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Role of dopamin in major depressive disorders final (2)

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Dr M. Nasar Sayeed Khan presentation in Multan

Dr M. Nasar Sayeed Khan presentation in Multan

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  • Disease burden Major depression is among the leading causes of disability worldwide (WHO): Leading cause of years lived with disability (YLD) Fourth major cause of disability worldwide after respiratory disorders, perinatal conditions and HIV/AIDS, in 1996 1 and 2000 2 and is projected to become second leading cause of disability (in terms of disability adjusted life years - DALYs), after ischaemic heart disease, by 2020 1 Projected to be second most common cause of disability by 2020 ranking of DALYs 1 YLD data from World Health Organisation YLD years lived with disability data from World Health Organisation. DALYS = The sum of years of potential life lost due to premature mortality and the years of productive life lost due to disability. 2 References World Bank’s Burden of Disease Estimates: Murray & Lopez eds The global burden of disease. Boston, MA: Harvard University Press for the WHO 1996. Ustun TB et al. Br J Psychiatry 2000;184:386-92.
  • Patients who have only one episode of depression in their lifetime suffer from what is called a single depressive episode. Recurrence risk The lifetime risk of experiencing a recurrence of depression after one previous episode is 50%. This episode occurs within a year of the first episode in about 20% of these patients. This increases to 80-90% after 2 episodes and is >90% following 3 episodes. 1,2 Patients who experience more than one episode of depression are said to have a recurrent depressive episode. Patients with recurrent depression often experience episodes of depression separated by at least 2 months of essentially “normal” functioning. While there is controversy regarding the natural history of depression, an untreated depressive episode lasts generally 3 to 12 months, with some episodes lasting 2 years or longer. Some patients will have multiple recurrent episodes and will require long-term therapy. When depression goes untreated for a long time, it can actually make the patient more vulnerable to recurrent episodes. This is one reason why it is very important to diagnose and treat depression as early as possible the first time it presents. References Kupfer DJ. J Clin Psychiatry. 1991;52(Suppl 5):28-34 Depression Guideline Panel. J Amer Acad Nurse Practitioners 1994;6:224-38
  • WHO study in 15 primary care sites across North America, South America, Asia, Africa and Europe Approximately 1500 adult patients screened at each site. Final sample included 5444 patients Diagnosis of depressive disorder and anxiety disorder was by ICD-10.
  • Anxious depression covers situations where symptoms of depression and anxiety meet full criteria for depressive and anxiety disorders (comorbid); both are sub-syndromal (mixed anxiety depressive disorder; full criteria for MDD met but with sub-syndromal anxiety symptoms; full criteria for anxiety disorder met but with sub-syndromal depressive symptoms The concept of sub-syndromal symptoms can be divided into three scenarios and includes patients with (A) chronic, stable symptoms of anxiety and depression that are not sufficiently severe to warrant a diagnosis of anxiety or affective disorder. In addition, patients may have (B) an MDD plus symptoms of anxiety not meeting the criteria for an anxiety disorder or (C), generalized anxiety disorder with symptoms of depression not meeting the criteria for an MDD. (Stahl et al. 1993)
  • There are numerous unresolved problems with regard to anxiety-depression comorbidity and to the question of a meaningful further delineation of what has been called mixed anxiety depression. To reduce the heterogeneity of definitions for MAD disorders across studies and to specify the criteria for ICD-10 MADD disorder, as a fairly poorly specified category, DSM-IV recently suggested a new set of criteria for this disorder. (DSM-IV-TR 2000)
  • As part of the Rhode Island Methods to Improve Diagnostic Assessment and Services project, this analysis examined the frequency of current and lifetime DSM-IV anxiety disorders in a large cohort of outpatients with depression seen in an outpatient psychiatric practice. A total of 373 adults presented with a primary diagnosis of depression. At the time of evaluation, 57.4% (n=214) of patients met the criteria for one of the 10 specific anxiety disorders. The mean number of current anxiety disorders, including those in partial remission and not-otherwise-specified disorders was 1.31 (SD 1.2), with the majority (57.1%) of patients with an anxiety disorder having more than one disorder. Social phobia was the most frequently diagnosed anxiety disorder, occurring in one-third of surveyed patients (Zimmerman et al. 2000).
  • 4008 women in the US surveyed by telephone as part of the National Women’s Study PTSD and MDD were assessed in accordance with DSM-IV Suicide attempts were assessed by asking the participants “Have you ever attempted suicide?”
  • As part of the Harvard/Brown Anxiety Disorders Research Program, which is a longitudinal, prospective, short-interval follow-up study of adults with a current or past history of anxiety disorders, the present analysis examined the probabilities of recovery and recurrence using standard survival analysis methods. The above figure compares the 12-year cumulative probability of recovery in adults with anxiety disorders and those with comorbid MDD at entry into the study. A higher probability of recovery from MDD than from the anxiety disorders existed, with the exception of panic disorder without agoraphobia. Analysis of recovery based on treatments received (e.g., SSRIs, benzodiazepines and tricyclics) revealed no link between a specific class of medication and recovery (Bruce et al. 2005).
  • As part of the Harvard/Brown Anxiety Disorders Research Program, which is a longitudinal, prospective, short-interval follow-up study of adults with a current or past history of anxiety disorders, the present analysis examined the probabilities of recovery and recurrence using standard survival analysis methods. Adults who recovered from their anxiety disorder had a high probability of subsequently having a recurrence. Those with GAD or social phobia who recovered were less likely to have a recurrence over the 12-year follow-up period compared with the other disorders analysed. There was a high probability of subsequent recurrence in adults with comorbid MDD (probability of 0.75) (Bruce et al. 2005).
  • The search for more effective treatments of MDD and other depressive disorders has fostered exploration of the physiologic role of dopamine in depression. Fairly recently, dopamine was first implicated in the etiology and treatment of depression. Evidence from clinical investigations support the finding that depressed patients have reduced cerebrospinal levels of homovanillic acid (HVA), the major metabolite of dopamine in the central nervous system. Neuroimaging studies of medication-free depressed patients have found decreased ligand binding to the dopamine transporter and increased dopamine binding potential in the caudate and putamen, a finding consistent with the interpretation that depressed subjects have a functional deficiency of synaptic dopamine.  Animal behavioural models also find an association of depressive behaviours with altered dopamine functioning of the mesolimbic pathway. Animals exhibiting “learned helplessness” behaviour show dopamine depletion in the caudate nucleus and nucleus accumbens, which can be prevented by pretreatment with a dopamine agonist. In the “forced swim test,” another animal model of depression, the immobility of animals can be reversed by administration of the DNRI nomifensine as well as by tricyclic antidepressants (TCAs). Dopamine D 2 /D 3 antagonists block the beneficial effects of these antidepressants in this behavioural model. Several animal models of depression have consistently found altered dopamine pathways associated with depressive behaviours. 
  • Dopamine is synthesized in the cytoplasm of presynaptic neurons from the amino acids phenylalanine and tyrosine . Dopamine exerts its effects on the postsynaptic neuron through its interaction with 1 of 5 subtypes of dopamine receptors, divided into 2 groups, the dopamine 1 (D1) family (comprising the D1 and D5 subtypes) and the D2 family (comprising the D2, D3, and D4 subtypes).
  • Most DA-producing neurons in the brain are located in brainstem nuclei: the retro-rubro field (A8), substantia nigra pars compacta (A9), and the ventral tegmental area (VTA) (A10). Projection pathways of the axons arising from these cell bodies follow 1 of 3 specific paths (with some overlap) via the medial forebrain bundle to innervate specific cortical and subcortical structures, unlike the more diffuse innervation patterns of serotonergic and noradrenergic cells. The mesocortical pathway arises from the VTA and projects to the frontal and temporal cortices, particularly the anterior cingulate, entorhinal, and prefrontal cortices. This pathway is believed to be important for concentration and executive functions such as working memory. The mesolimbic pathway also arises in the VTA but projects to the ventral striatum (including the nucleus accumbens), bed nucleus of the stria terminalis, hippocampus, amygdala, and septum. It is particularly important for motivation, the experience of pleasure, and reward.
  • Relatively few studies have examined DA system alterations in depression with neuroimaging methods. Published studies have focused largely on D2 receptor or DAT occupancy. Early studies found elevated striatal D2 binding levels in depressed inpatients. Elevated D2 receptor binding may reflect increased numbers of D2 receptors in depression. In a positron emission tomography study assessing DA neuronal function depressed patients with psychomotor retardation exhibited reduced striatal uptake of the radioligand compared with anxious depressed inpatients and healthy volunteers.
  • Diminished interest or pleasure: A high proportion of patients with MDD experience diminished interest or pleasure in their daily activities and things they would normally have enjoyed. Reduced dopaminergic activity has been linked to decreased incentive motivation, anhedonia (loss of pleasure) and loss of interest. The mesocorticolimbic dopaminergic pathway, in particular the nucleus accumbens, is a key regulator of pleasure. The ventral striatum (nucleus accumbens and olfactory tubercle) and prefrontal cortex are believed to be important regions involved in motivation and affect. Fatigue and loss of energy: Symptoms of fatigue and loss of energy can be physical or mental in nature. The exact neurobiological basis of these symptoms has not been elucidated. It has been proposed that brain areas controlling motor function may be involved in physical fatigue e.g., the striatum (innervated by dopaminergic and serotonergic neurones) and cerebellum (innervated by noradrenergic neurones). Mental fatigue and lack of mental energy may be related to other symptoms of depression, such as, apathy (absence in feeling, emotion, interest or concern) and lack of motivation. Cortical brain regions, especially the dorsolateral prefrontal cortex (DLPFC), are more likely to be involved in mental fatigue. Interest and drive: Loss of mental energy and loss of pleasure can lead to loss of interest and drive. Reference Stahl SM et al. J Clin Psychiatry 2003;64[suppl 14]:6–17 .
  • Positron emission tomography (PET) was used to assess the extent and duration of dopamine transporter receptor occupancy by bupropion HCl sustained-release tablets and its metabolites under conditions of steady-state oral dosing with bupropion SRin healthy volunteers. Six healthy male volunteers received bupropion SR 150 mg daily on days 1 through 3 and 150 mg every 12 hours on day 4 through the morning of day 11. PET investigations were performed between 1 and 7 days before initiation of bupropion SR dosing, as well as, 3, 12, and 24 hours after the last dose of bupropion SR on day 11. Bupropion and its metabolites inhibited striatal uptake of a selective dopamine transporter-binding radioligand (11C-ßCIT-FE). Bupropion and its metabolites induced a low occupancy of the striatal dopamine transporter over 24 hours under the conditions of steady-state oral dosing of therapeutic doses of bupropion SR . These data are consistent with the hypothesis that dopamine reuptake inhibition may be responsible, in part, for the therapeutic effects of bupropion. Reference: Learned-Coughlin SM et al. Biol Psychiatry. 2003;54:800-5.
  • SSRI = selective serotonin reuptake inhibitor SNRI = serotonin-norepinephrine reuptake inhibitor NDRI = norepinephrine-dopamine reuptake inhibitor
  • Redefining Efficacy: Remission, Not Just Response Success in treatment of depression has been redefined in recent years. Previously, treatment response, generally a 50% reduction in symptoms, was considered adequate. Success is now defined by remission. Different definitions of remission are used, but one of the most common in clinical trials is a reduction in HAMD-17 to 7 or less. HAMD-17 refers to the total score on the 17-item semi-structured Hamilton Rating Scale for Depression. Treatment to an endpoint of symptom remission leads to a lower risk of relapse and improved occupational and social functioning
  • This slide shows some of the issues facing physicians when managing major depressive episodes.
  • Nonadherence to antidepressant therapy is a major obstacle in the effective treatment of anxiety disorders and depression. A study by Maddox, et al, that analysed dropout rates over a 12-week period in patients who were prescribed antidepressant agents revealed that 52% of patients had discontinued their medication at the 10–12-week period; of these patients, 58% had dropped out due to adverse events. Over one half of patients who dropped out reported that their physicians did not know they had stopped their therapy. As might be expected, the worse the side effects, the less time for which the patient will take their medications, suggesting that the occurrence of side effects is an important reason for noncompliance. Reference Maddox JC et al. J Psychopharmacol 1994;8:48-53.
  • Patients who take SSRIs actually have more residual symptoms, such as sleepiness and fatigue, than patients who take bupropion. These are data from a meta-analysis of 6 double-blind, randomized clinical trials comparing bupropion (SR 100-400mg/day; XR 300-450mg/day; n=662) with the SSRIs (sertraline 50-200mg/day, paroxetine, 10-40mg/day and escitalopram, 10-20mg/day; SSRI total n=665). Baseline demographic characteristics of bupropion (n=308) and SSRI (n=324) remitters were not significantly different, showing similar hypersomnia and fatigue scores. Significantly fewer bupropion patients in remission experienced residual hypersomnia (p=0.0005) or residual fatigue (p=0.0004) compared to the SSRIs. 1 Improvement in sleepiness was evident as early as week 2 for bupropion (vs. SSRI and placebo) and as early as week 4 for fatigue (OC, ITT, p<0.01). 1 It was more effective in improving excessive sleepiness by wk 2 vs SSRIs and more effective than SSRIs in resolving fatigue by wk 4. Fatigue has proven the most potent predictor of progression to a chronic course in unipolar depression 2 References 1. Papakostas GI et al. Biol Psych 2006;60:1350-1355. 2. Moos RH and Cronkite RC. J Nerv Ment Dis 1999;187:360-368.
  • Transcript

    • 1. 2
    • 2. Dr. M. Nasar Sayeed KhanAssociate Professor and Head Department of Psychiatry, SIMS and SHL. nasarsayeed@yahoo.com A Presentation
    • 3. Definition DSM-IV: Major depressive episode Criteria for the Diagnosis of an Episode of Major Depression (adapted from  DSM-IV)5 or more symptoms nearly every day for 2 weeks with at least one of the symptoms being either depressed mood or diminished interest or pleasure:  Depressed mood most of the day nearly every day  Markedly diminished interest or pleasure in all or almost all activities  Clinically significant weight loss in the absence of dieting or weight gain (e.g., a change of more than 5% in body  weight in a month) or a decrease in appetite  Insomnia or hypersomnia  Observable psychomotor agitation or retardation  Fatigue or loss of energy  Feelings of worthlessness or excessive or inappropriate guilt  Diminished ability to think or concentrate, or indecisiveness  Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, a specific plan for committing  suicide, or a suicide attempt Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) system 4
    • 4. Major depression: A heterogeneous DSM-IV disorder Patient A Patient B• Depressed mood • Loss of pleasure• Insomnia • Hypersomnia• Appetite loss • Weight gain• Poor concentration • Fatigue• Agitation • Retardation 5
    • 5. Burden of major depression – Predicted global impact  in 2020 1. Ischaemic heart disease 2. Major depression Rankorder of 3. Road traffic accidentsdiseaseburden 4. Cerebrovascular disease 5. Chronic obstructive pulmonary disease 6. Lower respiratory infections World Bank’s Burden of Disease Estimates 1996: Murray & Lopez eds. The global burden of disease. Boston, MA: Harvard University Press for the WHO. 6
    • 6. MDD: Lifetime recurrence risk 1. Kupfer DJ. J Clin Psychiatry 1991;52(suppl 5):28-34; 2. Depression Guideline Panel. J Amer Acad Nurse Practitioners 1994;6:224-38. MDD Major Depressive Disorder 7
    • 7. Comorbidity of current depression and anxietyWHO Primary Care Study Current Current depressive anxiety disorder* 7.1% 4.6% 5.6% disorder** (11.7%) (10.2%)*Depressive episode or dysthymia;**GAD, panic disorder or agorophobia Sartorius N et al. Br J Psychiatry 1996;168(Suppl 30):38-43 8
    • 8. Prevalence of MDD US National Comorbidity Survey Replication (NCS-R)• N=9090 aged 18+; USA• Prevalence of MDD – Lifetime: 16.2% (95% CI 15.1,17.3) – 12-month: 6.6% (95% CI 5.9, 7.3) (using QIDS-SR: 10.4% mild; 38.6% moderate; 38.0% severe; 12.9% very severe)• 72.1% lifetime cases had comorbid CIDI/DSM-IV disorders• 78.5% 12-month cases had comorbid CIDI/DSM-IV disorders• 51.6% of 12-month cases received health care treatment for MDDBUT• Treatment was adequate in only 41.9% of these cases, resulting in 21.7% of 12- month MDD being adequately treated Kessler RC et al. JAMA 2003;289:3095-105. Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR) NCS-R National Comorbidity Survey Replication Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) system Composite International Diagnostic Interview (CIDI 9
    • 9. Depression and anxiety symptoms: Discrete entities  or a shared spectrum?• Depressive and anxiety disorders frequently co-occur1• Possible relationships between depression and anxiety include2: – Anxiety and depression are two separate entitles – Both anxiety and depression are reflections of the same phenomenon – There is a common factor for both anxiety and depression (e.g. stress, negative affectivity, or vulnerability)• Because of the overlap in symptoms and comorbidity, it is helpful to think about depression and anxiety on a spectrum1• The shared spectrum has implications for common treatment approaches1 1. Stahl SM et al. J Clin Psychiatry 1993;54:33-8. 2. Levine J et al. Depress Anxiety 2001;14:94–104; 10
    • 10. Diagnosis of anxious depression – Different scenarios• Anxiety and depression are classically viewed as discrete entities; however, MDD is increasingly recognized as a concomitant comorbid illness with anxiety disorders Definitions cover situations where symptoms of depression & anxiety meet  Full criteria for depressive and anxiety disorders (comorbid)  Both are sub-syndromal (mixed anxiety depression [MADD]) A  Full criteria for MDD but with sub-syndromal anxiety symptoms B  Full criteria for anxiety disorder but sub- syndromal depressive symptoms C Stahl SM et al. J Clin Psychiatry 1993;54:33-8. 12
    • 11. Diagnosing & differentiating: Mixed anxiety depression  DSM-IV-TR, 4th edition, 2000 13
    • 12. Diagnosing & differentiating: MDD with sub-syndromal anxiety• Sub-threshold anxiety occurs commonly with MDD; anxiety commonly precedes MDD1• High frequency of diagnostic overlap between both conditions warrants routine assessment for MDD in patients with signs of anxiety, and vice versa1• Recognizing sub-syndromal symptoms of anxiety may help identify patients vulnerable to psychosocial stressors2 – Behavioural interventions may help prevent development of severe and disabling anxiety2 – Anxiety is often confused with lifestyle issues, problems adjusting to daily life and self-actualization issues2 1. Wittchen HU et al. Hum Psychopharmacol Clin Exp 2001;16:S21-S30; 2. Stahl SM et al. J Clin Psychiatry 1993;54:33-8 . 14
    • 13. Diagnosing & differentiating: Anxiety with sub-syndromal depression• When anxiety is predominant presenting condition, symptoms may include fear and non-specific worry accompanied by inappropriate thoughts and actions1 – Physiological symptoms with motor tension and autonomic hyperactivity, such as repetitive foot movements, are often present 1• Depressive disorder may be suspected if patient has visited GP frequently with repeated, non-specific, medically unexplained physical complaints2• Differentiating anxiety symptoms associated with medical conditions from those caused by anxiety disorders can be difficult1 – Medical condition-associated anxiety may occur after 35 years of age and in the absence of personal or family history of anxiety disorders 1 1. Mynatt S, Cunningham P. Nurse Pract 2007;32 (8):28-36. 2. Howland RH, Thase ME. The Medical Library 2005 http://www.medical-library.org/j_psych/depression_and_anxiety.htm 15
    • 14. Screening for depression and anxiety (2)• Mixed anxiety depression – Symptoms include ≥1 physical symptom (e.g., pains, poor sleep, fatigue) plus anxiety and depressive symptoms present for >6 months1• MDD with sub-syndromal anxiety – Screening for depression recommended if patient presents at ≥3 visits with recurrent physical symptoms (e.g., headache, fatigue),2• Anxiety disorder with sub-syndromal depressive disorder – Risk factors for anxiety disorders include female, perinatal risk factors, parental history of mental disorder, poor financial situation2; sub-syndromal features of depression may include tearfulness, anticipating the worst, hopelessness and pessimism about the future3 – Mental Health 2005 http://www.library.nhs.uk/mentalhealth/viewresource.aspx?resid=82618; 1. Jenkins R. NHS Evidence 2. Mynatt S, Cunningham P. Nurse Pract 2007 32:28-36; 3. Howland RH, Thase ME. The Medical Library 2005 http://www.medical- library.org/j_psych/depression_and_anxiety.htm. 16
    • 15. Current and lifetime prevalence of anxiety disorders  in depressed subjectsAnxiety disorder*,1 Current prevalence (%)  Lifetime prevalence (%)Any 57.4 65.7Specific phobia 13.7 15.0Social phobia 33.0 35.7OCD 9.9 12.6GAD 15.0 15.0PTSD 13.4 24.1Panic disorder Without agoraphobia 2.9 4.0 With agoraphobia 14.2 19.3*According to DSM-IV. N=373  In a survey of over 8000 adults in Great Britain, the 1-month prevalence of mixed anxiety depression (on the basis of a score >12 on the Clinical Interview Schedule – Revised [CIS–R]) was 8.8%2 1. Table adapted from Zimmerman M et al. Am J Psychiatry 2000;157:1337-40; 2.. Das-Munshi J et al. Br J Psychiatry 2008;192:171-7. 17
    • 16. Greater number of suicide attempts in women with  MDD when PTSD is comorbidTelephone survey of 4008 US women Cougle JR et al. Depress Anxiety 2009;26:1151–7. 18
    • 17. Higher probability of recovery from comorbid MDD  than from anxiety disorders (except panic disorder)Prospective, naturalistic, longitudinal (12 year) study (HARP) Recovery: at least 8 consecutive weeks with at most residual symptoms Bruce et al. Am J Psychiatry 2005;162:1179-87. 19
    • 18. High probability of recurrence of comorbid MDD  following recoveryProspective, naturalistic, longitudinal (12 year) study (HARP) Recurrence: full diagnostic criteria for minimum period (2 weeks, other than GAD) Bruce et al. Am J Psychiatry 2005;162:1179-87. 20
    • 19. Key issues in managing MDD• Heterogeneous disorder: symptom profiles vary widely among individuals and between episodes1,2• Response to antidepressants is inconsistent and unpredictable1,2• Residual symptoms are common3,4• Side-effects negatively impact compliance and long-term outcome5,6 1. Belmaker RH, Agam G. N Engl J Med 2008;358:55−68. 2. Stahl SM et al. J Clin Psychiatry 2003;64(Suppl 14):6−17. 3. Nierenberg AA et al. J Clin Psychiatry 1999;60:221−5. 4. Nelson JC et al. J Clin Psychiatry 2005;66:1409−14. 5. Zajecka JM. J Clin Psychiatry 2000;61(Suppl 2)20-5; 6. Lin EHB et al. Medical Care 1995;33:67-74. 21
    • 20. Monoamine neurotransmitter regulation  of mood and behaviour Dopamine Interest Noradrenaline Motivation Alertness Pleasure Attention Energy Reward Mood Anxiety Serotonin Obsessions Compulsions Nutt DJ. J Clin Psychiatry 2008;69(Suppl E1):4-7. 23
    • 21. Dopamine and anhedonia Role of dopamine in depression• Impaired dopamine release is proposed to contribute to the pathophysiology of depression• Evidence from clinical investigations support the finding that depressed patients have reduced cerebrospinal levels of homovanillic acid (HVA), the major metabolite of dopamine in the CNS• Animal behavioural models also find an association of depressive behaviours with altered dopamine functioning of the mesolimbic pathway Dunlop BW, Nemeroff CB. Arch Gen Psychiatry 2007;64:327-37. 24
    • 22. Role of dopamine in depression• Dopamine is synthesized in the cytoplasm of presynaptic neurons• Dopamine exerts its effects on the postsynaptic neuron through its interaction with dopamine receptors• Dopamine receptors – D1 family – comprising D1 & D5 – D2 family – comprising D2, D3 & D4 Dunlop BW, Nemeroff CB. Arch Gen Psychiatry 2007;64:327-37. 25
    • 23. Neuroanatomical circuits involved in depression Dunlop BW, Nemeroff CB. Arch Gen Psychiatry 2007;64:327-37. 26
    • 24. MDD: Data from neuroimaging studies• Neuroimaging findings are not uniequivocal, but several studies support the hypothesis that major depression is associated with a state of reduced DA transmission, possibly reflected by a compensatory up-regulation of D2 receptors• Early studies found elevated striatal D2 binding levels in depressed patients• Elevated D2 receptor binding may reflect increased numbers of D2 receptors in depression, an increase in affinity of the receptor for the ligand, or a decrease in availability of synaptic DA (which competes with the radiolabeled ligand for D2 binding)• In a positron emission tomography study assessing DA neuronal function by measuring radioligand uptake in the striatum, depressed patients with psychomotor retardation exhibited reduced striatal uptake of the radioligand compared with anxious depressed inpatients and healthy volunteers. Another PET study observed reduced dopamine transporter binding in depression Dunlop BW, Nemeroff CB. Arch Gen Psychiatry 2007;64:327-37. 27
    • 25. Dopaminergic neurotransmitter systems and possible  regions of MDD symptom generation  Loss of physical energy, retardation Pre-frontal Loss of Striatum Cortex mental energy/ fatigue Substantia Nucleus Nigra Accumbens Ventral Loss of Tegmental Area Loss of interest pleasure Nutt D et al. J Psychopharmacol 2007;21:461-71. 28
    • 26.  Dopamine transport activity: In vivo binding of  11 C-βCIT-FE in humans Effect observed after treatment with bupropion HCl 150 mg every 12 hours Baseline 3 hours 12 hours 24 hours Normalized to cerebellum Learned-Coughlin SM et al. Biol Psychiatry 2003;54:800-5. 29
    • 27. International Consensus Statement on Major  Depressive Disorder (ICSMDD)• Existing treatment guidelines have the following basic principles in treating patients with MDD: – Establish a correct diagnosis by using screening and diagnostic tools along with a full clinical psychiatric assessment – Assess the patient’s depression severity, current stressors, comorbidities and suicide risk – Select a treatment setting (inpatient vs outpatient) depending on severity of depression – Establish a therapeutic alliance and educate the patient and family about depression and its treatment – Choose appropriate individualized treatments of an adequate dose and duration to help the patient achieve remission Nutt DJ et al. J Clin Psychiatry 2010;71 [Suppl E1]:e08. International Consensus Statement on Major Depressive Disorder (ICSMDD) 30
    • 28. ICSMDD: Selecting treatments for depression• Antidepressants are first-line therapy for moderate and severe major depression: – SSRIs, SNRIs, and NDRIs preferred due to tolerability profiles • SSRI (selective serotonin reuptake inhibitor) • SNRI (serotonin-norepinephrine reuptake inhibitor) • NDRI (norepinephrine-dopamine reuptake inhibitor)• Consider psychotherapy as monotherapy for mild depression and as adjunctive therapy for moderate or severe depression• Benzodiazepine monotherapy should be avoided• Treat to remission and monitor progress after remission Nutt DJ et al. J Clin Psychiatry 2010;71 [Suppl E1]:e08. International Consensus Statement on Major Depressive Disorder (ICSMDD) 31
    • 29. Second-generation antidepressants in MDD• No substantial difference in efficacy or effectiveness (meta- analysis of 203 studies)1-2• Response and remission rates generally similar between the SSRIs and between the newer classes3-6 1.Gartlehner G et al. Ann Intern Med 2008;149:734-50; 2. Qaseem A et al. Ann Intern Med 2008;149:725-33; 3. Thase ME. Psychopharmacol Bull 2008;41:58-85; 4. Thase ME et al. J Clin Psych 2005;66:974-81; 5. Papakostas GI et al. J Psychopharmacol 2008;22:843-8; 6. Olver JS et al. CNS Drugs 2001;15:941-54. 32
    • 30. ACP Review: Relative benefit of response  – SSRIs, SSNRIs, SNRIs & other 2nd-generation ADs Gartlehner G et al. Ann Intern Med 2008;149:734-50. ACP American College of Psychiatrists 34
    • 31. Antidepressants – How to choose?• Generally comparable overall efficacy for MDD – No substantial difference in efficacy or effectiveness (meta-analysis of 203 studies) 1-2 – Response and remission rates generally similar between SSRIs and newer classes 3-6• Second-generation antidepressants have better tolerability and safety than older classes7• Some may be better for specific symptom clusters or patient subpopulations 8• Consider psychiatric and medical comorbidity• Consider approved indications• Consider differing tolerability profiles – Poor tolerability can affect treatment adherence and, ultimately, patient outcomes 1.Gartlehner G et al. Ann Intern Med 2008;159:734-50; 2. Qaseem A et al. Ann Intern Med 2008;159:725-33; 3.Thase ME. Psychopharmacol Bull 2008;41:58-85; 4. Thase ME et al. J Clin Psych 2005;66:974-81; 5. Papakostas GI et al. J Psychopharmacol 2008;22:843-8.; 6. Olver JS et al. CNS Drugs 2001;15:941-54; 7. Nutt DJ et al. J Clin Psychiatry 2010;71 [Suppl E1]:e08; 8. Papakostas GI. J Clin Psychiatry 2010;71[suppl E1]:e03. 35
    • 32. Hypothetical model: Differential actions of ADs on  symptoms of positive and negative affect  Depression with loss of interest and energyLoss ofpositive Loss of affect pleasure/enjoyment Loss of motivation and energy Loss of DA/NE agents interest Low mood Sadness Guilt Depression Irritability with anxiety Fear Anxiety Negative affect NE/5HT agents Nutt D et al. J Psychopharmacol 2007;21:461-71. Ads Anti- Depressants. NE Norepinephrine/Serotonin Agents. DA/NE Dopamine Norepinephrine Agents 36
    • 33. Characteristics of depression • MDD is associated with two mood states1-3: 1. Negative affect: • broad range of negative mood states e.g. anxiety, irritability, hostility, guilt and loneliness • these mood states are associated with both depression and anxiety disorders 2. Decreased positive affect • loss of interest, loss of energy and loss of motivation• In addition, anxiety disorders are often comorbid with MDD4 1. Nutt D et al. J Psychopharmacol 2007;21:461-71. 2. Watson D, Tellegen A. Psychol Bull. 1985; 98: 219-35 3. Shelton RC, Tomarken A.J Psych Serv 2001;52:1469-78. 4. Rapaport MH. J Clin Psychiatry 2001;62(Suppl 24):6-10 37
    • 34. Remission: The goal of MDD treatment • Partial remission:  – Some MDD symptoms still present, but full diagnostic criteria for MDD no longer met• Full remission:  – No significant symptoms of depression American Psychiatric Association. DSM-IV-TR. Washington, DC: APA, 2000. 38
    • 35. Relapse risk decreases the longer one is well Remission Recovery Relapse Recurrence Normal mood Pro gres Relapse + SymptomsSeverity Response sion  to  50% improvement + diso rde Depression r Acute Continuation Maintenance Kupfer DJ. J Clin Psychiatry 1991;52(Suppl):28–34. 39
    • 36. Key Issues in managing MDD and achieving remission• MDD is a heterogeneous disorder: symptom profiles vary widely among individuals and between episodes1,2• Response to antidepressants is inconsistent and unpredictable1,2• Residual symptoms are common3,4• Side-effects negatively impact compliance and long-term outcome5,6 1. Belmaker RH,Agam G. N Engl J Med 2008;358:55−68; 2. Stahl SM et al. J Clin Psychiatry 2003;64(Suppl 14):6−17; 3. Nierenberg AA et al. J Clin Psychiatry 1999;60:221−225. 4. Nelson JC et al. J Clin Psychiatry 2005; 66:1409−14. 5. Zajecka JM. J Clin Psychiatry 2000;61(Suppl 2):20-5; 6. Lin EHB et al Medical Care 1995;33:67-74. 40
    • 37. Antidepressant non-adherence and early drop out…  common problems         • Nearly one-third stop in the first month1• About 44% no longer taking after 3 months2• Early drop out:3 – 28% by week 4 – 43% by week 8 – 52% by week 12 1. Golden RN et al. J Clin Psychiatry 2002;63:577-84; 2. Lin EHB et al. Medical Care 1995;33:67-74; 3. Maddox JC et al. J Psychopharmacol 1994;8:48-53. 41
    • 38. September 23, 2012 Ammoura Ayman H. 42
    • 39. Adverse events: A major cause of treatment  discontinuation  Poor early tolerability High early drop out• Reasons for outpatient non-adherence: – Adverse events: 62–66% of patients cited adverse events as a major cause of dropout – Lack of education about what to expect from antidepressants Lin EHB et al. Medical Care 1995;33:67-74; Maddox JC et al. J Psychopharmacol 1994;8:48-53. 43
    • 40. Side effects of antidepressants• All antidepressants carry some risk of side effects• Side effects can include – Nausea – Sedation – Insomnia – Sexual dysfunction – Weight gain• There is potential for emergence or worsening of suicidal behaviour during antidepressant therapy in patients aged <25 years• Although risk of side effects may deter patients from accepting treatment, they should be informed that risks of untreated depression probably outweigh risk of side effects• Choice of treatment should consider impact of possible AEs on individual patient Nutt DJ et al. J Clin Psychiatry 2010;71 [Suppl E1]:e08 AEs Adverse Events 44 .
    • 41. SSRI/SNRI associated nausea and rationale for  controlled-release SSRI/SNRI• Gut mucosa enterochromaffin cells secrete 5-HT• Rapid dissolution and absorption of SRIs leads to upper GI high mucosal drug concentrations• Nausea from 5-HT3 receptor stimulation in peripheral duodenal synapses• Optimizing rate and site of SRI absorption should minimize the incidence and severity of nausea Golden RN et al. J Clin Psychiatry 2002;63:577–84. Serotonin receptors, also known as 5-HT (5-hydroxytryptamine receptors) 45
    • 42. Side effects influencing psychiatrists’ choice of  antidepressant 25% Choice of antidepressant should take into 20.3% account: 17.7% -possible adverse events of different 20% treatments, and - what would be important for the individual patient% of Patients 15% 9.4% 7.2% 10% 6.4% 4.2% 5% 0% Sexual Weight Fatigue Anticholinergic Agitation Insomnia Dysfunction Gain Effects Zimmerman M et al. Am J Psychiatry 2004;161:1285-9. 46
    • 43. Pharmacotherapies: SSRIs • Better tolerated than tricyclic antidepressants1 • Citalopram 20–60mg/day • Escitalopram 10–20mg/day • High safety in overdose1 • Fluoxetine 10–40mg/day • May cause insomnia, agitation, sedation, GI distress and sexual dysfunction1 • Paroxetine 20–50mg/day • • Increased risk of hyponatraemia; older age and Sertraline 50–150mg/day1 female sex are risk factors2 • Interact with CYP-450 isoenzymes by inhibition2 • Can increase the anticoagulant effect of warfarin2 • Do not discontinue abruptly; taper the dose2 • Lower starting doses recommended in the elderly2 • Paroxetine may be associated with anti-cholinergic side effects2 1. Rush AR, Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadocks Comprehensive Textbook of Psychiatry. US: Lippincott Williams & Wilkins;US doses are listed. Please refer to local label 2. Sussman N. 2009. Chapter 31 In: Kaplan & Sadocks Comprehensive Textbook of Psychiatry. US:recommendations for dosing in the elderly Lippincott Williams & Wilkins. 47
    • 44. Pharmacotherapies: Tricyclics  Desipramine 75–300mg/day  Potential for anti-cholinergic and sedative effects2  Nortriptyline 40–200mg/day1  Avoid in patients with a QTc interval of 450 msec or greater2  May be fatal in overdose1, 2  Potentially dangerous when given with the MAOIs: fatal hypertensive reaction may occur when a large dose of a tricyclic is given to a patient already on an MAOI2 1. Rush AR, Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadocks Comprehensive Textbook of Psychiatry. US: Lippincott Williams & Wilkins; 2. Nelson JC. 2009. Chapter 31 In: Kaplan & Sadocks Comprehensive Textbook of Psychiatry. US:US doses are listed. Please refer to local label Lippincott Williams & Wilkins.recommendations for dosing in the elderly Monoamine oxidase inhibitors MAOI’s 48
    • 45. Pharmacotherapies: SNRIs  Duloxetine 60–120mg/day  Higher doses may cause hypertension  Sleep changes and GI distress are common  Venlafaxine 150–375mg/day  Abrupt discontinuation may result in discontinuation symptomsUS doses are listed. Please refer to local label Rush AR Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadocks Comprehensive Textbook of Psychiatry. US: Lippincott Williams & Wilkins.recommendations for dosing in the elderly 49
    • 46. Pharmacotherapies: NDRIs  Bupropion 200-400mg/day1  Dopamine Reuptake Inhibitor  No sexual dysfunction or weight gain.  Bupropion SR 300-400mg/day 2  Bupropion XL 300-450mg/day3 1. Rush AR Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadocks Comprehensive Textbook ofUS doses are listed. Please refer to local label Psychiatry. US: Lippincott Williams & Wilkins; 2. GSK.recommendations for dosing in the elderly 3. BTA Pharmaceuticals, Inc. Wellbutrin XL prescribing information 2010. 50
    • 47. Pharmacotherapies based on serotonin and  norepinephrine Norepinephrine, 5HT2 and 5HT3   Sedation and weight gain are common with mirtazapine3 antagonist Mirtazapine 15–30mg/day1 Serotonin antagonist and reuptake  inhibitor Nefazodone 300–600mg/day in divided doses2 Trazodone 150–600mg/day1 1. Rush AR. Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadocks Comprehensive Textbook of Psychiatry. US: Lippincott Williams & Wilkins; 2. Khan AA, Kornstein, SG. Chapter 31 In: Kaplan & Sadocks Comprehensive Textbook of Psychiatry. US: Lippincott Williams & WilkinsUS doses are listed. Please refer to local label 3. Thase ME. Chapter 31 In: Kaplan & Sadocks Comprehensive Textbook of Psychiatry. US: Lippincott Williams & Wilkins.recommendations for dosing in the elderly 51
    • 48. Pharmacotherapies: Stimulants• Reports of use of dextroamphetamine and methylphenidate for – Depression secondary to medical conditions – Apathy and depression secondary to CNS trauma – Augmentation in some cases of treatment-resistant depression• Studies suggest modafinil may also be useful in treatment-resistant patients for augmentation of antidepressant therapy Fawcett J. Chapter 31 In: Kaplan & Sadocks Comprehensive Textbook of Psychiatry. US: Lippincott Williams & Wilkins . 52
    • 49. Anti-depressive efficacy in MDD with anxiety symptoms • Clinical guidelines based on evidence  A review of second-generation from six head-to-head trials of antidepressants in 10 head-to- second-generation antidepressants head trials found comparable found similar antidepressive efficacies in the treatment of efficacies for:1 anxiety associated with MDD for: – Fluoxetine or paroxetine vs  Fluoxetine, paroxetine and sertraline sertraline – Sertraline vs bupropion  Sertraline and bupropion – Sertraline vs venlafaxine  Sertraline and venlafaxine • A pooled analysis of 10 studies  Citalopram and mirtazapine analysis showed comparable efficacy for bupropion and SSRIs in patients  Paroxetine and nefazodone with MDD and low to moderate levels of anxiety21. Qaseem A et al. Ann Intern Med 2008;149:725-33; Qaseem A et al. Ann Intern Med 2008;149:725-33.2. 2. Papakostas GI et al. J Clin Psychiatry 2008;69:1287–92. 53
    • 50. Augmentation With Bupropion: • Bupropion HCL Wellbutrin XL(BupropionHCL)combined with SSRI’s is well tolerated and may be effective in treating depressed patients who have an inadequate response to an SSRI 1 • Bupropion  HCL  augmentation facilitated treatment response in a majority of non-responders to SSRI monotherapy • Bupropion  HCL  with Escitalopram results in more rapid and increased remission related to effects of Escitalopram used as mono therapy31. Charles DeBattista et al. A prospective trial of Bupropion SR Augmentation of Partial and Non-Responders to Serotonergic Antidepressants, Journal of Clinical Psychopharmacology, Volume 23, 2003; 27-302. T Eller et al. Effects of Bupropion augmentation on pro-inflammatory cytokines in Escitalopram-resistant patients with major depression disorder, Journal of Psychopharmacology 2009 23; 8543. Stewart w. et al. Does dual antidepressant therapy as initial treatment hasten and increases remission from depression? Journal of Psychiatric Practice 2009: 15:337-345 47
    • 51. Bupropion XL for depression with reduced energy,  pleasure and interest• A prospective, double-blind, placebo-controlled study (n=274)• Entry criterion based on Inventory of Depressive Symptomatology (IDS) energy, pleasure, interest subset: – Item 19 - general interest/involvement – Item 20 - energy/fatigability – Item 21 - pleasure/enjoyment – Item 22 - sexual interest – Item 30 - leaden paralysis/physical energy – Entry: total score ≥7, minimum of 1 on ≥4/5 itemsSome subjects received daily doses of bupropion XL > 300mg during the study Jefferson JW et al. J Clin Psychiatry 2006;67:865-73. 55
    • 52. Less residual sleepiness and fatigue following remission with bupropion Pooled analysis of 6 randomized controlled studies# 50 Bupropion (n=308) SSRIs (n=324) % of patients with residual  40 32.1 30.2 30 symptoms * † 20.5 19.5 *p=0.0014 vs SSRIs 20 † p=0.002 vs SSRIs 10 0 Residual Sleepiness Residual Fatigue# Includes bupropion doses above the licensed dose for Europe and most non-North American Countries~52% of patients received doses of ≤300mg Papakostas GI et al. Biol Psychiatry 2006;60:1350-5. 57
    • 53. Bupropion XL: Patient-rated depressive symptomatology vs  placeboPrimary endpoint: Mean IDS-IVR-30 * * * *p<0.05 for difference between bupropion and placeboIDS-IVR-30 = 30-item Inventory of Depressive Symptomatology-Self-Report, interactive voice response version Jefferson JW et al. J Clin Psychiatry 2006;67:865-73. 58
    • 54. Conclusions1. MDD constitutes a significant public health and social burden globally2. It is often comorbid with other mental disorders, including anxiety3. MDD is under-recognized and often under- and/or inappropriately treated4. As a heterogeneous disorder, response to antidepressants is inconsistent and unpredictable and MDD is therefore under- and/or inappropriately treated5. A high proportion of patients with MDD experience diminished interest or pleasure in their daily activities (anhedonia) – reduced dopaminergic activity has been linked to this6. Treatments should be individualized based on depressive symptomatology 59
    • 55. Mujtaba Nasar 60