEART CHINESE UNIVERSITY HOSPITAL
  GU QIAN, NI LIDONG,
  HU WEIGUO, CHINA
• “PARIS OF THE ORIENT.” THE SHANGHAI FRENCH CONCESSION (1849-1946)
  D. CAMUS, FRANCE

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b y J . D . G u e l f i , F r a n c e

Julien Daniel GUELFI, MD Université Paris Descartes Clinique des Maladies Mentales et de l’Encéphale (CMME) Chef de Service: Pr F. Rouillon Hôpital Sainte-Anne Paris, FRANCE

Depression tends to be recurrent, presenting as a chronic rather than as a truly episodic condition, at least in most cases: 71% of patients remain symptomatic 1 year after diagnosis,1 and fewer than half are fully symptom-free 2 years after the index episode.2 Although the concept of remission has come under much recent scrutiny, there is still no consensus definition. In the last 15 years, attention has focused increasingly on the quality of recovery from an index episode, given that outcome in patients with residual symptoms is distinctly less favorable than in patients who are symptom- free. The present paper reviews recent developments in the concept of remission, before discussing the various methods proposed for its assessment and the clinical implications of the variable nature of residual symptoms. In a longitudinal study whose main results appeared in 2004, Kennedy et al3,4 showed that patients were only symptom-free for approximately half the mean 10-year follow-up; bouts of full depression occurred in 13% of follow-up months, bouts of minor depression in 15% of months, and bouts with residual symptoms in 20%. There is also evidence that the accumulation of recurrent depressive episodes aggravates the disease.2 Episode duration varies, becoming increasingly longer in some reports, but shorter in others.5 Long-term studies suggest that duration—whether symptom-free,6 with moderate symptoms, or full depression—is one of the most valuable criteria in patient assessment.

Several studies since the early 1990s have established that residual symptoms are common in treated depression, even in patients judged to be in remission. The most conclusive evidence, following a variety of preliminary studies,7-11 came from Paykel et al in 199512 and Judd et al in 1998 and 2000.1,13 Over 20% of patients retain clinically significant symptoms 1 year after depression.14 These percentages are much higher in the elderly.15,16
The presence of such symptoms is also a major predictor of early relapse. In 1992, Thase et al17 showed in 48 depressed patients receiving cognitive behavioral therapy (CBT) that the risk of relapse or recurrence in the year following the episode was much lower in full than in partial responders (9% vs 52%). Three years later, Paykel et al confirmed that symptom-free patients (n=40) had a much lower risk of early relapse (25%) than those with residual symptoms (n=17; 76%) (Figure 1).12
In their 10-year follow-up study, Judd et al1 found a mean time to relapse of 231 weeks in symptomfree patients, compared with 68 weeks in those with residual symptoms. The difference was even more striking when taking into account not just major depressive disorder but all types of depression (minor, acute, and chronic [dysthymia]): 184 versus 33 weeks. Review of major depressive episodes showed that symptom-free patients had a risk of relapse that was less than one-third that of patients with residual symptoms. A 2008 review by Möller18 cites two other studies highlighting the increased risk associated with residual symptoms: Lin et al in 199819 and Pintor et al in 2003,20 who found relapse risks of 15.2% versus 67.6% over 2 years.

Remission, generally defined as the disappearance of the diagnostic criteria of depression for at least 2 consecutive months, has gradually ousted treatment response as the gold-standard end point for evaluating antidepressant efficacy in long-term controlled trials. Partial remission, defined as the persistence of residual symptoms, is a risk factor for early relapse and subsequent recurrence; it is a heterogeneous state, in which the persistence of even mild symptoms reduces the hope of full functional recovery. The best criteria of high-quality remission are the disappearance of the diagnostic criteria of depression for _2 months, a score of 1 on the Clinical Global Impression–Improvement scale, a score _3 on the Hamilton Rating Scale for Depression, and a return to premorbid general functional status. Careful evaluation of residual symptoms informs the choice of the most appropriate therapeutic strategy for achieving full remission.
Medicographia. 2009;31:192-197. (see French abstract on page 197)

Keywords: depression; questionnaire; rating scale; remission; residual symptom

In 1989 the MacArthur Foundation Research Network convened a task force to establish operational criteria for the terms treatment response, remission, relapse, and recurrence. Its first publications, in particular by Ellen Frank, Robert Prien, David Kupfer, and others, were based on the review of 121 papers published in 1987-1988 in nine English-language journals. Their work differentiated the conventional efficacy measure, treatment response, from remission. Response had generally signified a 50% reduction in overall score on a validated depression scale. This end point gradually gave way to the remission end point following such studies as those by Bakish in 2001,21 Nierenberg and DeCecco the same year,22 Thase in 2003,11 and Cuffel et al23 and Keller24 in 2004. Lecrubier reviewed the widely differing definitions of remission in 2002.25
In addition to presence/absence of symptoms, duration is a key criterion. The diagnostic criteria of depression must disappear for _8 consecutive weeks before a depressive syndrome can be considered to have resolved. Until that time, the depression can be considered as being in remission to a degree, dependent on the persistence of certain symptoms, provided these are insufficient in number and intensity to warrant rediagnosis as depression. In 1994, the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) officialized the terminology of total and partial remission: “Full remission requires a period of at least 2 months in which there are no significant symptoms of depression. There are two ways for the episode to be in partial remission: (i) some symptoms of a major depressive episode are still present, but full criteria are no longer met; or (ii) there are no longer any significant symptoms of a major depressive episode but the period of remission has been less than 2 months.”
The American College of Neuropsychopharmacology Task Force adopted the following position. Remission came to be defined as the disappearance for at least 2 to 3 consecutive weeks of the main symptoms of depression (depressed mood, with loss of interest and pleasure) and the total or near dis- appearance of the nine DSM-IV diagnostic criteria of major depression. If these conditions remain stable for 4 months, remission becomes resolution.
Opting for strict criteria facilitated recognition of high-quality remission. In some cases it also revealed one antidepressant as more effective than another after comparison in terms of treatment response had failed to separate the two drugs. Thus Ferrier in 199926 combined the disappearance of the diagnostic criteria of depression and a Clinical Global Impression–Improvement (CGI-I) score of 1 to show that the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine was more effective than selective serotonin reuptake inhibitors (SSRIs).

Figure 1. Proportion of patients with ( ) and without ( ) residual symptoms relapsing after remission from depression.

After reference 12: Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25: 1171-1180. Copyright © 1995, Cambridge University Press.

◆ Diagnostic criteria
A clear distinction needs to be drawn between diagnostic criteria and rating scales or questionnaires. The purpose of diagnostic criteria is to confirm the presence or absence of a diagnosis, usually after completing a semi-structured or structured interview. DSM-IV criteria are the most commonly used, in combination with the Structured Clinical Interview for DSM-IV (SCID).27 This tool is used to confirm the absence of an ongoing depressive syndrome and to identify any residual symptoms. Kupfer published specific criteria for the elderly in 2005,28 and Kennard et al described application of the criteria to adolescents in 2006.29

◆ Rating scales
Rating scales are normally used to measure symptom intensity. The Hamilton Rating Scale for Depression (HAM-D)30 remains the world’s most widely used depression scale and the subject of a still-extensive literature, not all of which is favorable. The 2004 broadside from Bagby et al31 accused it of being psychometrically and conceptually flawed, and highlighted such shortcomings as poor inter-rater and retest reliability, and poor replication of the multidimensional factor structure. However, the consensitivity of HAM-D to change has been rarely questioned. Until recently, the scientific community more or less generally accepted the 1991 proposal by the MacArthur Foundation Task Force32 to define full remission as a maximum total score of 7 on the 17-item HAM-D (HAM-D17) and partial remission as a score of 7 to 13. This is no longer the case today. Zimmerman et al33 provided convincing evidence of heterogeneity in ex-depressive populations with average total scores <7, where the risk of relapse in particular was higher at scores of 6 or 7 than at 2 or 3. Nor do all symptoms carry equal weight. Anxiety, somatic concerns, and sleep disturbance are much less specific than loss of interest or anhedonia. Zimmerman et al also showed less psychosocial impairment in patients with a total HAMD17 score _2 than in those with a score of 3 to 7.33
Certain investigators34 continue to defend the use of HAM-D, especially when concentrated into more homogeneous subscales: 7-item scales have proved sensitive to change,35,36 with a score of 3 on HAM-D7 being equivalent to 7 on HAM-D17. Even a 6-item subscale has proved both sensitive to change and highly homogeneous.37
The Montgomery–Åsberg Depression Rating Scale (MADRS)38 has attracted similar criticism, having been found to be sensitive to change but with an unstable factor structure. Nor does a low final score (<10) guarantee remission in the absence of the duration criterion.
The Inventory of Depressive Symptomatology (IDS) was developed from 1986 onward,39 with the main validation study being published 10 years later. 40 A 16-item short form was produced in 2003,41 with further publications in 200642,43 comparing clinician and patient ratings. Our own (unpublished) studies with E. Corruble showed that the sensitivity to change of the self-rated questionnaire did not exceed that of its clinician-rated counterpart.
Depression questionnaires have yet to prove more sensitive to change than HAM-D, even if the Beck Depression Inventory (BDI)44 has been used to assess change primarily via its cognitive variables. However, this relative overall insensitivity does not disqualify questionnaires from being used to assess change in depressed patients. Residual symptoms are sufficiently varied to justify a palette of therapeutic measures and sophisticated symptom analysis, without forgetting the physical symptoms45 that must always be taken into account before deciding treatment. Specialized questionnaires can also often be useful in association with certain psychotherapy techniques. In a quarter of depressed outpatients, there is discordance between self-reported symptom severity and psychosocial functioning ratings46 that must also enter into assessment, especially in patients who deny concurrent psychosocial impairment. Thus the quality of functional remission must also be assessed.

Several investigators have emphasized the importance of functional remission in conjunction with a return to premorbid cognitive function. This type of assessment is based in part on tools designed to evaluate social and occupational integration, executive functions, well-being, or more generally, quality of life. Thus Zimmerman et al46,47 showed that the three items most frequently judged to be critical in determining remission were the presence of features of positive mental health such as optimism and self-confidence, a return to one’s normal self, and a return to usual level of functioning.
One of the best questions to ask ex-depressives is whether they feel back to their pre-depression normal self in terms of general functioning. Indeed the return to normal activity and premorbid functioning is now considered the main treatment objective. When general functioning remains impaired and there is a suggestion of personality disorder, assessment of the relationship between residual symptoms and personality becomes particularly important. The tools most frequently used for this purpose are the SCID or similar instruments for assessing personality according to the DSM-IV classification, such as the Structured Interview for DSM-IV Personality (SIDP-IV)48 or the Personality Assessment Schedule49 favored by Gene Paykel’s group in Cambridge UK.12,50,51
Assessment of full remission is ultimately a simple matter, involving confirmation of the lasting disappearance of depressive symptoms and the return to previous functioning (complete with the date of the anticipated return to work, as applicable).
Functional remission in the presence of persistent residual symptoms is a trickier problem, requiring psychometric screening to pinpoint the residual symptoms concerned, given that these vary in their functional impact. The 2-year study in 219 depressives with psychotic characteristics published by Tohen et al52 in 2000 is a case in point. Alongside conventional syndromal recovery, Tohen et al used the concept of functional recovery defined by the return to patients’ former vocational and residential status. Time to this result was shortest in bipolar married patients aged _30 years with no comorbidity, treated from disease outset, and hospitalized only briefly. In this study, functional recovery proved 2.5-fold less frequent than symptomatic recovery. Alongside specialized tools such as the Modified Vocational Status Index and Modified Vocation Code Index, the main end point was simply a CGI-I score of 1 to 2 for at least 8 weeks.
This recent transformation in the primary end point of randomized controlled trials with antidepressants inevitably results in studies that are longer than the classic efficacy trials with improvement as the primary end point.11,26 Thus whereas after treatment for 12 weeks the majority of patients have improved and are therefore considered as responders, the percentage of those in remission generally remains around 30%.45 Longer follow-up is mandatory in order to confirm the stability and quality of the remission achieved. Specific tools have been proposed for this purpose such as the Longitudinal Interview Follow-up Evaluation (LIFE) published by Keller et al in 1987.53
Considerable effort is still needed to improve antidepressant compliance. Most randomized consensitivity trolled trials reach over-optimistic conclusions in so far as the patients they include tend to be young, in good physical health, with little comorbidity, and no major risk of suicide. In real life, however, half the patients prescribed an antidepressant stop taking it within the first month, and only one quarter continue treatment for more than 3 months.18,54 Hence the importance of assessing compliance during treatment and making the requisite effort to improve it as appropriate.

Boulenger’s 2004 review55 of residual symptoms emphasized the heterogeneity among patients in partial remission. In most cases some depressive symptoms persist; in other cases, symptoms predate the depressive syndrome. They typically include anxiety, substance abuse,23 and somatic concerns that may also herald relapse or recurrence. Many symptoms are in fact antidepressant side effects, in particular sleep disturbance,45,56 cognitive impairment, and various somatic (notably sexual) complaints, all of which are often long-term in nature,57 although in a study performed by Nierenberg et al in 1999,58 insomnia and fatigue appeared to persist after treatment (Figure 2).59
In the general population residual impairment in occupational functioning or other activities often resolves more rapidly than residual symptoms.14 Also, a higher level of symptom variability during maintenance treatment carries a higher risk of recurrence, 60 with personality playing a role in the frequency of symptom episodes.
Awareness of the importance of remission inspired a number of studies specifically designed to treat residual symptoms, whether with drugs, psychological approaches using information and psychoeducation, or CBT.9,22,43,56,59,61-67 Some emphasized the importance of cotreatments to control anxiety, sleep disturbance, drowsiness, apathy, and cognitive impairment.22,59 These included the use of various agents, including psychostimulants to enhance antidepressant efficacy or diminish side effects.67 The drawback to this type of approach, for which patients often plead on a drug per symptom basis, is that it results in multiple cotreatments that only compound the risk of side effects.
Results in the CBT literature are a mixed bag. In some cases, CBT provides no added benefit over an increase in antidepressant dose66; in other hands, it has positive effects.61-63,65,68-70 (reviewed in Perlis et al66). Its efficacy may be due to the fact, according to the Cambridge UK group, that it “changes the way that [patients] process depression-related material rather than changing belief or depressive thought content.”65 This multicenter controlled trial used classic rating tools supplemented by a number of questionnaires developed by specialists in the cognitive approach: (i) Peterson et al’s 1982 Attributional Style Questionnaire (ASQ),71 comprising three 7-point scales; (ii) Weissman and Beck’s 1978 Dysfunctional Attitudes Scale (DAS),72 comprising 40 7-point statements; (iii) Perceived Uncontrollability of Depression (UNCONTROL),65 a 10-item ad hoc scale; (iv) Characterological Self Blame for Depression (BLAME),65 a 7-point 10-item ad hoc scale; and (v) Metacognitive Awareness Questionnaire (MAQ),65 a 7-point 9-item instrument.

Figure 2. Frequency of residual major depressive disorder symptoms in responders (215 patients with major depressive disorder received a fixed dose of fluoxetine 20 mg for 8 weeks).

After reference 59: Fava M. Pharmacological approaches to the treatment of residual symptoms. J Psychopharmacol. 2006;20:29-34. Copyright © 2006, British Association for Psychopharmacology.

Analysis of patient responses revealed that “extreme responses (‘totally agree’ or ‘totally disagree’) to depression-related questionnaire items are the ‘tip of the iceberg’ reflecting underlying activity of mood-dependent, developmentally early, depressogenic schematic processing, uncorrected by subsequent reappraisal. Such schematic processing, it is suggested, is an integral part of self-perpetuating patterns of negative thinking.”65 The positive effects of therapy appear more probably due to the acquisition of compensatory skills than to changes in thought content.

Kennard et al29 treated 439 depressed adolescents with fluoxetine, CBT, a combination of the two, or placebo with clinical management (combination therapy proved significantly the most effective). The two main instruments were the Children’s Depression Rating Scale–Revised (CDRS-R) by Poznanski and Mokros,73 comprising 17 items scored from 1 to 5 or from 1 to 7, and Shaffer et al’s Children’s Global Assessment Scale (CGAS).74
In this study, the end point of a CDRS-R score <28 proved stricter than the disappearance of the diagnostic criteria of depression on Kaufman et al’s Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (Kiddie-SADS-P/L).75

Assessment of remission quality in depression needs to combine semistructured interviews to determine the degree of disappearance of the diagnostic criteria of depression, specialized scales to assess the extent of residual symptoms, duration criteria, and questionnaires that target subjective mood as well as more objective end points of return to the normal functional self, return to work and normal social activities, and quality of life. Evaluation of associated symptoms, such as anxiety, substance abuse, or personality vulnerability, often provides a valuable guide to treatment. _

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58. Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry.1999;60:221-225.
59. Fava M. Pharmacological approaches to the treatment of residual symptoms. J Psychopharmacol. 2006; 20:29-34.
60. Karp JF, Buysse DJ, Houck PR, Cherry C, Kupfer DJ, Frank E. Relationship of variability in residual symptoms with recurrence of major depressive disorder during maintenance treatment. Am J Psychiatry. 2004;161:1877-1884.
61. Fava GA, Grandi S, Zielezny M, Rafanelli C, Canestrari R. Four-year outcome for cognitive behavioral treatment of residual symptoms in major depression. Am J Psychiatry. 1996;153:945-947.
62. Riso LP, Thase ME, Howland RH, Friedman ES, Simons AD, Tu XM. A prospective test of criteria for response, remission, relapse, recovery, and recurrence in depressed patients treated with cognitive behavior therapy. J Affect Disord. 1997;43:131-142.
63. Fava GA, Rafanelli C, Grandi S, Canestrari R, Morphy MA. Six-year outcome for cognitive behavioral treatment of residual symptoms in major depression. Am J Psychiatry. 1998;155:1443-1445.
64. Fava GA. Subclinical symptoms in mood disorders: pathophysiological and therapeutic implications. Psychol Med. 1999;29:47-61.
65. Teasdale JD, Scott J, Moore RG, Hayhurst H, Pope M, Paykel ES. How does cognitive therapy prevent relapse in residual depression? Evidence from a controlled trial. J Consult Clin Psychol. 2001;69:347-357.
66. Perlis RH, Nierenberg AA, Alpert JE, et al. Effects of adding cognitive therapy to fluoxetine dose increase on risk of relapse and residual depressive symptoms in continuation treatment of major depressive disorder. J Clin Psychopharmacol. 2002;22:474-480.
67. Menza M, Marin H, Opper RS. Residual symptoms in depression: can treatment be symptom-specific? J Clin Psychiatry. 2003;64:516-524.
68. Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in residual depression by cognitive therapy: a controlled trial. Arch Gen Psychiatry. 1999;56:829- 835.
69. Scott J, Teasdale JD, Paykel ES, et al. Effects of cognitive therapy on psychological symptoms and social functioning in residual depression. Br J Psychiatry. 2000;177:440-446.
70. Jarrett RB, Kraft D, Doyle J, Foster BM, Eaves GG, Silver PC. Preventing recurrent depression using cognitive therapy with and without a continuation phase: a randomized clinical trial. Arch Gen Psychiatry. 2001; 58:381-388.
71. Peterson C, Semmel A, von Baeyer C, Abramson LY, Metalsky GI, Seligman ME. The attributional Style Questionnaire. Cogn Ther Res. 1982;6:287-299.
72. Weissman AN, Beck AT. The Dysfunctional Attitudes Scale. Presented at the annual meeting of the Association for the Advancement of Behavior Therapy, Chicago USA, November, 1978.
73. Poznanski EO, Mokros HB. Children’s Depression Rating Scale-Revised, Manual. Los Angeles, USA: Western Psychological Services; 1996.
74. Shaffer D, Gould MS, Brasic J, et al. A children’s global assessment scale (CGAS). Arch Gen Psychiatry. 1983;40:1228-1231.
75. Kaufman J, Birmaher B, Brent D, et al. Schedule for Affective Disorders and Schizophrenia for School- Age Children-Present and Lifetime Version: Initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36:980-989.

FRENCH-LANGUAGE LITERATURE
A selection of recent publications in French devoted wholly or in part to the determinants of outcome in depression:
– Guelfi JD, Corruble E, Duret C, Pham-Scottez A, Purper-Ouakil D. Personnalité et Troubles de l’Humeur. Paris, France: Doin; 1999.
– Guelfi JD, Rouillon F. Psychiatrie. Paris, France: Elsevier-Masson; 2007.
– Hardy-Bayle MC, Olivier V. Quels Critères de Guérison Pour les Etats Dépressifs? Paris, France: Doin; 1998.
– Loas G, Chaperot C, Kapsambelis V, Legrand A. L’Anhédonie. L’Insensibilité au Plaisir. Paris, France: Doin; 2002.
– Olié JP, Poirier MF, Lôo H. Les Maladies Dépressives. 2nd ed. Paris, France: Médecine-Sciences Flammarion; 2003.
– Passerieux C, Hardy-Bayle MC. La Guérison des Etats Dépressifs. Paris, France: Doin; 2004.
– Rouillon F. Les Troubles Dépressifs Récurrents. Paris, France: John Libbey Eurotext; 2003.

Le critère de rémission a progressivement remplacé celui de réponse thérapeutique dans l’évaluation de l’efficacité des traitements antidépresseurs. C’est en effet ce critère qui est désormais le gold standard dans les essais contrôlés au long cours. On considère généralement qu’un patient est en rémission lorsque les critères diagnostiques de dépression ont disparu depuis plus de deux mois consécutifs. La persistance de symptômes résiduels dans les rémissions partielles représente un facteur de risque de rechute précoce puis de récidive. L’état de rémission partielle est lui-même hétérogène puisque l’espérance d’une récupération fonctionnelle complète est moindre lorsque persistent plusieurs symptômes, même d’intensité légère. Les meilleurs critères d’une rémission de haute qualité sont la disparition des critères diagnostiques durant au moins deux mois, une note de 1 à la CGI-amélioration, une note nulle ou au maximum égale à 3 à l’échelle de dépression de Hamilton et un retour à l’état de fonctionnement général prémorbide. L’évaluation fine d’une symptomatologie résiduelle éventuelle permet de retenir la stratégie thérapeutique paraissant a priori la plus adaptée pour obtenir une rémission complète des troubles.

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by P. M o n t e l e o n e a n d M . M a j , I t a l y

Palmiero MONTELEONE, MD Mario MAJ, MD, PhD Department of Psychiatry University of Naples SUN Naples, ITALY

Mood disorders, especially unipolar depression and seasonal affective disorder, have been linked to endogenous circadian rhythm abnormalities. Evidence is emerging that disruption of the normal circadian rhythmicity occurs at least in a subgroup of depressed patients, although whether there is a causal link between endogenous circadian rhythm disruption and depression has not been firmly demonstrated. Nonetheless, improvements in some forms of depression in response to strategies that manipulate circadian rhythms support the idea that circadian abnormalities observed in depressed patients may constitute a core component of the pathophysiology of depression and are worthy of therapeutic consideration. Chronotherapeutic interventions, which include both nonpharmacological strategies, such as sleep deprivation, light therapy, and interpersonal and social rhythm therapy, and pharmacological treatments based on the use of drugs specifically endowed with chronobiotic properties, such as agomelatine, have been shown to have antidepressant effects. Therefore, normalization of circadian rhythms seems to represent a possible new direction for the development of either pharmacological or nonpharmacological innovative therapeutic strategies, which could have an important future role as alternatives or adjuvants to currently available antidepressant treatments, in order to achieve a better quality of remission and a persistent amelioration of patients’ social functioning and quality of life.
Medicographia. 2009;31:132-139. (see French abstract on page 139)

Keywords: circadian rhythm; depression; remission; chronotherapy; antidepressant

Over the course of evolution, organisms have developed cellular clock mechanisms sensitive to light, and have adapted by organizing their activities in 24-hour cycles determined by sunrise and sunset. These cycles do not simply reflect an organism’s passive response to environmental changes, such as the light-dark cycle, but rather represent pre-adapted endogenous rhythms, which arise from a timekeeping system within the organism and that persist in the absence of any environmental stimuli. The endogenous timekeeping system or biological clock allows the organism to anticipate and prepare for the changes in the environment that are associated with day and night in order to function optimally. In humans and other mammals, circadian rhythms are generated by an internal clock or pacemaker, which is located in the suprachiasmatic nucleus (SCN) of the hypothalamus.¹ Individual neurons from the SCN, when dissociated and held in vitro, retain a robust circadian rhythm in electrical firing, and this can continuously be recorded for several weeks, showing a slight deviation from 24 hours (usually longer).² Thus, the intrinsic rhythmicity of the endogenous clock requires daily synchronization to the 24-hour day by regularly occurring environmental signals or “zeitgebers.” Light, the major zeitgeber for the SCN, reaches the SCN neurons directly via the retinohypothalamic tract, a non– image-forming pathway, and indirectly via the intergeniculate leaflet of the lateral geniculate complex. The activity of SCN neurons is also modulated by serotonin (5-HT) released by nervous fibers ascending from the raphe nuclei³ and by melatonin secreted in the pineal gland.⁴

The major output of the SCN is to the paraventricular nucleus (PVN) of the hypothalamus, and via a multisynaptic pathway, to the pineal gland, where melatonin is synthesized according to the length of the photoperiod. In this way, melatonin is secreted at night and suppressed by light during the day. Melatonin is a biochemical transducer of photoperiodic information to all cells in the body (including SCN neurons), signaling the seasonal variations of the day/night cycle length.⁵ The PVN is also the site of autonomic neurons, which communicate the time-of-day signal to different body organs, and corticotrophin-releasing factor–secreting neurons, which are part of the hypothalamopituitary- adrenal (HPA) axis, endowed with a diurnal rhythmicity. Therefore, the SCN time signal is translated into hormonal and autonomic signals for peripheral organs mainly within the PVN.
Beside light there are also other nonphotic zeitgebers (among them exercise, food availability, temperature, jobs, and social demands) and these also act directly or indirectly on the SCN to synchronize its rhythmic activity. Furthermore, it is now widely demonstrated that multiple endogenous clocks are distributed in every organ and perhaps in every cell of the organism, and each of them has its own zeitgebers.⁶
Nearly all physiological and behavioral functions in humans are rhythmic, and examples to be mentioned here are the secretion patterns of hormones (prolactin, corticotrophin, cortisol, growth hormone, melatonin), the sleep-wake cycle, core body temperature, thyroid function, urine output, and bronchial smooth muscle reactivity. These rhythms enable the organism to synchronize endogenous processes of the internal milieu and to anticipate the periodic fluctuations in its external environment, with the aim of optimally dealing with them.

Given that most human functions demonstrate circadian rhythmicity, it is intuitive that alterations in the endogenous machinery regulating biorhythms may lead to both physical and mental disorders.^7-9 In particular, disruptions of endogenous biological rhythms have been strongly associated with mood disorders, especially unipolar depression, for which alterations of circadian rhythms were first described more than 20 years ago.¹⁰ There are several lines of evidence supporting the occurrence of a dysregulation of the endogenous clock system in subgroups of affective patients (Table I).^11-53

◆ Diurnal mood variation
First of all, on the one hand, some affective disorder patients suffer from regular cycles of recurrence of mood episodes, and on the other hand, approximately 20% of depressive patients show marked diurnal mood swings. In a recent post-hoc analysis of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, it was reported that 21.6% of the depressed patients enrolled in the study experienced diurnal mood variation, and that compared with patients without diurnal mood variation, they exhibited more severe depression and were more likely to meet the criteria for the melancholic subtype of depression.¹¹ Of note, a pattern of worse mood in the morning is incorporated into the formal formal DSM-IV (Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition) criteria for the melancholic subtype of major depression, although in the post-hoc STAR*D study analysis, diurnal mood variation was more meaningfully related to symptoms of melancholia if the definition was expanded to include also afternoon and evening worsening of mood.¹¹ Also, patients with other forms of depression actually appear to report a pattern of diurnal mood variation.⁵⁴ In a recent investigation using a two-factor model of mood categorized according to positive affect and negative affect, diurnal variations in these two mood dimensions were compared between a group of patients with major depression and a group of healthy controls.⁵⁵ Results indicated that depressed patients showed lower overall levels of positive affect, which increased over the course of the day as in healthy controls but with a backward-shifted acrophase, and higher overall negative affect levels, with maximum values occurring in the late morning and then decreasing over the rest of the day. Furthermore, Germain et al¹² provided preliminary evidence that diurnal mood variations in major depressive disorder patients were paralleled by diurnal variations in regional brain glucose metabolism.

Table I. Evidence in support of a dysregulation of the endogenous clock system in some patients with mood disorders.

◆ Core body temperature
For core body temperature, a robust circadian rhythm has been well established, with the highest values occurring in the evening and the nadir occurring during the last third of the night. An elevated nocturnal body temperature is the most consistently observed circadian abnormality in depression,^13,56 and this aberration generally normalizes with clinical improvement.⁵⁷ Although not confirmed by all studies, a phase-advance in the overall 24-hour pattern of body temperature has been also reported in many depressed patients.^13-16 Moreover, in subjects experiencing a depressive episode, nighttime changes in body temperature have been found to be inversely correlated with nighttime changes in plasma levels of thyroid stimulating hormone (TSH).¹³ The mean plasma concentration of TSH during sleep, its nocturnal peak concentration, and the amplitude of its circadian rhythm have been reported to be lower in depressed subjects compared with both normal controls and remitted patients.¹⁷ Finally, the time of the nocturnal TSH peak has been found to be advanced during a depressive episode.¹⁷

◆ Cortisol secretion
In healthy subjects, maximal secretion of cortisol occurs in the morning; thereafter, there is a progressive decline over the day until the nadir is reached in the evening, immediately after falling asleep. Dysregulation of the HPA axis is extremely frequent in depressed patients. A meta-analysis on cortisol in depression revealed an overall increase in cortisol secretion, with the largest effect at the nadir of the circadian rhythm and an earlier onset of the first cortisol secretory episode, consistent with a phase-advance of the cortisol circadian rhythm in depression.¹⁸

◆ Melatonin secretion and the sleep-wake cycle
Several studies have also reported on alterations in the melatonin secretory pattern in depression: the most consistent finding has been a lower blood concentration of melatonin and a phase advance, or a trend toward a phase advance, of the melatonin circadian rhythm in individuals suffering from major depression^19,20; this was, however, not confirmed in all studies.⁵⁸ Moreover, a modified sensitivity of demonstrated in bipolar patients and their offspring.^21,22
The sleep-wake cycle is the most obvious circadian rhythm in humans, and sleep disturbances represent a prominent feature of depression. Epidemiological studies estimate that 50% to 90% of patients with diagnosed depression complain about impairment of their sleep quality.^23,24 Typically, the complaints of depressed patients are about the difficulty in falling asleep, frequent nocturnal awakening, and early morning awakening. Insomnia is thereby not only experienced subjectively, but also reflected objectively in altered sleep architecture, as first demonstrated by Kupfer and colleagues in the early 1970s.25 These abnormalities consist of impaired sleep continuity and duration, a reduction of slow-wave sleep (SWS), a shortening latency of the initial rapid eye movement (REM) phase, an increase in the proportion of REM sleep in the early part of the night, a prolongation of the first REM period, an increased amount of total REM sleep, and an increased number of eye movements during REM periods (REM density).²⁶ Longitudinal electroencephalogram studies in depressed patients have described a tendency for REM sleep abnormalities to resolve with improvement of the depression,^59,60 and even total normalization has been reported after successful treatment.⁶¹ However, other studies have reported the persistence of REM sleep and SWS abnormalities during remission, even after nonpharmacological treatments.^62-64 Persistent and/or residual sleep disturbance has thereby been associated with an increased risk of relapse,⁶⁵ and the persistence of reduced SWS has similarly been associated with more rapid and more frequent recurrence of depression.⁶⁶

◆ Motor activity
Motor activity shows a typical circadian rhythm in humans, and most although not all investigations have documented a phase advance (early daily peak) of the circadian motor activity rhythm in bipolar disorder patients in both the depressive and the manic phases as well as during euthymia.^27-29

◆ Seasonal affective disorder
Seasonal changes in mood, appetite, sleep, and daily living function occur physiologically in many individuals. If these variations are of sufficient severity to meet the criteria for a major depressive episode, occur regularly during fall/winter, and are generally followed by a remission during the subsequent spring and summer period, they may be regarded as an episode of seasonal affective disorder (SAD). SAD is a disorder with a circannual period, and patients with SAD present with apparent chronobiological abnormalities; hence, it is currently assumed that SAD is a disorder of seasonal biological rhythms.⁶⁷ Abnormalities of circadian rhythms in SAD patients include sleep disturbances, quantitative changes and phase delays in cortisol and melatonin secretion patterns, and increases in the minima of the nocturnal body temperature as well as a phase delay of its 24-hour rhythm.^68-70

The fact that a wide variety of endogenous rhythms are disrupted in individuals with depression has led to speculation that such disturbances are not unique to specific rhythms, but are associated, instead, with a disruption in the activity of the circadian master pacemaker in the SCN. Therefore, it is plausible that alterations of the molecular components of the endogenous clock system play a role in the disturbed circadian rhythms of mood disorder patients. The cellular machinery behind the circadian timing within the SCN neurons has been largely identified, and it is believed to be under genetic control. Genes encoding essential elements of the clock include, in mammals, period (per1, per2, per3), neuronal PAS domain protein-2 (NPAS2), circadian locomotor output cycles kaput (CLOCK), cryptochrome (Cry1, Cry2), and brain and muscle ARNT-like-1 (bmal1) genes. The proteins encoded by these genes are part of a circadian autoregulatory loop incorporating activators and suppressors of genes, whose activity thereby oscillates with a circadian period, thus generating the endogenous rhythmicity of SCN neurons.⁷¹
Both animal and human studies have provided preliminary evidence of a role for circadian genes in mood disorders. Mice carrying a mutation in the CLOCK gene display a behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, reduced depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation.⁷² Interestingly, many of those mania-like behaviors are reverted by chronic lithium administration and are rescued by expressing a functional CLOCK protein specifically in the ventral tegmental area of CLOCK mutant mice.⁷²
Studies in humans have begun to identify polymorphisms in certain circadian genes that are associated with mood disorders and, in particular, bipolar disorder. The T3111C single nucleotide polymorphism (SNP) of the CLOCK gene has been investigated in both major depression and bipolar disorder. Whereas no differences were found in allelic frequencies between individuals with a history of major depression and healthy controls,³⁰ the CC genotype has been associated with a greater severity of insomnia during antidepressant treatment, a higher recurrence rate of bipolar episodes, and a reduced need for sleep in bipolar patients.^31-33 In a family-based sample of bipolar patients, an analysis of 46 SNPs in 8 clock genes revealed a significant although modest association of BMAL1 and TIM genes with the mood disorder.³⁴ An independent study using haplotype analysis confirmed the association of bipolar disorder with the BMAL1 gene and detected a new association with the PER3 gene.³⁵ Finally, bipolar patients with the TT genotype of the T50C SNP of the glycogen synthase kinase-3β gene, which encodes an enzymatic protein regulating central clock mechanisms, were found to be of an earlier age at the onset of bipolar disorder and to experience less improvement from lithium therapy than patients with the TC or CC genotypes.^36,37 Recent studies suggest that SNPs of PER2, NPAS2, and BMAL1 genes are associated with an increased risk for SAD; furthermore, certain allelic combinations of SNPs of these three genes have an additive effect, increasing the risk of developing SAD by 4.43 over other genotypes, and 10.67 over the most protective genotype.³⁸
Based on the above findings, it could be suggested that primary or secondary alterations of the biological clock at the molecular level could lead to disruptions in endogenous circadian rhythms, which in turn may generate the depressed state. Alternatively, it has been proposed that instead of or in addition to molecular abnormalities of the endogenous pacemaker, disturbances in environmental zeitgebers may cause depressive symptoms in biologically predisposed individuals.⁷³ This social zeitgeber theory specifically postulates that depressive episodes arise as a consequence of life events causing a disturbance of social zeitgebers (ie, social factors such as the timing of meals, work schedules, social demands, personal relationships), which, in turn, derail an individual’s social rhythms. These disruptions can place substantial stress on the body’s capacity to maintain stable biological rhythms, particularly sleep-wake, energy, alertness, and appetite rhythms. Whereas in most individuals such rhythms will restabilize shortly after the destabilizing events, in predisposed subjects, they may precipitate a major depressive episode.
Finally, as suggested by Turek,⁷⁴ the expression of most rhythms at the behavioral, physiological, and biochemical level is regulated by the integration of inputs from the circadian clock and the sleepwake state of the organism. Thus, the circadian and sleep control centers have evolved together to ensure a timely coordination between the internal and external environment in order to optimize the survival of the species. Therefore, it could be that a primary circadian disturbance of the sleep-wake cycle leads to insomnia that may desynchronize many endogenous rhythms, which then, in turn, may lead to a depressed state. In support of this latter view, evidence has been provided that insomnia is a risk factor for the development of depression,^75-77 as well as for relapse and recurrence.^78-80 Most of the circadian abnormalities observed in the depressed state normalize with recovery, therefore it cannot be excluded that they arise as consequence of depression and do not represent the primary determinants of the affective disorder. However, even if so, the presence of disrupted endogenous rhythms might potentially contribute to the maintenance of depressive symptoms and might affect the course and/or the prognosis of the affective episode. Therefore, circadian abnormalities of depressed patients are worthy of clinical and therapeutic consideration.

The ideal antidepressant treatment should combine high short-term efficacy for the acute phase of treatment with long-term efficacy and tolerability for the maintenance phase. This would result in a high quality of remission, in which patients are asymptomatic with no or only minimal residual symptoms, and experience a full restoration of day-today functioning and quality of life. Currently used antidepressant drugs, which act more or less specifically on brain monoamines, are frequently associated with significant limitations such as low remission rates, high risk of relapse, slow onset of response, discontinuation symptoms, and side effects— especially sleep disturbances. Since a disruption of the normal circadian rhythmicity occurs at least in a subgroup of depressed patients and is believed to play a role in the pathophysiology of depression, it is theoretically likely that interventions able to induce phase shift within the circadian system, so that normal rhythmic patterns are restored, may result in a high quality of remission. Therefore, chronotherapeutic interventions have been developed, and these include both nonpharmacological strategies, such as sleep deprivation, light therapy, and interpersonal and social rhythm therapy (IPSRT), and pharmacological treatments based on the use of drugs specifically endowed with chronobiotic properties.

◆ Sleep deprivation
One night of total sleep deprivation induces rapid and effective, although short-lasting, antidepressant effects.³⁹ Variants of total sleep deprivation, such as selective REM sleep deprivation and partial sleep deprivation, especially in the second half of the night, are also effective, although total sleep deprivation seems to be superior.³⁹ However, the therapeutic effect of sleep deprivation does not last longer than one or maximally a few days, and this intervention seems to work in less than 50% of patients.³⁹

◆ Light therapy
Light therapy is the treatment of choice for SAD, where its astonishing success has led to the conclusion that it has to be considered the most successful clinical application of the circadian rhythm concept in psychiatry. It moves from the hypothesis that reduced ambient light during fall/winter leads to SAD symptoms in predisposed individuals⁴⁰; thus lengthening the photoperiod by exposing patients to bright light early in the morning before dawn or in the evening has been proven to exert antidepressant effects.⁴¹ It has subsequently been proposed that most patients with SAD become depressed in fall/winter at least in part because the later dawn in winter causes a delay in the patients’ endogenous circadian rhythms with respect to clock time and the sleep-wake cycle.⁴² Therefore, providing a corrective phase advance should be useful in realigning endogenous rhythms with the sleepwake cycle. In SAD patients, exposure to bright light in the morning, which causes a phase advance of endogenous circadian rhythms, has been shown to produce higher antidepressant effects than exposure in the evening, which causes a phase-delay of endogenous rhythms.⁴⁰ However, some SAD patients are actually phase-advanced, and this may explain why in some studies, bright light scheduled in the evening has been proven to have an antidepressant effect that is equal to that of morning exposure.⁴⁴ Guidelines for the treatment of SAD patients with bright light have recently been provided.⁴⁵ Standard light treatment involves exposure to 1 to 2 hours of a 2500-10000 lux light box in the morning immediately upon awakening, and for those patients who do not respond to this schedule, a trial of evening bright light (7-9 PM) may be necessary.

◆ Interpersonal and social rhythm therapy
IPSRT was specifically designed to maintain regular daily rhythms, as well as identify and manage potential precipitants of rhythm disruptions, in accordance with the social zeitgeber theory that depressive episodes arise as a consequence of life events that disturb social zeitgebers.⁷³ Therefore, restoring the depressed patient’s social zeitgebers, such as personal relationships, meals, exercise, and social demands, would result in normalization of biological rhythms and an improvement in mood. Two preliminary studies have shown that although increasing bipolar individuals’ social rhythm regularity did not improve their mood, participants treated with IPSRT experienced longer episode-free periods and were more likely to remain well in the 2-year preventive maintenance study phase.^46,47

◆ Agomelatine
As for pharmacologic interventions, melatonin has been identified as having chronobiotic properties in both rodents and humans^81,82; therefore, it is supposed that the pineal hormone has an antidepressant effect. However, the few studies in which melatonin has been administered to depressed patients have found an improvement in sleep, but no effect on depressive symptoms^83,84 and no enhancing effect on existing antidepressant therapies in patients with treatment-resistant depression.⁸⁵ By contrast, agomelatine, a compound with agonistic properties at melatonergic MT1 and MT2 receptors and antagonistic properties at 5-HT2C receptors,⁸⁶ which are highly expressed in the SCN,⁸⁷ has shown antidepressant properties in both preclinical and clinical studies.^88-91 It must be pointed out that the antidepressant effect of agomelatine is not solely mediated via its melatonergic action at the MT1 and MT2 receptors, but rather also depends on the compound’s 5-HT2C antagonistic property.⁹² This may explain the above reported lack of antidepressant action of exogenous melatonin, which acts only on MT1 and MT2 receptors. It seems that, differently from currently available antidepressant drugs, agomelatine possesses specific chronobiotic properties, since it was able to regulate the sleep-wake cycle and restore abnormal circadian rhythms in animal models of disrupted circadian rhythms.^48-50 In patients suffering from major depression, a recent polysomnographic study indicated that agomelatine increased the duration of SWS and normalized its distribution throughout the night.⁵¹ In a headto- head comparison study between venlafaxine and agomelatine in major depressive disorder patients, an earlier and better improvement of subjective measures of getting to sleep, quality of sleep, and ease of awakening have been reported with agomelatine.⁵² Moreover, agomelatine has been shown to be significantly superior to placebo in rates of clinical response and remission in a study in which the remission criteria (Hamilton Rating Scale for Depression score _6) were more stringent than usual⁵³; the comparator in this study, paroxetine, had lower response and remission rates.⁵³ Finally, in all the above clinical trials, agomelatine exhibited a favorable sexual side-effect profile and was in general well tolerated. All these data are indicative of agomelatine’s potential to renormalize circadian rhythms, including sleep-wake cycle alterations, without sedative effects and no sexual impairment, which could possibly lead to better adherence to antidepressant treatment, optimization of the achievement of full recovery with a high quality remission, and restoration of patients’ quality of life.

Although a number of effective antidepressant drugs have been introduced in recent years, there remain significant unmet needs in the treatment of depression. Only approximately 30% of depressed patients achieve remission, and even for remitted patients, residual symptoms or drug side effects (eg, sleep disturbances, sexual dysfunction, weight gain) can re- duce the quality of remission. Moreover, some antidepressant side effects can impair short-term and long-term patient adherence to treatment, thus favoring no response, relapse, and/or recurrence.
At present, it is clear at the descriptive level that some individuals with depression have circadian rhythm abnormalities; whether there is, however, a causal link between endogenous rhythm disruption and depression has not been firmly demonstrated, although evidence seems to be emerging that this is the case. Nonetheless, improvement in some forms of depression in response to strategies that manipulate circadian rhythms support the idea that circadian abnormalities observed in depressed patients may constitute a core component of the pathophysiology of depression. Therefore, normalization of circadian rhythms seems to represent a possible new direction for the development of either pharmacological or nonpharmacological innovative therapeutic strategies to treat depression. This new direction, in which circadian rhythms are directly targeted, could hold promise for the identification of chronotherapeutic strategies that, compared with currently-available antidepressant treatments, could have more solid efficacy and fewer side effects, achieving a better quality of remission and a persistent amelioration of patients’ social functioning with a more complete restoration of their quality of life. _

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Les troubles de l’humeur, et en particulier les troubles dépressifs unipolaires et les troubles affectifs saisonniers, sont liés à des anomalies endogènes du rythme circadien. La perturbation de la rythmicité circadienne normale interviendrait au moins dans un certain sous-groupe de patients déprimés, le lien causal entre la perturbation du rythme circadien endogène et la dépression n’ayant néanmoins pas été formellement démontré. Cependant, l’amélioration de certaines formes de dépression en réponse à des stratégies agissant sur les rythmes circadiens permet de penser que les anomalies circadiennes observées chez les patients déprimés pourraient constituer une composante clé de la physiopathologie de la dépression méritant d’être prise en considération. Des actions chronothérapeutiques, comprenant à la fois des stratégies non pharmacologiques, telles que la privation de sommeil, la luminothérapie et la psychothérapie interpersonnelle et des rythmes sociaux (PTIRS), ainsi que des traitements pharmacologiques fondés sur l’utilisation de médicaments dotés de propriétés chronobiotiques, comme l’agomélatine, ont montré des effets antidépresseurs efficaces. Ainsi, la normalisation des rythmes circadiens représente une nouvelle direction possible pour le développement de stratégies thérapeutiques innovantes, pharmacologiques ou non, qui pourraient avoir un rôle futur important comme alternative ou adjuvant aux traitements antidépresseurs actuellement disponibles, afin d’obtenir une meilleure qualité de rémission et une amélioration durable de la qualité de vie et de fonctionnement social des patients.

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b y D . S . B a l d w i n a n d A . T. V. L o p e s , U n i t e d K i n g d o m

David S. BALDWIN, DM FRCPsych Antonio T. V. LOPES, MB BS, MRCPsych Clinical Neuroscience Division School of Medicine, University of Southampton Mood and Anxiety Disorders Service Hampshire Partnership Trust Southampton, UNITED KINGDOM

Anxiety symptoms are common in patients experiencing major depressive episodes, being reported by approximately 60% of patients, and comorbid anxiety disorders are seen in around 50% of patients with major depressive disorder. 1 One of the early findings of the influential US Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was that “anxious depression,” defined as a score of 7 or greater on the anxiety- somatization subscale of the Hamilton Rating Scale for Depression,2 was seen in 49% of the patients in primary care, and by 42% of those treated in secondary care.3 Furthermore, a comorbid anxiety disorder was present in approximately half of patients, regardless of the treatment setting.4 This degree of comorbidity is also seen in nonclinical samples: for example, the results of a systematic review of European community studies among people aged 18-65 years found that approximately 30%- 40% of patients with a depressive disorder had a comorbid anxiety disorder, and vice versa.5 The recent European Study of the Epidemiology of Mental Disorders (ESEMeD) also found a high 12-month prevalence of comorbid mood and anxiety disorders (Figure 1).6
There have been few studies of the comorbidity between anxiety and depressive disorders in later life, although a Dutch community study of people aged 55-85 years found that 47.5% of those with a major depressive disorder also met criteria for at least one anxiety disorder, and 26.1% of those with anxiety disorders fulfilled the criteria for major depression. 7 This observation is supported by the findings of studies involving clinical samples of older depressed patients, in whom comorbid anxiety disorders have been found to vary in frequency from between 3%-65%.8-10

Coexisting anxiety symptoms and comorbid anxiety disorders are common in patients with major depressive disorder. This review examines three aspects of the relationship between major depressive disorder and comorbid anxiety disorders: whether the comorbid condition is more severe than “pure” major depression; whether the comorbid condition is associated with worse clinical outcomes than are seen in major depressive disorder alone; and whether the response to antidepressant treatment differs between depressed patients with or without comorbid anxiety disorders. Although not all evidence is consistent, in general terms, the presence of comorbid anxiety disorders in patients with major depressive disorder is associated with greater severity of symptoms and more pronounced impairment. The course of illness is less favorable in patients with the comorbid condition, and relatively fewer depressed patients respond to antidepressant treatment and achieve remission of symptoms if affected by comorbid anxiety disorders. There is a need for randomized placebo-controlled studies specifically in patients with comorbid major depressive disorder and anxiety disorders, in order to determine whether this patient group differs from those with “pure” major depression in its responsiveness to pharmacological or psychological interventions.
Medicographia. 2009;31:126-131. (see French abstract on page 131)

Keywords: major depression; anxiety disorder; comorbid; outcome; response

This review examines three key aspects of the relationship between major depressive disorder and comorbid anxiety disorders. First, whether the comorbid condition is more severe than “pure” major depression; second, whether the comorbid condition is associated with worse clinical outcomes than are seen in major depressive disorder alone; and third, whether the response to antidepressant treatment differs between depressed patients with or without comorbid anxiety disorders.

Early studies supported the widespread consensus that patients with comorbid mood and anxiety disorders had more severe symptoms.11-14 Subsequent studies have in general supported this view. For example, a comparison of 276 US primary care depressed patients with or without a lifetime comorbid anxiety disorder demonstrated that the presence of comorbid panic disorder was associated with greater severity of depressive symptoms, more marked impairment in psychosocial functioning, and greater risk of prematurely stopping treatment.15
Similar findings were seen in a more recent naturalistic study of the effects of coexisting anxiety symptoms or comorbid anxiety disorders on symptom severity at baseline and treatment response, in Italian outpatients with major depressive disorder. It was found that the presence of anxiety symptoms and disorders was associated with more frequent suicidal thoughts, greater psychomotor retardation, and greater severity of diurnal variation of symptoms, sexual dysfunction, somatic concerns, and weight loss, when compared with patients with major depressive disorder alone.16
The greater symptom severity associated with the presence of comorbid anxiety disorders is also seen in other age groups: for example, a comparison of the effectiveness of interpersonal psychotherapy versus “treatment as usual” in depressed adolescents (aged 12-18 years) found that comorbidity was associated with both a greater severity of depressive symptoms at baseline, and with lower response rates in both treatment groups.17
The greater symptom severity of the comorbid condition is reflected in a more pronounced degree of impairment of social and occupational functioning. For example, a recent large cross-sectional primary care study performed in Belgium and Luxembourg found that patients with comorbid major depressive disorder and generalized anxiety disorder reported greater impairment of work, and social and family life, than did patients with major depression or generalized anxiety disorder alone.18
Epidemiological studies demonstrate that a number of individuals have multiple comorbid diagnoses, and some of the greater impairment that is associated with comorbid depressive and anxiety disorders may reflect the presence of additional mental health problems. For example, the presence of comorbidity for an anxiety disorder in patients with major depressive disorder has also been associated with greater risk of comorbidity for personality dis- orders: in the aforementioned comparison of US primary care depressed patients, lifetime comorbidity for panic disorder was also associated with the presence of avoidant personality disorder.15

Figure 1. Prevalence of pure and comorbid 12-month mood, anxiety, and alcohol use
disorders in the general population. Findings from the European Study of the Epidemiology
of Mental Disorders.
After reference 6: Alonso J, Angermeyer MC, Bernert S, et al. Prevalence of mental disorders in Europe:
results from the European Study of the Epidemiology of Mental Disorders (ESEMeD). Acta Psychiatrica
Scand. 2004;109(suppl 420):21-27. Copyright © 2004, John Wiley & Sons, Inc.

The adverse effects of anxiety disorder comorbidity in patients with unipolar depressive disorder are sometimes also seen in patients with the diagnosis of bipolar disorder, although not all studies have produced consistent findings. An investigation in a consecutive sample of French bipolar inpatients found that those with a lifetime comorbid anxiety disorder (24% of the overall sample) did not differ in terms of disorder severity (assessed by number of hospitalizations, presence of psychosis, substance misuse comorbidity, and suicide attempts), although their response to anticonvulsant drugs was lower than that of the group without comorbid anxiety disorders.19 By contrast, in a longitudinal study of the effects of comorbid anxiety disorders on bipolar disorder patients treated with psychotropic drugs, either alone or in combination with family intervention, comorbidity was associated with greater symptom severity at baseline (even after controlling for depressive symptom severity) and with poorer overall treatment response over 28 months, regardless of the treatment modality.20 The link between bipolar disorder and anxiety disorders is also emphasized by the findings of an investigation of the factors associated with non-response to antidepressant treatment in patients with apparent unipolar depression, which found that the presence of comorbid anxiety disorders was associated with a greater “risk” of unrecognized bipolar disorder.21

The presence of comorbid anxiety disorders with major depression is usually found to be associated with a less favorable long-term outcome. For exam- ple, an early systematic review of the clinical outcome of anxiety and depressive disorders found that patients with comorbid anxiety and depression had generally worse outcomes than patients with either an anxiety disorder alone, or a depressive disorder alone.22
The findings of the United States National Comorbidity Survey indicate that participants were significantly more likely to continue presenting with symptoms of a major depressive if they also fulfilled criteria for comorbid generalized anxiety disorder. Similarly, patients with generalized anxiety disorder and comorbid major depression were more likely to experience continued anxiety symptoms than those without depressive symptoms (Figure 2).23

Figure 2. Persistence of comorbid major depressive
disorder and generalized anxiety disorder (GAD).
MDE, major depressive episode.
After reference 23: Kessler RC, Gruber M, Hettema JM, Hwang I,
Sampson N, Yonkers KA. Co-morbid major depression and generalized
anxiety disorders in the National Comorbidity Survey follow-up.
Psychological Med. 2008;38:365-374. Copyright © 2007, Cambridge
University Press.

In general terms, this adverse effect of comorbidity is manifest through longer persistence of symptoms and with a greater risk of continuing social and occupational impairment. For example, an evaluation of the effects of comorbid post-traumatic stress disorder in female patients with major depressive disorder treated with either antidepressant drugs, cognitive behavior therapy, or through community health referral, found that comorbidity was associated not only with greater severity of depressive and anxiety symptoms at baseline, but also with greater impairment at 1-year follow-up.24 This adverse effect of this pattern of comorbidity on the clinical outcomes supports the earlier findings of a delayed response to treatment of depression in both the acute phase25 and the continuation phase26 of treatment, in depressed patients with comorbid post-traumatic disorder.
The adverse effects of coexisting anxiety symptoms or comorbid anxiety disorder are also seen in older depressed patients. In a study of the effectiveness of antidepressant treatment and interpersonal psychotherapy in patients aged 70 years or older, the presence of greater anxiety symptom severity was associated with a longer duration of symptoms and with higher recurrence rates.27 Similar findings had been seen in an earlier investigation of the course of illness in elderly patients with comorbid major depression and generalized anxiety disorder.28
The adverse effects of comorbidity are also manifest through a greater risk of recurrence of symptoms and possibly through an increased risk of suicide. By way of illustration, long-term follow-up (up to 5 years) of a Finnish nationally representative sample of outpatients with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition)–defined major depressive disorder found that the severity of symptoms and the presence of comorbidity, especially for social phobia, predicted both a higher probability of recurrence and a greater number of recurrences.29
While the increased risk of suicide in depression has been known for many years, it remained uncertain as to whether anxiety disorders were also associated with an elevated risk of suicide. However, in recent years, epidemiological studies and a systematic review have demonstrated that anxiety disorders are associated with suicidal thoughts and with attempted, if not completed, suicide.30-32 Moreover, current data indicate that comorbid anxiety disorders amplify the risk of suicide attempts in people with mood disorders.30 As the two greatest risk factors for completed suicide are suicidal thoughts and a recent suicide attempt, it therefore seems reasonable to assume that anxiety disorders carry an increased risk for completed suicide.

The presence of prominent anxiety symptoms in depressed patients is generally thought to be associated with a lower overall response rate to treatment. For example, an early comparison of the effectiveness of interpersonal psychotherapy or treatment with the tricyclic antidepressant nortriptyline in 157 depressed patients in primary care found that lifetime comorbidity for an anxiety disorder was associated with higher treatment drop-out rates, a delayed recovery in patients with comorbid generalized anxiety disorder, and particularly poor response rates in patients with lifetime panic disorder.33
Subsequently, a comparison of small groups of patients with major depressive disorder that did or did not respond to antidepressant treatment found that comorbid anxiety disorders (and reports of childhood emotional abuse) were significantly more frequent among the nonresponders.34 A much larger randomized trial of stepped collaborative care of 228 depressed patients in a US health maintenance organization found that the presence of comorbid panic disorder was associated with both greater symptom severity at baseline, and with a significantly lower treatment response.35
Furthermore, in a recent investigation of the determinants of non-response in patients with treatment- resistant depression, a comorbid anxiety disorder was the clinical factor most strongly associated with non-response.36
The adverse effects of comorbidity on the response to treatment are seen in a variety of age groups. For example, an evaluation of the effectiveness of cognitive behavioral therapy, systemic behavioral therapy, and nondirective supportive therapy in 101 adolescents (aged 13 to 18 years) fulfilling DSM-III-R criteria for major depression found that the presence of anxiety disorder comorbidity was predictive of symptom persistence.37 At the other end of the age distribution, a longitudinal study in older adults undergoing case management, cognitive behavior therapy, or the combination for treatment of depression found that comorbid anxiety disorders were associated with greater symptom severity at the end of treatment and at follow-up at 6 and 12 months.38
However, not all the evidence for the effect of coexisting anxiety symptoms or comorbid disorders on treatment response is consistent. For example, a comparison of small groups of Australian inpatients with DSM-III-R–defined major depression found that the presence of comorbid anxiety disorders did not affect either treatment choice, or the effectiveness of treatment interventions.39 In addition, a greater severity of coexisting anxiety symptoms at baseline among patients with either chronic major depression or “double depression” (that is, dysthymia plus supervening acute major depression) did not affect overall response rates with either the tricyclic imipramine or the selective serotonin reuptake inhibitor (SSRI) sertraline.40 Furthermore, in both a comparison of the effectiveness of the tricyclic nortriptyline and the SSRI paroxetine in 116 depressed patients aged 60 years or older, and a second comparison of the effectiveness of paroxetine or interpersonal psychotherapy in 125 patients aged 69 years or older, no difference was found in the proportion responding to treatment or in the time to response, between patients with or without anxiety.41
Although outside the scope of this review, it is worth noting that the adverse effects of comorbidity are also seen among patients with primary anxiety disorders. For example, a recent evaluation of clinical outcomes at 1 year following cognitive behavioral therapy in outpatients with panic disorder, with or without agoraphobia, found that the presence of comorbid mood disorders was associated with lower response rates and a reduction in the proportion entering symptomatic remission.42
Comorbidity of major depressive disorder with anxiety disorders has also been associated with a reduced likelihood of achieving symptomatic remission with antidepressant treatments. The findings of STAR*D, sequential treatment of 2876 depressed patients, found that the presence of a comorbid anxiety disorder at baseline was associated with significantly lower rates of achieving symptomatic remission during the initial intervention (with the SSRI, citalopram).43 However, as with studies of overall treatment response, not all evidence is consistent: for example, an evaluation of the effects of comorbid anxiety disorders on response to treatment with the SSRI fluoxetine in 329 patients with DSM-IV– defined major depressive disorder, found no major adverse effects of comorbidity on the likelihood of achieving symptomatic remission.44
Lower response rates and reduced likelihood of achieving symptom remission are factors that may lead to a greater perceived need to utilize antidepressant drugs, and to the concomitant use of two or more antidepressant or other psychotropic drugs, in an attempt to improve outcomes. Data from the recent Canadian Community Health Survey on Mental Health and Well-Being show that the comorbidity of major depressive disorder with anxiety disorders is associated with somewhat higher rates of use of antidepressant drugs than that seen for major depressive disorder alone.45

The presence of comorbid depressive disorders is usually regarded as an exclusion criterion in randomized placebo-controlled trials of antidepressants in patients with primary anxiety disorders, where proof of efficacy requires the demonstration that anxiety symptoms do not resolve indirectly, mediated by an effect on depression. In addition, depressed patients with comorbid anxiety disorders are often excluded from participating in studies with new antidepressant treatments, perhaps because the presence of significant anxiety symptoms may reduce response rates, and thereby impede the chance to distinguish antidepressant from placebo effects. However, comorbidity is the rule in clinical practice, and it is helpful to know whether a single medication can diminish the severity of both anxiety and depressive symptoms in patients with comorbid conditions. However, there are relatively few studies that have specifically focused on investigation of the treatment response in comorbid patients.
An investigation of the effectiveness of open treatment with the SSRI fluoxetine (20 mg/day) in 123 US outpatients with major depressive disorder and at least one comorbid anxiety disorder, both defined according to DSM-III-R criteria, found that it reduced depressive symptom severity between baseline and study end point: however, patients with depression and comorbid obsessive-compulsive disorder were significantly less likely to respond to treatment than patients with other comorbid anxiety disorders.46 A subsequent open but controlled comparison of paroxetine (20-40 mg/day) with moclobemide (a reversible inhibitor of monoamine oxidase A) at a dosage of 300-600 mg/day in 123 Italian outpatients with DSM-III-R–defined major depressive disorder or dysthymia and comorbid anxiety disorder found no significant difference in overall response between the two antidepressants: however paroxetine was superior to moclobemide in the subgroup of 32 patients with comorbid panic disorder.47
The open design and lack of placebo control in these investigations together prevent definitive conclusions being drawn about the potential efficacy of certain antidepressant treatments in comorbid patients. A randomized double-blind comparatorcontrolled trial of sertraline (50-100 mg/day) and imipramine (100-200 mg/day) in patients with comorbid major depressive disorder and panic disor- der found no differences between treatments in the reduction of depressive and panic symptom severity, treatment outcome being concordant for both diagnoses in approximately 70% of patients.48 Again, the absence of a placebo control hinders definitive conclusions, and there is a persistent need for large multicenter studies in patients with comorbid mood and anxiety disorders, that employ a placebo-controlled design.

Anxiety symptoms are integral to major depressive episodes, and many patients with major depressive disorder will have prominent anxiety symptoms: furthermore, a significant proportion of depressed patients will show either lifetime or concurrent comorbidity for anxiety disorders. In general terms, the presence of comorbid anxiety disorders is associated with a greater severity of symptoms and more pronounced symptom-related disability and impairment, with a less favorable outcome, greater risk of symptom persistence, recurrence, and possibly suicide, and a less satisfactory response to antidepressant treatment. It is also associated with lower rates of recovery and a reduced likelihood of achieving symptomatic remission. There is a clear need for further randomized controlled trials in patients with comorbid mood and anxiety disorders, as this group comprises a probable majority of depressed individuals seen within routine clinical practice settings.

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16. Altamura CA, Montresor C, Salvadori D, Mundo E. Does comorbid subthreshold anxiety affect clinical presentation and treatment response in depression? A preliminary 12-month naturalistic study. Int J Neuropsychopharmacol. 2004;7:481-487.
17. Young JF, Mufson L, Davies M. Impact of comorbid anxiety in an effectiveness study of interpersonal psychotherapy for depressed adolescents. J Acad Child Adolesc Psychiatry. 2006;45: 904-912.
18. Ansseau M, Fischler B, Dierick M. Albert A, Leyman S, Mignon A. Socioeconomic correlates of generalized anxiety disorder and major depression in primary care: the GADIS II Study (Generalized Anxiety and Depression Impact Survey II). Depress Anxiety. 2008;25:506-513.
19. Henry C, Van den Bulke D, Bellivier F, Etan B, Rouillon F, Leboyer M. Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer. J Clin Psychiatry. 2003;64:331-335.
20. Gaudiano BA, Miller IW. Anxiety disorder comorbidity in bipolar I disorder: relationship to depression severity and treatment outcome. Depress Anxiety. 2005;21:71-77.
21. Calabrese JR, Muzina DJ, Kemp DE, et al. Predictors of bipolar disorder among patients currently treated for major depression. Med Gen Med. 2006;8:38.
22. Emmanuel J, Simmonds S, Tyrer P. Systematic review of the outcome of anxiety and depressive disorders. Br J Psychiatry. 1998;34(suppl):S35-S41.
23. Kessler RC, Gruber M, Hettema JM, Hwang I, Sampson N, Yonkers KA. Co-morbid major depression and generalized anxiety disorders in the National Comorbidity Survey follow-up. Psychological Med. 2008;38:365-374.
24. Green BL, Krupnick JL, Chung J, et al. Impact of PTSD comorbidity on one-year outcomes in a depression trial. J Clin Psychology. 2006;62:815-835.
25. Hegel MT, Unutzer J, Tang L, et al. Impact of comorbid panic and posttraumatic stress disorder on outcomes of collaborative care for late-life depression in primary care. Am J Geriatr Psychiatry. 2005;13:48-58.
26. Hollon SD, DeRubeis RJ, Shelton RC, et al. Prevention of relapse following cognitive therapy vs medications in moderate to severe depression. Arch Gen Psychiatry. 2005;62:417-422.
27. Andreescu C, Lenze EJ, Dew MA, et al. Effect of comorbid anxiety on treatment response and relapse risk in late-life depression: controlled study. Br J Psychiatry. 2007;190:344-349.
28. Schoevers RA, Deeg DJ, van Tilburg W, Beekman AT. Depression and generalized anxiety disorder: co-occurrence and longitudinal patterns in elderly patients. Am J Geriatr Psychiatry. 2005;13:31-39.
29. Holma KM, Holma IA, Melartin TK, Rytsala HJ, Isometsa ET. Long-term outcome of major depressive disorder in psychiatric patients is variable. J Clin Psychiatry. 2008;69:196-205.
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31. Bolton JM, Belik SL, Enns MW, Cox BJ, Sareen J. Exploring the correlates of suicide attempts among individuals with major depressive disorder: findings from the national epidemiologic survey on alcohol and related conditions. J Clin Psychiatry. 2008;69: 1139-1149.
32. Hawgood J De LD. Anxiety disorders and suicidal behaviour: an update. Curr Opin Psychiatry. 2008;21:51-64.
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37. Brent DA, Kolko DJ, Birmaher B, et al. Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression. J Acad Child Adolesc Psychiatry. 1998; 37:906-914.
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b y J . P r i c e a n d G . M . G o o d w i n , U n i t e d K i n g d o m

Jonathan PRICE, MD Guy M. GOODWIN, MD PhD Department of Psychiatry University of Oxford The Warneford Hospital Oxford, UNITED KINGDOM

Antidepressants such as the selective serotonin reuptake inhibitors are used widely to treat major depression. While they have reasonable efficacy, they also produce adverse effects. The best known of these relate to physical effects like nausea and the impact on sexual function. However, anecdotally there appears to be a broader impact on emotional experience. This is usually described as a reduction in sensitivity or a sense of numbing or blunting, which may emerge as depression remits. While it may be confounded by the residual effects of depression, patients often attribute it to their medication. We propose that this phenomenon of emotional side effects of antidepressants requires further study. There is laboratory evidence to relate it under experimental conditions to the processing of emotion. Reduced detection of negative emotion in the faces of others can be demonstrated in healthy volunteers who have taken citalopram or reboxetine for just 1 week. This effect may predict the clinical problems that we see. We have now also developed an assessment scale expressly for use in clinical studies. The future will be to look at antidepressants whose profile appears to be less emotionally blunting—like agomelatine and other medications now in development with novel mechanisms of action—in well-designed clinical studies that can illustrate the absolute and relative frequency of what is an increasingly troublesome side effect of current treatments.
Medicographia. 2009;31:152-156. (see French abstract on page 156)

Keywords: depression; emotional processing; sexual function; clinical trial; outcome assessment; SSRI; side effect; pharmacotherapy; antidepressant

An emerging body of evidence indicates that antidepressants have adverse effects on emotional experience in some people. It is now well known among health care professionals that antidepressants such as selective serotonin reuptake inhibitors (SSRIs) may cause anxiety and agitation, especially in the early days of administration. However, it is much less well known that antidepressants are associated with a syndrome of emotional numbing or blunting, often emerging as depression remits, which can be troublesome enough to lead to noncompliance. We call this phenomenon “emotional side effects of antidepressants” rather than “emotional blunting,” because of the broad range of impacts on emotional functioning that are seen.

Some patients taking antidepressants report that while they feel less emotional pain than before commencing their antidepressant medication, they also experience a restricted range of emotions and, in particular, cannot get a “normal” emotional response to everyday events that would usually be associated with, for example, joy or sadness. This complaint is prominent on Web sites where patients may post their views about their medicines, such as Cybercity and Rxlist. Box 1 provides several examples derived from such Web sites.
The reduced level of positive emotion in patients taking SSRIs may be linked both physiologically, and in the minds of patients who complain about the experience, to reduced sexual interest. This has been widely described. There is a reduction both in desire and arousal. As always in studies in depressed subjects, there is the potential for confounding the effects (and after-effects) of depression itself with the drugs employed to treat it.1 However, in the case of sexual side effects, there is clear evidence from effects in healthy male volunteers that the SSRI paroxetine has an important and immediate effect on sexual function.2 Moreover, a comparison between the sexual function of patients recovering from depression but treated with venlafaxine (serotonin and norepinephrine reuptake inhibitor; SNRI) in one group and the non-SNRI/non-SSRI, agomelatine, in the other, clearly demonstrates an adverse effect of venlafaxine.3

The situation for emotional side effects as we have defined them is much less clear. A review of the wider medical literature re- veals that little formal research has been done on antidepressant-associated emotional blunting. However, there has been a steady trickle of reports since 1990, when Hoehn-Saric and colleagues reported dose-dependent apathy, indifference, loss of initiative, and disinhibition in patients on fluvoxamine or fluoxetine.4 There have, for example, been further reports of SSRI-induced apathy, indifference, and reduced motivation in children, adolescents, adults, and older adults5-9; of inability to cry10; of reduction in irritability, aggression, and negative affect11; and of reduced emotional lability resulting from cerebrovascular accident12-14 or other brain injury.15,16 Opbroek and colleagues17 moved the field conceptually by linking the rating of a wider impact of SSRIs on emotion to effects specifically on sexual function. The Laukes Emotional Intensity Scale (LEIS) was used in 15 participants meeting criteria for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition) major depression who reported SSRI-induced sexual dysfunction, and in a control group of 16 hospital employees. Compared with controls, the SSRI group reported significant reductions in 12 of the 18 LEIS items, including ability to cry, irritation, care about others’ feelings, sadness, erotic dreaming, creativity, surprise, anger, expression of their feelings, worry, sexual pleasure, and interest in sex.
However, the way in which emotional side effects should be understood, measured, and so definitively investigated has remained uncertain. We have recently investigated the nature of this phenomenon by conducting interviews with people who attribute emotional symptoms to their SSRI.18 This study provided evidence that some patients taking SSRIs experienced significant emotional symptoms that they strongly attributed to their antidepressant, and that had a demonstrable impact on their functioning and played a role in their decision making about ongoing antidepressant adherence. These emotional symptoms could be described within six key themes—general effects on all emotions, reduction in positive emotions, reduction in negative emotions, emotional detachment, just not caring, and a changed personality. These themes are expanded, and examples given, in Box 2.

There are no good data to indicate the frequency of emotional side effects, when they are most frequent and most problematic, and whether they are more common with some currently available antidepressants than others. However, it is clear from Internet reports, our clinical experience, and our experience of recruiting patients to research studies, that emotional side effects are not uncommon, and that there is a spectrum of experience from mild side effects through to severe side effects that is the source of bitter complaint. Some patients report that they suffered emotional side effects only as they experienced remission, while others report that they experienced them throughout the period of antidepressant administration. While SSRIs appear to be most closely associated with emotional side effects, other classes of antidepressant such as SNRIs and mood stabilizers such as lithium salts have also been described as doing the same thing.

Box 1. Patient descriptions of emotional blunting taken from the Internet.
All rights reserved.

Box 2. Emotional side effects of selective serotonin reuptake inhibitors: key themes. Based on data from reference 18.

Little is known about the impact of emotional side effects on quality of life in remission. However, our recent qualitative study investigated this in a sample of patients with chronic antidepressant use (median duration 23 months) and modest levels of depression (median Beck Depression Inventory–II score 12.5).18 The impact of emotional side effects on participants’ daily lives varied widely, both in extent and in perceived helpfulness. Some participants described emotional side effects as being helpful. For example, the reduction of certain emotional responses, such as anger, aggression, or worry might benefit personal relationships. Furthermore, emotional detachment and reduced anxiety might enable a person to think more clearly and objectively about their life situation.
However, some participants were concerned that blunting of their emotions and, thereby, of their day to day concerns, might mask or hide problems. This might prevent them resolving their own emotional issues, prevent them engaging with other problems or issues requiring their attention, and “cover up” who they really were. “Just not caring” had an unhelpful effect on everyday responsibilities, resulting in financial problems and problems at work or college. Emotional detachment from family and reduced emotional responsiveness had an unhelpful impact on family life, and on perceived quality of parenting. Reduced inspiration, reduced imagination, reduced motivation, and reduced passion for and enjoyment of creative activities, had adversely affected some participants’ creativity. In some participants, emotional side effects had led to reduced sociability. Finally, emotional flattening, emotional detachment from other people, and reduced concern for other people’s needs and feelings had unhelpful effects on relationships within families, with a significant other, and at work.

Clinical assessment
It is likely that emotional side effects are under-reported in clinical populations due to the lack of systematic enquiry by health care professionals. We recommend that clinicians ask routinely about emotional side effects when they are assessing progress with antidepressants. This might comprise asking a broad screening question, and then, if necessary, following up with more specific questions to characterize the nature and extent of the problem, the extent to which the patient attributes the problems to their antidepressant, and its contribution to their decision-making regarding ongoing adherence. An effective screening question might be: “Have you experienced any emotional side effects from your antidepressant? (prompt if required…) Emotional side effects are varied, but might include, for example, feeling emotionally ‘numbed’ or ‘blunted’ in some way, lacking some positive emotions or negative emotions, feeling detached from the world around you, or ‘just not caring’ about things that you used to care about.”

Scientific assessment: in the laboratory
Changes in emotional processing can also be shown to accompany the administration of SSRI and SNRI drugs to healthy volunteers.19 By emotional processing, one means the capacity of subjects to identify either the emotional expression in the faces of others (a perceptual expression of emotional sensibility) or to remember emotionally charged self-referent words. The SSRI citalopram given to healthy volunteers for 7 days and the selective noradrenergic drug reboxetine given for the same period of time both reduced the capacity of volunteers to accurately detect negative emotion in faces presented to them in an experimental paradigm. There was even a reduced signal in the amygdala in response to the same faces presented subliminally.20 This could imply that these individuals might be less sensitive socially to the expression of negative emotions by others. While this could be a helpful change in emotional processing with regard to both anxiety and depression, it could also, when patients have recovered, lead to a changed sense of the immediacy of experience.
Changes could also be demonstrated in the domain of emotional memory following the administration of antidepressants to healthy volunteers. In this case, subjects were more able to recall positive than negative adjectives that could refer to them. This effect may be interpreted as reflecting a potentially therapeutic change in how emotion is processed. However, in potential contrast with the perception of emotion in faces, it would not itself lead to a predictable change in emotional experience that would be likely to be negative. Therefore it is possible that one way to screen for the presence or absence of emotional blunting from any medication would be to compare the impact on a patient’s immediate judgment of emotional valence with the impact on how emotionally charged adjectives are recalled from memory. It is a strong hypothesis of the Oxford group that emotional blunting may be associated with the former, while antidepressant efficacy per se will be associated with the latter. Findings with the new antidepressant agomelatine, whose novel mechanism of action comprises melatonergic agonist activity at MT1 and MT2 receptors and antagonist activity at serotonergic 5-HT2C receptors, when given for 1 week to healthy volunteers, will be an important test: the further question will be whether these properties of agomelatine translate as we would predict into antidepressant efficacy without emotional blunting. However, to know if this occurs we will require a better measure of the clinical as opposed to the laboratory experience.

Scientific assessment: in the clinic
A sensitive and valid questionnaire measure of this phenomenon is needed. This would enable research into the prevalence of the emotional side effects of antidepressants, and comparison of the extent to which individual antidepressants are associated with them. It could be an important outcome measure in clinical trials designed to compare different products. Such a measure needs to be carefully designed and validated. Unfortunately, the two existing measures that attempt to address this issue appear to lack either careful design or validation.
The first is LEIS,17 a self-report instrument comprising 18 questions asking patients to rate an aspect of their emotional life compared with their “usual” state according to a 5-point scale (a lot less/ somewhat less/same as usual/somewhat more/a lot more). This scale is unvalidated, and the single published report of its use in an observational study gives few details about its development, stating only that “we systematically questioned patients treated with SSRIs about their subjective emotional experience before and after treatment,” and that “these unstructured interviews led to the development of a rating scale for SSRI-induced emotional blunting.”
The second is the Bell-Shipman Apathy/Emotional Blunting Questionnaire,21 which is described in the study report as “under development.” This self-completion questionnaire comprises five questions, each rated on a six point scale from “strongly disagree” to “strongly agree,” which relate to aspects of four of the themes we identified—reduction in positive emotions, reduction in negative emotions, emotional detachment, and not caring. However, there are no published details of the development and selection of these questions, and no validation work appears to have been carried out.
We have used the results of the careful observational work in our recent study to develop the Oxford Questionnaire of Emotional Side effects of Antidepressants (OQESA), which we have now piloted, refined, and validated in a sample of over 200 people taking antidepressants. The OQESA comprises 26 questions/statements in three sections. The respondent rates the extent of their agreement with each statement along a 5-point scale ranging from disagree to agree, according to their experience during the past week. Section 1 includes 12 statements relating to the respondent’s experience of emotional side effects during the past week (eg, “All my emotions, both ‘pleasant’ and ‘unpleasant,’ are ‘toned down’”). Section 2 includes 8 statements relating to experience of emotional side effects during the past week compared with the respondent’s experiences before they developed their illness/problem (eg, “Day to day life just doesn’t have the same emotional impact on me that it did before my illness/ problem”). Within the 20 statements in Sections 1 and 2, the 4 dimensions, general reduction in emotions (GR), reduction in positive emotions (RP), emotional detachment from others (ED), and not caring (NC) are each represented by 5 statements. Finally, Section 3 comprises 5 statements regarding the extent to which respondents believe their antidepressant is responsible for their emotional symptoms (eg, “The antidepressant is preventing me from feeling my emotions in some way”), and a final statement regarding actual or contemplated non-adherence due to emotional side effects. A total score can be calculated, being the sum of the scores of the four dimensions, and represents the extent to which the respondent is affected by emotional side effects. If required, the further attributional dimension can be scored.
An important and, as yet, unanswered question is the extent to which emotional symptoms attributed to antidepressants are actually manifestations of residual depression, rather than being emotional side effects. Our validation data suggest that two of the four dimensions of the OQESA (RP and NC) may be closely related to depression as well as antidepressant- associated emotional blunting, whereas the other two dimensions (GR and ED) are less closely related to depression. We therefore recommend that, in high quality experimental work investigating emotional side effects of antidepressants, two subtotals are calculated—RP plus NC, and GR plus ED.

In summary, there is emerging evidence that one important adverse effect of SSRIs and related medicines is a negative impact on the processing of emotional experience. This was first described by patients themselves, and investigators are now catching up with the complaint by devising improved ways of measuring it, both experimentally and, perhaps most critically, clinically, by the use of an innovative scale. There is an appropriate and increasing emphasis upon the patient experience in judging the outcome of treatment with any intervention for mood disorder. In the case of antidepressants, the potentially negative effect on emotional experience is easily confounded with the symptoms of depression itself, but is a cause for concern and further research. It remains to be seen as to whether it proves to be an easy task to first devise the means to better measure the experience and second to develop treatments that will be effective in treating depression without producing the problem. The test of this will come from antidepressants with novel mechanisms of action, one of the first examples of which will be agomelatine.
_ Acknowledgements. Some of the work described here was supported by a grant from Servier to G. M. Goodwin.

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3. Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol. 2008;28:329-333.
4. Hoehn-Saric R, Lipsey J, McLeod D. Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol. 1990;10:343-345.
5. Barnhart WJ, Makela EH, Lotocha MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatr Pract. 2004;10:196-199.
6. Garland EJ, Baerg EA. Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents. J Child Adolesc Psychopharmacol.2001;11:181-186.
7. Hoehn-Saric R, Harris GJ, Pearlson GD, Cox CS, Machlin SR, Camargo EE. A fluoxetine-induced frontal lobe syndrome in an obsessive compulsive patient. J Clin Psychiatry.1991;52:131-133.
8. Reinblatt SP, Riddle MA. Selective serotonin reuptake inhibitor- induced apathy: a pediatric case series. J Child Adolesc Psychopharmacol. 2006;16:227-233.
9. Wongpakaran N, van Reekum R, Wongpakaran T, Clarke D. Selective serotonin reuptake inhibitor use associates with apathy among depressed elderly: a case-control study. Ann Gen Psychiatry. 2007;6:7.
10. Oleshansky M, Labbate L. Inability to cry during SRI treatment. J Clin Psychiatry. 2006;57:593.
11. Knutson B, Wolkowitz OM, Cole SW, et al. Selective alteration of personality and social behaviour by serotonergic intervention. Am J Psychiatry. 1998;155:373-379.
12. Andersen G, Vestergaard K, Riis JO. Citalopram for poststroke pathological crying. Lancet. 1993;342:837-839.
13. Nahas Z, Arlinghaus KA, Kotrla KJ, Clearman RR, George MS. Rapid response of emotional incontinence to selective serotonin reuptake inhibitors. J Neuropsychiatry Clin Neurosci.1998;10: 453-455.
14. Panzer MJ, Mellow AM. Antidepressant treatment of patho logic laughing or crying in elderly stroke patients. J Geriatr Psychiatry Neurol. 1992;4:195-199.
15. McCullagh S, Feinstein A. Treatment of pathological affect: response for laughter and crying. J Neuropsychiatry Clin Neurosci. 2000;12:100-102.
16. Seliger GM, Hornstein A, Flax J, Herbert J, Schroeder K. Fluoxetine improves emotional incontinence. Brain Inj. 1992;6: 267-270.
17. Opbroek A, Delgado PL, Laukes C, et al. Emotional blunting associated with SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses? Int J Neuropsychopharmacol. 2002;5: 147-151.
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21. Bell S, Shipman M, Bystritsky A, Haifley T. Fluoxetine treatment and testosterone levels. Ann Clin Psychiatry.2006;18:19-22.

Les inhibiteurs sélectifs de la recapture de la sérotonine sont des antidépresseurs largement utilisés dans le traitement de la dépression sévère. D’une efficacité satisfaisante, ils ont aussi des effets indésirables dont les plus connus sont des effets physiques comme la nausée et la dysfonction sexuelle. De façon anecdotique, ces effets semblent également avoir un impact touchant plus largement le plan émotionnel. Cet impact est généralement décrit comme une réduction de la sensibilité ou une sensation d’engourdissement ou d’émoussement qui apparaît lorsque la dépression diminue. Bien que parfois confondus avec les effets résiduels de la dépression, les patients attribuent souvent ces signes à leur traitement. Nous considérons que ces effets secondaires des antidépresseurs sur l’émotion nécessitent d’être plus amplement étudiés. Des données expérimentales permettent sous certaines conditions, de les relier au processus de traitement de l’émotion. Des volontaires sains qui avaient reçu pendant juste 1 semaine du citalopram ou de la réboxétine ont montré qu’ils détectaient moins les émotions négatives sur les visages d’autrui. Un tel effet pourrait être prédictif des problèmes cliniques que nous observons. Nous avons développé une échelle d’évaluation expressément pour l’usage clinique. L’avenir est donc aux antidépresseurs entraînant moins d’émoussement émotionnel, possédant de nouveaux mécanismes d’action, comme l’agomélatine et d’autres médicaments actuellement en développement. Ces médicaments devront faire l’objet d’études cliniques bien construites capables de mettre en évidence les fréquences absolues et relatives d’un effet secondaire de plus en plus gênant liés aux thérapeutiques actuelles.

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b y C . R . S o l d a t o s a n d C . G . T h e l e r i t i s , G r e e c e

◄ Constantin R. SOLDATOS,* MD Christos G. THELERITIS,*† MD *National and Kapodistrian University of Athens, Mental Health Care Unit Evgenidion Hospital, Athens, GREECE †National and Kapodistrian University of Athens, First Psychiatry Department Eginition Hospital, Athens GREECE

Sleep disorders have been long associated with depression; they are often used to identify newly presenting depressive patients, and may be part of a more general alteration of biological rhythms. Furthermore, persistent insomnia is a common residual symptom in incompletely remitted depression. As a rule, to avoid the recurrence of depressive symptomatology, treatment of associated insomnia should be pursued in patients taking antidepressants. Combining pharmacotherapy with nonpharmacological treatments that take into account the sleep-wake cycle (sleep deprivation, light therapy) could help in the resolution of both depressive symptoms and associated sleep disorders. A novel pharmaceutical agent, agomelatine, an agonist of melatonergic MT1 and MT2 receptors, as well as an antagonist of 5-HT2C receptors, shows a unique synchronizing effect on circadian rhythms and demonstrates robust antidepressant efficacy.
Medicographia. 2009;31:140-145. (see French abstract on page 145)

Keywords: insomnia; sleep disorder; slow-wave sleep; rapid eye movement; incomplete remission; circadian rhythm; psychotherapy; pharmacotherapy

It has long been reported that sleep is disturbed in depression.^1-5 Epidemiological studies have demonstrated that 50% to 90% of patients suffering from depression complain of poor sleep.⁶ In a large European community study, for instance, 63% of patients diagnosed with depression reported sleep problems.⁷ On the other hand, it has been reported that about 20% of subjects with insomnia screened in general population studies are found to be depressed.^8-10 Moreover, subjective reports of sleep disturbance and objectively assessed polysomnographic abnormalities have been correlated with an increased risk of new-onset major depression,¹¹ persistence of depressive symptomatology,¹² and recur- rence of depression following successful treatment.¹³ Polysomnographic studies have documented several sleep disturbances in depression: difficulty in initiating and maintaining sleep, prolonged sleep onset latency, multiple awakenings during the night, early morning awakening, and decreased total sleep time.^1,3,5,6 Furthermore, slow-wave sleep (SWS) and rapid eye movement (REM) sleep are often found to differ between depressed patients and healthy individuals.^1,14 Abnormal sleep architecture in depressed patients is reflected in reduced SWS,¹⁵ a greater number of stage shifts, earlier onset and a higher percentage of REM sleep, especially in the early part of the night, and an increased REM density.¹⁶
It should also be noted that computerized sleep electroencephalogram (EEG) analysis of SWS frequently reveals a lower level of delta wave activity during the first non-REM period than in the second non-REM period, ie, a lower delta sleep ratio, which is contrary to what happens in normal individuals.¹⁷ However, it should be noted that no single sleep abnormality is specific for depression, because similar polysomnographic aberrations have also been reported in several other psychiatric conditions.¹

Sleep mechanisms and the pathophysiology of depression are closely interrelated. Monoaminergic and cholinergic neurotransmission are heavily involved in both.¹⁸ Therefore, it is not surprising that depression is almost invariably associated with sleep abnormalities. Several hypotheses have been proposed to explain their occurrence. The first hypothesis suggests that an imbalance between the monoaminergic and cholinergic systems in the central nervous system could be responsible for both the pathophysiology of depression and the observed sleep aberrations.^18-20 According to another hypothesis, increased pressure of REM sleep might be responsible^18,21; however, a number of medications (bupropion, nefazodone, and trazodone) with welldocumented antidepressant efficacy do not suppress REM sleep, which suggests that REM sleep suppression might not be necessary for an antidepressant treatment response.²² The third hypothesis proposes an hypothalamic-pituitary-adrenal axis dysregulation.²³
The last hypothesis suggests that a deficiency in the mechanism responsible for non-REM sleep, as explained by the two-process model of sleep regulation, may be implicated. According to Borbély,²⁴ the interaction of two processes is responsible for sleep regulation: a homeostatic process (process S), with an increase of EEG slow waves during waking and an exponential decline during sleep, interacts with a circadian process (process C)—an internal clock—so that the timing and architecture of sleep is determined. It was proposed that process S is deficient in patients with depression. In fact, the clinical sleep disturbance of early morning awakening could be attributed to an impaired functioning of process S during waking or an earlier timing of process C. The fast antidepressant effect gained from sleep deprivation might arise from an increase in process S to normal levels.²⁴ By contrast, the slow antidepressant effect of a phase advance of the sleepwake cycle might be related to gradual shifts of process S toward a correct phase relationship with regard to process C. However, it should be noted that the antidepressant effect of phase advance has not been confirmed in all studies.²⁵ Moreover, decline of either process S during sleep or of the phase and amplitude of process C are other possible abnormalities that might be involved in sleep disturbances.²6

The biological clock in the suprachiasmatic nucleus (SCN), a master pacemaker driving circadian rhythms in the brain and body, is synchronized to the external light-dark cycle via retinal light input. Nocturnal synthesis of the pineal hormone melatonin is driven by the SCN. Yet, circadian oscillators are found in every organ,²⁷ and each organ has its own appropriate synchronizer. Although light is the major synchronizer for the SCN, it does not affect clocks in the liver; the synchronizer for the latter is food, but food is not a synchronizer for the SCN.²⁷
Individuals have different preferences for timing their sleep²⁸; some like to go to sleep early and wake up early in the morning, while others go to sleep late and wake up late. In addition, individual genetic characteristics of the molecular mechanisms of the biological clock might determine features of mood disorders, including age at onset,²⁹ recurrence, 30 symptoms of insomnia and response to its treatment,^31,32 and response to sleep deprivation.²⁹ Furthermore, it has been proposed that there is an intimate relationship between the neurotransmitter systems targeted by drugs and the circadian rhythms targeted by chronotherapeutics.³³ These genetic factors may actually provide a chronobiological vulnerability for depression; in this case, a “double desynchronization” may occur—“internal desynchronization” between different clocks in the body and brain, and “external desynchronization” between the timing of body rhythms with respect to the light-dark cycle.33
Stable internal and external phase relationships appear to be crucial for a stable mood state (ie, the timing between cortisol and temperature body rhythms as well as the timing of sleep with respect to the day-night cycle).³⁴ Any desynchronization might cause mood disturbances, particularly in vulnerable individuals. Certain synchronizers have been used to stabilize phase, with light and melatonin being the most important, but also sleep deprivation having been successfully applied in everyday practice.^35,36

◆ Nonpharmacological interventions on circadian rhythms
Manipulations of the sleep-wake cycle, whether its duration (total or partial sleep deprivation) or its timing (partial sleep deprivation, phase advance), have profound and rapid effects on depressed mood in 60% of all diagnostic subgroups of affective disorders.³⁷ The therapeutic effect of sleep deprivation is postulated to be linked to an increase in homeostatic sleep pressure; additionally, sleep deprivation– induced sleepiness may counteract the hyperarousal state that is often present in depression.²⁶
Though sleep deprivation may have a transient effect on mood, it should always be considered as an option, since it might be the most rapid antidepressant therapeutic solution35,36; however, most patients tend to relapse soon after recovery of sleep. The combination of sleep deprivation with lithium (with or without light therapy)^38-40 or pindolol⁴¹ may prevent relapse.
Light therapy was specifically developed as a synchronizer in the treatment of patients with seasonal affective disorders⁴²; however, it has also shown efficacy in nonseasonal depression,^43,44 and it can prevent relapse after sleep deprivation.⁴⁵ Bright light has three major effects on the circadian system: it increases circadian amplitude, shifts circadian phase (depending on the time of its application), and thereby modifies the phase relationships between the internal clock and sleep, and the external lightdark cycle.²⁶ As mentioned, it has been reported that bright light can prevent relapse after sleep depriva- tion; it was also recently demonstrated that light therapy combined with a selective serotonin reuptake inhibitor (SSRI) leads to more rapid and more profound improvement in patients with nonseasonal major depression,^45,46 suggesting an advantage of using combined approaches.

◆ Psychotherapeutic and psychosocial interventions
There is evidence from studies of primary insomnia that cognitive behavioral therapy (CBT) results in improvements that are as substantial as those of pharmacotherapy with sedative-hypnotics.⁴⁷ The greatest advantage of CBT is that its effectiveness is more durable than that of pharmacotherapy and the benefits persist after therapy is terminated.⁴⁸ CBT has also been reported to be efficient in the management of depression.⁴⁹ Further research, however, is needed regarding the efficacy of CBT—in combination with antidepressant therapy—for insomniac patients with major depressive disorder.⁵⁰
Behavioral modification of social rhythms may help in the treatment of depression. Frank and colleagues developed the Interpersonal and Social Rhythm Therapy (IPSRT) Intervention Program in order to establish regular social rhythm regularity (having regular bed, wake, and meal times, switching to a more regular work schedule, and incorporate a regular daily exercise session). IPSRT reduces the risk of recurrence in bipolar patients, regularizes social rhythms, accelerates remission in depressed patients, and lowers relapse rates; these effects are comparable with those of intensive pharmacotherapy.⁵¹ Further studies should determine whether IPSRT should be used alone or as an adjunctive treatment in major depression.⁵²

◆ Psychopharmacological treatment approaches
Melatonin, exogenously administered, acts as a synchronizer of circadian rhythms and sleep (eg, in blind persons) but does not appear to have any major effects on mood.⁵³ Antidepressants alleviate symptoms of depression by altering the levels of various central nervous system neurotransmitters that are also involved in sleep regulation, and may have a considerable impact on sleep patterns. In general, the majority of antidepressant drugs suppress REM sleep and increase REM latency, although this is not always the case. As far as sleep efficiency and total sleep time are concerned, antidepressants can be distinguished as being either sedative or energizing.⁵⁴ Currently-available antidepressants have notable limitations in terms of their only moderate efficacy compared with placebo, relatively slow onset of action, possible withdrawal symptoms, and problems of compliance. Sleep disturbances are often used to identify newly presenting depressive patients, and may be part of a more general alteration of bodily rhythms.⁵⁵ Persistent insomnia is one of the most common residual symptoms in incompletely remitted depression.⁵⁶
Residual depressive symptoms are one of the predictors of subsequent relapse risk,^57,58 and of persistent functional disability. Complete relief of associated insomnia should be pursued in patients under treatment with antidepressants to avoid the recurrence of depressive symptomatology.⁵⁹ In general, the sleep disturbances associated with depression improve as depressive symptom severity lessens with treatment, but different antidepressants have characteristic effects on sleep, particularly in the early stages of treatment.
On short-term administration, most tricyclic antidepressants (TCAs) promote sleep by increasing total sleep time and SWS. Furthermore, REM sleep suppression is reported with all TCAs except trimipramine.^60,61 More specifically, amitriptyline, trimipramine, nortriptyline, dothiepin, and doxepin have all been associated with sedation (although imipramine⁶² and desipramine⁶³ are less likely to be linked with sedation and have been associated with insomnia instead). Because of their sedative properties, these agents are often used as hypnotics in depressed patients suffering from insomnia.^64-68 However, daytime drowsiness and poor functioning during the next day may be an untoward side effect of sedative TCAs, in particular amitriptyline and doxepin. It should also be noted that TCAs may cause insomnia by inducing or worsening periodic limb movement disorder, and that their use is often associated with nightmares.⁶⁹
The reversible monoamine oxidase inhibitor moclobemide is associated with less REM sleep suppression and appears not to affect sleep notably.⁷⁰ SSRIs are considered to be more energizing agents than other antidepressants. Although SSRIs are commonly associated with insomnia, sedation and daytime sleepiness have been occasionally reported with high doses of these drugs. Fluvoxamine and paroxetine have been reported as being more sedating than other SSRIs.^22,26,67,69 Objective polysomnographic findings on the effects of SSRIs on sleep show prolongation of sleep onset latency, increased wakefulness, decreased sleep efficiency, increased number of arousals during the night, increased REM latency, and decreased total REM sleep, when compared with placebo and sedative TCAs.^64-67,69 Furthermore, SSRIs can exacerbate periodic limb movement disorder and can cause nightmares. However, patients’ subjective sleep ratings whilst taking SSRIs are frequently positive. The same is also true in terms of clinicians’ ratings of sleep items on the Hamilton Rating Scale for Depression in clinical trials that investigated citalopram, sertraline, fluoxetine, fluvoxamine, and paroxetine. However, it is unlikely that a depressed patient with a history of severe sleep disturbance will benefit more from SSRI treatment than from the administration of more sedative antidepressants.
Venlafaxine,^70,71 a serotonin and norepinephrine reuptake inhibitor (SNRI), decreases total sleep time and may cause insomnia in 4% to 18% of depressed patients. Also, its administration has been associated with REM sleep behavior disorder. Venlafaxine and duloxetine⁷² (another SNRI), as well as reboxetine, a norepinephrine reuptake inhibitor, appear to have a similar profile to SSRIs regarding their influence on REM sleep and overall sleep architecture. Another antidepressant that may cause insomnia is bupropion, a dopamine and norepinephrine and lengthens REM latency.
Trazodone, a serotonin, á1-adrenergic, and histamine receptor blocker, increases total sleep time, enhances SWS, and may cause excessive daytime sleepiness. Trazodone does not suppress REM sleep.⁵ It is a very sedative antidepressant and has often been used for the management of severe insomnia in depression. A number of trials have shown that trazodone is more effective than the TCAs and equally as effective as a hypnotic agent, zolpidem, in improving sleep.^64-67,69 Nefazodone, a compound closely related to trazodone, is a potent antagonist of postsynaptic 5-HT2 receptors, but with a less potent á1-adrenoreceptor–blocking activity and no affinity for histamine receptors. It promotes sleep without suppressing REM sleep.⁵ Its pharmacological profile makes it one of the best antidepressants to relieve insomnia in the context of depression, and it is widely used as an adjunct to SSRIs and SNRIs.⁵ Also, maprotiline, which acts by inhibiting reuptake of norepinephine and blocking the histamine receptor, causes sedation and suppresses REM sleep. Similarly, amoxapine, which blocks the serotonin and histamine receptors and inhibits the uptake of norepinephrine, is another antidepressant that causes sedation. Tianeptine, a glutamate modulator,⁷³ enhances sleep continuity and ameliorates subjective sleep quality without significantly modifying REM sleep parameters.⁵⁴
Mirtazapine is a selective serotonin and á2- adrenoreceptor blocker, which also blocks histamine receptors (noradrenergic and specific serotonergic antidepressant). Potent antagonism of H1 receptors causes immediate, nonspecific sedative effects upon administration. Mirtazapine increases total sleep time and suppresses REM sleep. It is frequently used when sleep complaints are a major concern in depression and its efficacy is comparable to that of sedative TCAs.^64-67,69
Agomelatine, an agonist of melatonergic MT1 and MT2 receptors, as well as an antagonist of 5-HT2C receptors, uniquely combines circadian synchronizing effects with selective norepinephrine and dopamine augmentation properties in the prefrontal cortex, and demonstrates robust antidepressant efficacy.^74-76 When administered in the evening, it advances circadian phase and directly increases sleepiness through thermoregulatory mechanisms.^77,78 This promotes a rapid sleep onset, but is without any after-effects the following day. The drug does not raise extracellular serotonin levels, and that is why it does not produce any of the side effects (diarrhea, nausea, sexual dysfunction, insomnia) usually observed with SSRIs. Furthermore, agomelatine does not block histaminergic, á1-adrenergic, and muscarinic receptors, and as a result does not share the side effects of TCAs.⁷⁹

◆ Combination therapy
There is evidence from everyday clinical experience, and a few controlled studies as well, that combining benzodiazepine hypnotics⁸⁰ or nonbenzodiazepine selective gamma aminobutyric acid (GABA) type A receptor antagonists, such as zolpidem, zopiclone, eszopiclone, and zaleplon, with antidepressants from the beginning of therapy may result in a faster relief of the concomitant sleep disturbance, and thereafter bring about a faster improvement in depressive symptoms.⁸¹ Therefore, it is common practice to use such combinations for the initial management of insomnia in the context of depression.⁵ Benzodiazepines commonly used for the management of insomnia are lorazepam, temazepam, alprazolam, oxazepam, triazolam, diazepam, flurazepam, and midazolam. All benzodiazepines shorten sleep onset latency, increase total sleep time and stage 2 sleep, and suppress REM sleep and SWS. Excessive daytime sleepiness is a troublesome side effect, which is more pronounced with long-acting benzodiazepines. Development of tolerance and exacerbation of insomnia with rebound of REM sleep upon withdrawal is also a major concern.^82,83 Nonbenzodiazepine hypnotics have a better pharmacological profile with fewer and milder side effects than the benzodiazepines, and are currently preferred for the treatment of sleep problems in affective disorders.^61,84 Recently, ramelteon, a novel selective agonist of melatonin MT1 and MT2 receptors, was approved for the treatment of primary insomnia. In comparison with the other hypnotics, it is claimed that ramelteon has the advantage of no potential for abuse. However, experience with this novel hypnotic agent in the treatment of insomnia associated with depression is still limited.⁵
In cases resistant to treatment, the combination of antidepressants and antipsychotics should be considered. Adding an antipsychotic to the patients’ daily regimen (ie, olanzapine) might alleviate sleep disturbances by increasing SWS.⁸⁵

Sleep disturbances often occur in depressed patients, and they may be used to identify newly presenting or recurrent episodes of depression. Moreover, persistent insomnia is one of the most common residual symptoms in incompletely remitted depression. Generally, complete relief of associated insomnia should be pursued in patients under treatment with antidepressants to avoid the recurrence of depressive symptomatology. Currently-available antidepressants have notable limitations, mainly relating to their only moderate efficacy relative to placebo. A combination of nonpharmacological interventions (sleep deprivation, light therapy, CBT, IPSRT) together with pharmacotherapy could be used to improve management of sleep disturbances associated with depression. A novel antidepressant compound, agomelatine, an agonist of melatonergic MT1 and MT2 receptors as well as an antagonist of 5-HT2C receptors, has been recently introduced; it shows a synchronizing effect on circadian rhythms and demonstrates robust antidepressant efficacy, while it produces a superior and earlier improvement in the sleep-wake cycle compared with other antidepressant agents. This sleep-restorative antidepressant offers the possibility of an improved quality of remission, while minimizing relapses or recurrences of depressive episodes.

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Les troubles du sommeil sont associés depuis longtemps à la dépression ; souvent utilisés pour identifier les patients débutant une dépression, ils pourraient appartenir à une perturbation plus générale des rythmes biologiques. De plus, l’insomnie persistante est un symptôme résiduel fréquent d’une dépression incomplètement guérie. Afin d’éviter la récidive des symptômes dépressifs, il est de règle de poursuivre le traitement de l’insomnie chez les patients traités par antidépresseurs. L’association de traitements médicamenteux et non médicamenteux ciblant le cycle veille-sommeil (privation de sommeil, luminothérapie) peut contribuer à la disparition des symptômes dépressifs et des troubles du sommeil associés. L’agomélatine, une nouvelle molécule agoniste des récepteurs mélatoninergiques MT1 et MT2 et antagoniste des récepteurs 5-HT2C, possède un effet unique de synchronisation des rythmes circadiens et une bonne efficacité antidépressive.

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b y S . H . K e n n e d y a n d S . R i z v i , C a n a d a

Sidney H. KENNEDY, MD, FRCPC Sakina RIZVI, HBSc Department of Psychiatry University Health Network University of Toronto Toronto, CANADA

The adoption of remission as a clinical outcome in the treatment of major depressive disorder (MDD) has served to emphasize the important adverse consequences of residual symptoms following antidepressant treatment. These limitations are further underscored by differences between clinician and patient perceptions of remission, highlighting the need to extend outcome measures to include a broader evaluation of quality of life in patients who have received treatment for MDD. Sexual dysfunction is frequently reported as a symptom of MDD and more frequently occurs as a result of many current antidepressant treatments. The consequences of sexual dysfunction in many depressed patients include impairment of quality of life as well as treatment nonadherence and ultimately drug discontinuation. Many antidotes to alleviate antidepressant-induced sexual dysfunction have been advocated, but few have robust, randomized controlled trial evidence to support their recommendation. Where possible, monotherapy with an antidepressant that respects sexual function is a preferred strategy.
Medicographia. 2009;31:146-151. (see French abstract on page 151)

Keywords: sexual dysfunction; remission; quality of life; antidepressant; nonadherence; discontinuation

Remission in major depressive disorder (MDD) typically refers to symptom remission; that is, the near absence of all pre-existing symptoms endorsed on an established rating scale for depressive symptoms.¹ Virtually all studies on the treatment of a major depressive episode utilize either the 17-item Hamilton Rating Scale for Depression (HAM-D17)² or the Montgomery–Åsberg Depression Rating Scale (MADRS)³ to assess remission. For the HAM-D17, a score of 7 or less to connote remission has achieved the greatest acceptance.⁴ On MADRS, scores of 10 or less, or in some instances 12 or less, have been advocated to reflect remission.^5,6
Evidence shows that there is variation among remission rates for different antidepressants and in different patient populations. Higher remission rates have been reported with venlafaxine (40%- 45%) compared with selective serotonin reuptake inhibitors (SSRIs; 35%-40%) in some,^7,8 but not all, meta-analyses of randomized controlled trials.^9,10 Patients in effectiveness trials typically achieve even lower rates of remission. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,¹¹ only 28% of patients who received citalopram (SSRI) for up to 14 weeks met remission criteria.
Failure to achieve remission is associated with many adverse consequences, including high rates of recurrence, decreased work productivity, greater medical comorbidity, and an overall decrease in quality of life.^4,12 Even patients treated to remission report a substantial burden of subthreshold or threshold symptoms: insomnia (44%), fatigue (38%), and anhedonia (27%) were the most prevalent residual symptoms in fluoxetine-treated remitters,¹³ while anxiety and loss of libido were also prevalent in other patient populations following remission.^14,15 Although clinically meaningful, a limitation in the concept of remission is that it may not fully reflect the patient’s perspective regarding the balance between symptom change, side effect burden, and functional outcome. Patients reported “presence of positive mental health,” “return to one’s usual normal self,” and “return to usual level of functioning” as the three most important items in determining remission.¹⁶

Table I. Symptoms influencing psychiatrists’ antidepressant choice for outpatients.
Modified from reference 21: Zimmerman M, Posternak M, Friedman
M, et al. Which factors influence psychiatrists’ selection of antidepressants?
Am J Psychiatry. 2004;161:1285-1289. Copyright ©
2004, American Psychiatric Association

By assessing a patient’s overall sense of satisfaction and personal wellbeing, quality of life measures reflect outcomes beyond symptom improvement. Patients with MDD may experience limitations in the areas of physical health, work efficiency, and social interactions. Measures have been developed for use across a wide range of disorders and populations (eg, Euro Quality of Life-5D, Short-Form 36-Item Questionnaire), across different psychiatric populations (eg, Social Adjustment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire), or specifically, in depressed patients (Social Adaptation and Self-Evaluation Scale).¹⁷ These scales have been valuable in demonstrating that psychosocial impairment persists in MDD even beyond remission,^18,19 indicating that symptom improvement and quality of life do not necessarily improve at the same rate. When MDD patients were evaluated periodically over 5 years of treatment, marital and sexual satisfaction ratings were persistently lower compared with controls.²⁰ Achieving symptomatic remission has to be partnered with minimal side effect burden to attain the best treatment outcome. This was recognized as an important issue by psychiatrists, who ranked sexual dysfunction as the highest consideration in prescribing an antidepressant, followed by weight gain and fatigue (Table I).²¹

In addition to sleep and alertness²² and neurocognitive symptoms,²³ healthy sexual function is an important component of good quality of life, yet sexual dysfunction is a frequent consequence of antidepressant therapy,^24-26 and is unacceptable tomany patients. In a large study involving over 6000 patients who received antidepressant therapy, 85% rated sexual functioning as “extremely important,” “very important,” or “important,” while only 3% felt it was “not important.”²⁴ Unfortunately, sexual dysfunction is a relatively neglected aspect of both remission and quality of life, despite its simple measurement, high prevalence, and negative impact on treatment adherence.

Classification and measurement
The International Classification of Diseases and Related Health Problems–10th Edition (ICD-10)²⁷ lists 10 forms of sexual dysfunction (Table II), which can be associated with physical or psychiatric conditions, medication treatments, or psychosocial factors. Sexual dysfunction in MDD typically involves problems with desire, arousal or orgasmic/ejaculatory function, and may occur across several of these areas. While the Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition Text Revision (DSM IV-TR) does not explicitly include loss of sexual interest or desire as a core item, clinicians consider libido as a component of “diminished interest or pleasure,” and a single item on HAM-D17 captures desire or interest in sex as a component of overall symptom severity. However, this scale does not assess the broader impact of sexual dysfunction on quality of life.

Table II. Classification of sexual dysfunction according to the International Classification of Mental and Behavioural Disorders–10th edition. Based on data from reference 27.

The issue of measurement across the spectrum of sexual dysfunction is of particular importance when considering the adverse impact that SSRIs and other antidepressants can have on diverse ar areas of sexual function.28,29 Several easy to use sexual function scales are available (Arizona Sexual Experience Scale, Changes in Sexual Functioning Questionnaire, Psychotropic-Related Sexual Dysfunction Questionnaire, and the Sex Effects Scale).25 The importance of administering direct assessment scales is underscored by the findings that symptom reports increase twofold (69%) with direct questioning compared with reliance on spontaneous self-report (35%).30

Prevalence and risk factors
The prevalence of sexual dysfunction in the community is estimated to be approximately 20%- 30%^31,32: a considerably higher prevalence rate of 50% or more has been reported in untreated depressed patients, and even higher rates are reported during antidepressant treatment.30 Risk factors for sexual dysfunction among psychiatric inpatients include: (i) history of physical, emotional, and sexual abuse; (ii) self-harm and depression; (iii) poor self-rated health and cardiopulmonary conditions; and (iv) use of antidepressants.³³

Adherence and discontinuation
Treatment-emergent sexual dysfunction can cause significant distress to depressed patients, which adversely affects quality of life³⁴ and leads to antidepressant nonadherence.^35,36 Sexual dysfunction was the most bothersome side effect in a survey of more than 400 patients treated with SSRIs for approximately 3 months.³⁷ Beside being a troublesome adverse event, sexual dysfunction is also one of the most common side effects leading to treatment discontinuation during short-term and long-term care.^38,39 Further supporting this finding, Rosenberg and colleagues⁴⁰ reported that 42% of men and 15% of women discontinue antidepressant treatment over perceived beliefs about sexual side effects.

In order to reduce treatment nonadherence, several strategies can be used to mitigate treatmentemergent sexual dysfunction, including augmentation with an antidote, switching medications, or preferably prescribing an antidepressant with fewer sexual side effects in the first instance. Although primary prevention is the optimal solution, this is not always possible in the treatment of MDD. Several antidepressants are associated with treatmentemergent sexual dysfunction in less than 10% of patients, while others result in significant impairment in 30% or more patients (Table III).⁴¹ These differences have been linked to putative neurotransmitter and neuropeptide abnormalities associated with sexual dysfunction, and the beneficial or adverse effects of various antidepressants on these targets. Four mechanisms associated with drug-induced sexual dysfunction involve: (i) decreased dopaminergic activity; (ii) agonism of 5HT2 and 5HT3 receptors; (iii) blockade of adrenergic and cholinergic receptors; and (iv) inhibition of nitric oxide synthase. Various antidotes targeting one or more of these mechanisms have been advocated to mitigate these adverse effects.

Antidotes to mitigate sexual dysfunction
Enhancement of dopaminergic activity
Bupropion, psychostimulants, and amantadine have all been evaluated as treatments to relieve sexual dysfunction. In two out of three bupropion add-on studies, a dose of 150 mg versus placebo failed to improve sexual dysfunction associated with SSRIs,^42,43 although augmentation with bupropion SR 150 mg twice daily was significantly better than placebo in improving desire and frequency of sexual activity in remitted depressed patients on SSRI therapies.⁴⁴ It was also observed in an open-label augmentation study that bupropion not only improved sexual dysfunction in venlafaxine-treated patients, but also increased blood levels of venlafaxine approximately threefold.⁴⁵
Stimulants such as methylphenidate have also been advocated to treat sexual dysfunction on the basis of their prodopaminergic effects. Although augmentation of antidepressant monotherapy with sustained release methylphenidate did not signifi- cantly enhance depression outcomes, there was a significant improvement in sexual function, as well as apathy and fatigue, compared with placebo.⁴⁶ In clinical practice, other stimulants are used to enhance sexual function (dextroamphetamine, modafanil), but there are no randomized-controlled trials to support these recommendations. On a cautionary note, various dopamine agonists used to treat Parkinson’s disease (pramipexole, ropinirole, and pergolide) have been associated with pathological hypersexuality.⁴⁷

Table III. Frequency of sexual dysfunction during antidepressant treatment with different antidepressant medications. Based on data from reference 41.

Antagonism of 5HT2 and 5HT3 receptors or agonism of 5HT1A receptors
Several antidepressants are known to display antagonist effects at 5HT2 or 5HT3 receptors. In the case of mirtazapine, there was found to be no advantage over placebo when the drug was added to fluoxetine in depressed women experiencing druginduced sexual dysfunction.⁴⁸ There is preliminary evidence that mirtazapine added to duloxetine improves duloxetine-induced sexual dysfunction,⁴⁹ and anecdotal support for cyproheptadine, a 5HT2 antagonist, particularly for anorgasmia,^50,51 although granisetron, a 5HT3 antagonist, did not offer any advantage over placebo.⁵²
The potentially beneficial antagonism of 5HT2A and 5HT2C receptors by atypical antipsychotics is countered by other mechanisms likely to increase serotonergic output and exacerbate sexual dysfunction. Despite the increasing use of “atypicals” such as risperidone, olanzapine, aripiprazole, quetiapine, and ziprasidone to treat patients with mood disorders, only minimal attention has been paid to sexual function. There was found to be no significant advantage of olanzapine versus placebo in reversing antidepressant-induced side effects,48 and contradictory findings were reported in two small openlabel studies using risperidone: a reduction in sexual function in one study and potentially beneficial effects in the other.^53,54 The only systematic comparison of sexual dysfunction across atypical antipsychotics was performed in a large cross-sectional study involving more than 600 schizophrenia patients. Sexual dysfunction was reported in 43% of patients receiving risperidone, 35% on olanzapine, and 18% on quetiapine.⁵⁵ Differences in diagnosis, underlying neurotransmitter function, dosing of atypical antipsychotics, and baseline sexual function limit the generalizability of these findings to the MDD population. Several agents with 5HT1A agonist properties have been evaluated as antidotes for sexual dysfunction. The anxiolytic, buspirone, has been shown to improve SSRI-induced sexual dysfunction, with more pronounced effects in women than men.⁵⁶ Though flibanserin failed to demonstrate antidepressant efficacy, this 5HT1A agonist and 5HT2A antagonist with minimal DA4 agonist effects⁵⁷ has been evaluated for the treatment of Hypoactive Sexual Desire Disorder in women, with positive results.⁵⁸ VML-670 is a novel 5HT1A agonist with weak 5HT1D agonist properties. It was not superior to placebo in overall improvement of sexual dysfunction in previously depressed male and female patients.⁵⁹
_ Blockade of adrenergic and cholinergic receptors
Yohimbine is an á-adrenergic agonist with favorable anecdotal evidence about its role in treating sexual dysfunction, but negative results under placebo- controlled conditions.48 Bethanecol has mixed central and peripheral cholinergic and adrenergic effects. It was effective in reversing clomipramineinduced ejaculatory delay under placebo-controlled conditions.⁶⁰
_ Inhibition of nitric oxide synthase
The largest trials and most robust evidence for reversal of SSRI-induced sexual dysfunction involve treatment with sildenafil, the prototypic phosphodiesterase inhibitor. Sildenafil in doses of 25-100 mg has been shown to significantly enhance sexual function in both men^61,62 and women⁶³ treated to remission with SSRIs. Preliminary evidence also supports the role of tadalafil in reversing SSRI-induced sexual dysfunction in both men⁶⁴ and women.⁶⁵

Comparison of sexual dysfunction across antidepressant monotherapies
Sexual dysfunction is a significant problem with first generation monoamine oxidase inhibitors and tricyclic antidepressants, although other adverse effects have been of much greater clinical concern.
The consensus from a series of well-designed comparative studies is that up to 60% of patients receiving SSRIs report some form of treatmentemergent sexual dysfunction.^24,28,66-71 All of the SSRIs have been associated with delayed or absent orgasm/ ejaculation, and in some instances, a reduction in libido and arousal.^28,72,73
Similar rates of sexual dysfunction have been reported with serotonin norepinephrine reuptake inhibitors,^68,74 although some evidence supports a lower rate with duloxetine, desvenlafaxine, and milnacipran, potentially related to greater noradrenergic blockade.^75-77 Reboxetine is the only second generation norepinephrine receptor inhibitor, and is not widely available as an antidepressant. Nevertheless, it is associated with a relatively favorable sexual function profile compared with SSRIs.⁷⁸
Among antidepressant monotherapies with the least likelihood of inducing sexual dysfunction, other variables beyond efficacy need to be considered. In the case of mirtazapine, switching to this from an SSRI resulted in lower rates of sexual dysfunction,⁷⁹ but other adverse effects including weight gain and daytime sedation resulted in high rates of discontinuation.⁴⁸ Nefazodone, a 5HT2 receptor antagonist and norepinephrine reuptake inhibitor, was relatively sparing of sexual function,⁸⁰ but is now largely unavailable because of hepatotoxicity concerns.81 Bupropion, with its synergistic effects on dopamine and norepinephrine systems, results in less sexual dysfunction than SSRIs^5,82 or venlafaxine.⁷⁴ Similarly, moclobemide, a reversible inhibitor of monoamine oxidase A, has a favorable impact on sexual dysfunction, although it is not generally considered to be a first-line antidepressant.^28,83,84
Agomelatine, a novel antidepressant with direct agonist effects on the melatonergic MT1 and MT2 receptors, as well as 5HT2C antagonist properties,⁸⁵ has favorable effects on sexual function. Both mechanisms may synergistically account for its lack of sexual dysfunction, since agomelatine exerts putative antagonistic effects on 5HT2 receptors, which are in turn involved in sexual behaviour.86 In addition to antidepressant efficacy,^87-89 agomelatine has been evaluated in depressed patients and healthy volunteers with sexual function as a primary outcome measure.^5,90 Among sexually active remitted patients, there was significantly less treatmentemergent sexual dysfunction in patients receiving agomelatine compared with venlafaxine, specifically in the domains of sexual drive/desire in men and orgasm in women. This was illustrated by significantly greater deteriorations on the Sex Effects scale with venlafaxine for sexual drive/desire in men and orgasm in women (an approximately fivefold difference compared with agomelatine for both).⁵ In other agomelatine trials in which the Arizona Sexual Experience Scale was used, the rate of sexual dysfunction with agomelatine was comparable to or lower than that reported in the placebo group. These results are supported by a study carried out in healthy male volunteers who were randomized to receive agomelatine, paroxetine, or placebo for 8 weeks. The percentage of volunteers who experienced severe or moderate sexual dysfunction was under 5% for agomelatine, 62% for paroxetine, and 0% for placebo.⁹⁰

The narrow clinical concept of remission, while valuable in a number of ways, fails to capture the broader domains associated with good quality of life. Healthy sexual function is an important outcome for patients with MDD, yet the majority of currently prescribed antidepressants induce or exacerbate sexual dysfunction. While there are various pharmacological approaches to mitigate drug-induced sexual dysfunction, prescribing a first-line antidepressant treatment that respects sexual function is a preferred approach. _

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