Unipolar Depression .ppt
- 1. Unipolar Depression Dr. Lara Alqam 1st year resident in psychiatry
- 2. Major Depressive Disorder Mood disorder Had at least 2 weeks of a major depressive episode which caused significant distress or disability. Had no history of mania or hypomania. This was not due to a medical or substance use disorder. Vincent Van 1890
- 3. Diagnostic Criteria A. Five (or more) of the following symptoms have been present during the same 2-week period : (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood most of the 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. 4. Insomnia or hypersomnia. 5. Psychomotor agitation or retardation 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) 8. Diminished ability to think or concentrate. 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.
- 4. B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The episode is not attributable to the physiological effects of a substance or to another medical condition. D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. E. There has never been a manic episode or a hypomanic episode.
- 5. Approximately 10% of men and 20% of women are affected Heritability: 25% (less severe depression) to 50% (more severe depression) Depression is common, economically burdensome, and can be a lifelong disorder for some patients. Recurrence rates vary from 50% after 1 episode to 90% after 3 episodes of depression. The Epidemiology of Depression
- 6. Nearly 75% of people who meet criteria for depression, also meet criteria for another psychiatric disorder (anxiety, substance- use, impulse control) Most episodes of depression resolve without treatment, however vast majority of those who recover will experience recurrences. Over 25% of patients will suffer from chronic depression
- 7. Increasing Importance of Depression MDD is among the most costly diseases in the world, and it is becoming more prevalent. DALYs=disability-adjusted life years. DALYs for a disease are the sum of the years of life lost due to premature mortality (YLL) in the population and the years lost due to disability (YLD) for incident cases of the health condition In 2000, MDD was the number 4 cause of DALYs among 15-44 year olds. MDD is estimated to be the number 2 cause of Years Lived with Disabilities (YLDs) in 2020.
- 8. The Socioeconomic Burden of Depression Significantly more people with sub-- syndromal depressive symptoms or major depression reported impairment in eight of 10 functional domains than did subjects with no disorder
- 9. Multiple Core and Associated Symptoms in MDD To establish that depression is a complex disorder that can manifest through a variety of emotional, physical, cognitive, and other associated symptoms (e.g., anxiety, worry, and pain). Note that the complexity of symptom presentation can lead to depression being a difficult condition to diagnose. The variety of symptoms of depression suggests that many areas of the brain and neural networks may be involved in depression.
- 10. Amygdala - controls autonomic responses associated with fear,arousal, formation of memories of emotional events Changes in amygdala volume and activity observed in depressed patients. Most consistent change: increased amygdala activity Prefrontal cortex (PFC) –Executive function of the brain: discrimination between conflicting, thoughts, planning complex, cognitive behaviors, working toward goal, personality expression , etc. One of PFC functions is to inhibit the activity of amygdala to allow focus on tasks fMRI and PET show decreased PFC activity in depressed vs. healthy individuals Hippocampus : Depressed patients exhibit memory loss (orientation, text recall tests) • The underlying cause is thought to be decrease in the functionality and the volume of hippocampus • Hippocampus is responsible for spatial orientation and long-term memory Regions of brain involved in depression
- 11. Persistent Depressive Disorder (Dysthymia) vs. MDD persistent depressive disorder (dysthymia) is a depressed mood that occurs for most of the day, for more days than not, for at least 2 years, or at least 1 year for children and adolescents.
- 12. Depression: Treatment Goals Once depressive disorders are diagnosed, the initial objectives of treatment, in order of priority, are to – Reduce and ultimately remove all signs and symptoms of the depressive disorder – Restore occupational and psychosocial roles/functions to the asymptomatic state – Minimize the risk of relapse and recurrence
- 13. Residual Depressive Symptoms are Associated with Greater Risk of Relapse Presence of residual symptoms of depression was associated with a relapse rate of 76% compared with a relapse rate of 25% among patients who did not have residual symptoms In this study Patients with residual symptoms relapsed almost 3 times faster (median 68 weeks vs. 23 weeks) compared with asymptomatic patients
- 14. Many Residual Symptoms are Physical Many Residual Symptoms are Physical With current antidepressant treatment, residual symptoms are often physical symptoms.
- 15. Depression: Response vs. Remission Epidemiologic and clinical data support the goal of treating depressed patients to wellness or full remission. Many patients improve but fail to achieve full remission with antidepressant treatment and continue to have residual symptoms, which cause distress and dysfunction. These residual symptoms may meet criteria for sub- syndromal and minor depression. Patients who have these milder syndromes after treatment have a greater risk of relapse and recurrence than do those who remain symptom-free.
- 16. Depression: Response vs. Remission The HAMD17 has 17 items and the scores go up to 52. The typical depressed patient in primary care tends to have HAMD between 15 and 19 The typical Psychiatric outpatient tends to have HAMD between 20 and high 20s.
- 17. Multiple Core and Associated Symptoms in MDD – To establish that depression is a complex disorder that can manifest through a variety of emotional, physical, cognitive, and other associated symptoms (e.g., anxiety, worry, and pain). – Note that the complexity of symptom presentation can lead to depression being a difficult condition to diagnose. – The variety of symptoms of depression suggests that many areas of the brain and neural networks may be involved in depression.
- 18. 5-HT(hydroxytryptamine) and NE: The Role in Both the Brain and Spinal Cord Serotonin has been implicated in depression through its brain pathways, starting in the Raphe nuclei and projecting up to the prefrontal cortex and limbic system. Norepinephrine has been similarly implicated, with its brain pathways starting in the Locus Ceruleus and projecting up to the same regions in the prefrontal cortex and limbic system. However, there are also downward projections of these serotonin and norepinephrine pathways from their brainstem nuclei into the spinal cord, and these pathways also have implications for the symptoms and treatment of depression.
- 19. 5-HT and NE: The Role in Both the Brain and Spinal Cord Antidepressants that effect either serotonin or norepinephrine specifically are effective agents. But while serotonin and norepinephrine do mediate a broad range of depressive symptoms, they do have distinguishable profiles in mediating symptoms. Therefore, dual-acting agents may provide benefits in treating the full range of depressive symptoms, both emotional and physical.
- 20. 5-HT and NE at the Synaptic Level: Healthy vs. Depressed The depressed person has a relative reduction in the amount of serotonin and norepinephrine available in the synaptic cleft
- 22. Neurotransmitter Depletion Studies: A Schematic View
- 23. TCAs at the Synaptic Level While TCAs may bind to and block the serotonin and norepinephrine transporter, (their proposed mechanism of action), they also bind to the adrenergic, histaminic and cholinergic receptors within their recommended dose range. Adrenergic blockade can cause orthostatic hypotension, histamine blockade can cause sedation and weight gain, and cholinergic blockade can cause dry mouth, urinary retention, constipation, and tachycardias.
- 24. TCAs; advantages and disadvantages TCAs have the advantage of greater efficacy in depression through their dual mechanism of action. They also have proven efficacy in pain symptoms, as well as in treating chronic pain syndromes. Unfortunately their use is limited by side-effects produced through the need to titrate to higher doses and their poor receptor site selectivity. Orthostatic hypotension, anticholinergic and antihistaminic side-effects can occur at the starting doses. Tricyclic antidepressants are cardiotoxic in overdose through their inhibition of sodium fast channels.
- 25. SSRIs Enhance 5-HT at the Synaptic Level SSRIs increase the amount of serotonin available in the synapse, but do not effect the levels of norepinephrine
- 27. SNRIs Enhance Both 5-HT and NE at the Synaptic Level By blocking both the serotonin and norepinephrine reuptake transporter, SNRIs increase the amount of both neurotransmitters available in the synapse.
- 29. Depression: Reduced Activity from Descending 5-HT and NE Pathways 5-HT and NE are the neurotransmitters in the descending inhibitory pain pathway. If depression has caused a decrease in these neurotransmitters, then there would be a decrease in the pain inhibition mediated by this spinal pathway, leading to increased pain perception.
- 30. The Role of 5-HT and NE in Painful Somatic Symptoms NE and 5-HT neural circuits directly modulate the descending pathways and compose an integral part of the complex system that controls pain perception
- 31. The Role of 5-HT and NE in Pain Perception 5-HT and NE contribute to the centrally-mediated emotional and sensory response to pain. They also mediate pain perception through the descending modulatory pain pathway, which inhibits the ascending signal.
- 32. Neurotransmitter Pathway Story: It’s Not All in Your Head Why the dual action (serotonin and norepinephrine) agents to treat aches and pains? – 5-HT and NE are instrumental in the treatment of depression and pain. – 5-HT and NE modify the effects of substance P, GLU, GABA and other pain mediators
- 33. Physical Symptoms are Not Adequately Addressed by SSRIs While SSRIs were effective in treating core emotional symptoms of MDD, they were not very effective in treating the physical symptoms of depression. This prospective open-label study with various SSRIs further validates the hypothesis that single–action agents are not that effective for treating the full spectrum of depressive illness.
- 37. Ten Leading Causes of Disability in the World Type of Disability Cost (in DALYs) Cumulative % of Cost Unipolar major depression 42,972 10.3 Tuberculosis 19,673 14.9 Road traffic accidents 19,625 19.6 Alcohol use 14,848 23.2 Self-inflicted injuries 14,645 26.7 Bipolar Disorder 13,189 29.8 War 13,134 32.9 Violence 12,955 36.0 Schizophrenia 12,542 39.0 Iron deficiency anemia 12,511 42.0
- 38. Antidepressants - History 1958 Monoamine oxidase inhibitors (MAOIs) 1958 Tricyclics (TCA’s) 1982 Trazodone (Deseryl) 1988 Fluoxetine (Prozac) 1989 Bupropion (Wellbutrin) 1994 Nefazodone (Serzone) 1994 Venlafaxine (Effexor) 1996 Mirtazapine (Remeron)
- 39. Treatment Response Categories STATE OBJECTIVE CRITERION CLINICAL STATUS PREVALENCE IN RCTS Remission HAM-D ≤ 7 No residual psychopathology ~ 40% Response ≥ 50% decrease in HAM-D without remission Substantially improved, but with residual sxs ~ 25% Partial response 25%-50% decrease in HAM- D Mild-moderate improvement ~ 10% Nonresponse < 25% decrease in HAM-D No clinically meaningful response ~ 25%
- 41. Fig. 1. Survival analysis of weeks to major depressive episode relapse (MDE): comparing patients with unipolar major depressive disorder who recovered from intake MDE with residual subsyndromal depressive symptoms vs. asymptomatic status. Wilcoxon Chi Square Test of Difference=47.96; P<0.0001.
- 42. Why Is Achieving Remission Important? Residual symptoms put patients at high risk of relapse and recurrence – Patients with residual symptoms after medication treatment are 3.5 times more likely to relapse compared to those fully recovered (Judd et al, 1998) – This risk is greater than the risk associated with having ≥ 3 prior depressive episodes – Similar finding exists after response to cognitive therapy
- 43. Subtypes of Depression •Atypical Reverse neurovegetative symptoms Mood reactivity Hypersensitivity to rejection MAO-I’s and SSRI’s are more effective treatments
- 44. Subtypes of Depression Psychotic (~10% of all MDD) •Delusions common, may have hallucinations •Delusions usually mood congruent •Combined antidepressant and antipsychotic therapy or ECT is necessary
- 45. Subtypes of Depression Melancholic •No mood reactivity •Anhedonia •Prominent neurovegetative disturbance •More likely to respond to biological treatments
- 46. Subtypes of Depression Catatonic •Motoric immobility (catalepsy) •Mutism •Ecolalia or echopraxia
- 47. What is the course of antidepressant response?
- 48. Why a temporal delay for maximal therapeutic benefit -adrenergic receptor down- regulation 5-HT2 receptor down-regulation
- 49. Tricyclic Antidepressants (TCAs) Characteristic three-ring nucleus Clinical effects Normalization of mood and resolution of neurovegetative symptoms Biochemical effects Inhibit monoamine uptake at nerve terminals May potentiate action of drugs that cause neurotransmitter release Temporal delay of weeks for clinical effects, although biochemical effects are immediate
- 50. Mechanism of action of TCAs “Tertiary” TCAs Inhibit 5-HT uptake imipramine (weaker inhibition of NE uptake) amitriptyline clomipramine “Secondary” TCAs Inhibit NE uptake desipramine (weaker inhibition of 5-HT uptake) nortriptyline
- 51. TCA Metabolism N CH3 H3C N N CH3 H3C N N CH3 H N CH3 H nortriptyline imipramine amitriptyline desipramine tertiary amines secondary amines
- 52. In vivo action of TCAs If one administers a tertiary TCA there is always both the tertiary and the secondary amine in the circulation If one administers a secondary TCA there is only the secondary amine in the circulation.
- 53. Neuropharmacology of TCAs Inhibit monoamine uptake (NE and 5- HT) Muscarinic cholinergic antagonism H1 histamine antagonism 1-adrenergic antagonism
- 54. Tricyclics- Contraindications QTc greater than 450 msec Conditions worsened by muscarinic blockade (eg myasthenia gravis, BPH) pre-existing orthostatic hypotension Seizure disorder
- 55. Side effect profile of TCAs Dry mouth Constipation Dizziness Tachycardia Urinary retention Impaired sexual funtion Orthostatic hypotension
- 56. Low therapeutic index of TCAs Cardiotoxicity: resulting from combination of: Conduction defects, arrhythmias Delirium Potentiation of effects of other sedating drugs Consequences suicide requires care in prescribing monitoring drugs that might have synergistic effects on monoamine function
- 57. Monoamine Oxidase Inhibitors (MAOIs) Irreversibly inhibit monoamine oxidase enzymes Effective for major depression, panic disorder, social phobia Drug interactions and dietary restrictions limit use
- 58. Biochemistry of MAO Occurs as two isoenzymes MAO-A – • Oxidizes norepinephrine, serotonin, tyramine MAO-B selective for dopamine metabolism
- 59. Dietary and Drug Interactions Increased stores of catecholamines sensitize patients to effects of sympathomimetics Accumulation of tyramine (sympathomimetic) = high risk of hypertensive reactions to dietary tyramine requires dietary restrictions Interactions with other sympathomimetic drugs Antidepressants OTC cold remedies • phenylpropanolamine Meperidine L-dopa
- 60. Examples of MAOIs Irreversible, non-selective MAOIs phenelzine isocarboxazid tranylcypromine Selective MAO-B inhibitors deprenyl (selegiline) loses its specificity for MAO-B in antidepressant doses Reversible monoamine oxidase inhibitors (RIMAs) Moclobemide – not approved Appears to be relatively free of food/drug interactions
- 61. Serotonin syndrome Evoked by interaction between serotonergic agents e.g., SSRIs and MAOIs Combination of increased stores plus inhibition of reuptake after release Symptoms Hyperthermia Muscle rigidity Myoclonus Rapid changes in mental status and vital signs Can be lethal
- 62. Selective Serotonin Uptake Inhibitors (SSRIs) Currently marketed medications fluoxetine (Prozac). sertraline (Zoloft). paroxetine (Paxil) fluvoxamine (Luvox) citalopram (Celexa) escitalopram (Lexapro) Selectively inhibit 5-HT (not NE) uptake Differ from TCAs by having little affinity for muscarinic, as well as many other neuroreceptors
- 63. Selective Serotonin Uptake Inhibitors (SSRIs) Much higher therapeutic index than TCAs or MAO-I’s Much better tolerated in early therapy Equal or almost equal in efficacy to TCAs
- 64. Side effects associated with SSRIs Nausea Sexual dysfunction Delayed ejaculation/anorgasmia Anxiety Insomnia
- 65. Selective Norepinephrine- Serotonin Reuptake Inhibitors Venlafaxine (Effexor) Duloxetine (Cymbalta): relatively devoid of antihistaminergic, anticholinergic, and antiadrenergic properties nonselective inhibitor of both NE and 5- HT uptake. Adverse effects: GI , Sexual dysfunction, hypertension (venlafaxine)
- 66. Other antidepressants Trazodone mixed 5-HT agonist/antagonist • 1 antagonist • H1 antagonist Nefazodone (Serzone) 5 HT2 antagonist Bupropion (Wellbutrin; Zyban) Inhibits uptake of DA and NE antismoking properties probably involves parent molecule Lacks sexual side effects Seizure risk
- 67. Mirtazapine (Remeron) 2 antagonist 5H2 and 5HT3 antagonist Net effect selective increase in 5HT1A function H1 antagonist advantages: sedation, no adverse sexual effects
- 68. Antidepressants and drug interactions Pharmacodynamic – Additive effects with alcohol and other sedating drugs – MAOI interactions Pharmakokinetic – Cytochrome P450-2D6 inhibition Fluoxetine and paroxetine Increased levels of TCAs, antipsychotics, warfarin – Cytochrome P450-3A4 inhibition Nefazodone and fluvoxamine Increased levels of terfenadine, astemizole, cisapride – can cause fatal arrhythmias
- 69. Other uses for antidepressants Panic Disorder Obsessive Compulsive Disorder Only the ADs that inhibit serotonin reuptake Social Phobia Post Traumatic Stress Disorder Premenstrual Dysphoric Disorder Chronic pain syndromes
- 70. Treatment Course One episode – 50% chance of reoccurence Two episodes – 70% chance of reoccurence Three or more episodes - >90% chance of reoccurence
- 71. When Do You Characterize a Response As Treatment Resistant? After a patient has been on an antidepressant at for a reasonable amount of time at an adequate dose No commonly accepted time point – Most drug trial data comes from 8 week long studies – If no onset of response by weeks 4 or 6, there is a 73- 88% chance of not having onset of response by end of 8 wk trial (Nierenberg et al, 2000), so 4 weeks is a reasonable point to increase dose – An 8-12 week course is consistent with acute treatment framework and allows patients 8 weeks at a dose expected to produce response