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Current Issues in Depression and Bipolar Disorder Descartes Li, M.D. Associate Professor of Clinical Psychiatry University of California, San Francisco [email protected] 5/24/2017 By the end of the seminar, a participant should: Describe efficacy of using first line antidepressants for Major Depression in primary care. Understand the STAR*D results regarding augmentation and switch strategies in antidepressant treatment. Identify the key diagnostic signs and symptoms of Bipolar Disorder. Be aware of high rates of bipolar disorder in primary care settings and in the general population. Major Depressive Episode: SIG E CAPS criteria Depressed mood (or anhedonia), plus: S –Sleep symptoms I—lack of Interest. G—feelings of Guilt E—lack of Energy. C--lack of Concentration. A--lack of Appetite. P--Psychomotor changes S--thoughts of Suicide Major Depressive Episode: DSM IV Criteria Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). (In children and adolescents, this may be characterized as an irritable mood.) 2. markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day 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 nearly every day Major Depressive Episode: DSM IV Criteria (continued) 5. psychomotor agitation or retardation nearly every day 6. fatigue or loss of energy nearly every day 7. feelings of worthlessness or excessive or inappropriate guilt nearly every day 8. diminished ability to think or concentrate, or indecisiveness, nearly every day 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. Major Depressive Disorder Treatments Psychopharmacological: SSRI’s, TCA’s, MAOI’s, psychostimulants Psychosocial (may also be used first-line): Cognitive-behavioral therapy, interpersonal therapy Somatic: Electroconvulsive therapy, transcranial magnetic stimulation, vagal nerve stimulation (efficacy remains unclear) N.B. All treatments for major depression about equally efficacious (ECT may be a bit better) What percentage of patients have a successful outcome with an initial trial of antidepressant? (How does pharma make their drugs look good?) Current Issues in Depression Sequenced treatment alternatives to relieve depression (STAR*D) 2,876 outpatients started on citalopram “real world” practices: mixed psychiatric and primary care settings Only exclusions: schizophrenia, bipolar disorder, eating disorders, OCD Advocated usage of standardized depression measure each visit (Quick Inventory of Depressive Symptoms) available free at http://www.ids-qids.org/ Not placebo-controlled, therefore unblinded Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40. Current Issues in Depression Sequenced treatment alternatives to relieve depression (STAR*D) The average STAR*D patient: Six prior episodes of depression Continuously depressed for two years Recurrent episodes over the past 15 years Three or more medical conditions Education below college level Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40. Current Issues in Depression Sequenced treatment alternatives to relieve depression (STAR*D) – Steps one and two Step One: citalopram (Celexa) up to 60mg/d Step Two: switch to venlafaxine (Effexor) XR, bupropion (Wellbutrin) SR, sertraline (Zoloft) or cognitive therapy OR augment with buspirone (Buspar), bupropion SR or cognitive therapy Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40. Current Issues in Depression STAR*D study Remission rates were 32.9%, response rate was 47% (QIDS-SR) No difference in response rates between primary care and psychiatric settings Mean exit dosage = 41.8mg/d (started at 20mg/d; inc. to 40mg/d by week 4, 60mg/d by week 6) Most subjects responded by week 8 Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40. Figure 3: Percent of patients who achieved response or remission Current Issues in Depression STAR*D study Baseline features associated with response/remission: Caucasian (24% non-Caucasian subjects) Female, better educated, better paid Having private insurance, fewer concurrent medical/psychiatric conditions, greater life satisfaction, shorter current episode Being married or living with someone Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40. What percentage of patients respond to a switch in therapy? Switching Antidepressants: STAR*D Unblinded, no placebo Patients had a choice: switch or augment Therefore, the patients who switched who those who tended to have more side effects and less initial benefit Patients randomly (equipoise) switched to bupropion, sertraline, or venlafaxine XR. Bupropion-SR, Sertraline, or Venlafaxine XR After Failure of SSRI’s for Depression. AJ Rush et al. NEJM 2006, 354:1231-42. Switching Antidepressants 56% could not tolerate CIT 250 VEN XR 62 (25.0%) remit 194mg/d avg dose Bupropion-SR, Sertraline, or Venlafaxine XR After Failure of SSRI’s for Depression. AJ Rush et al. NEJM 2006, 354:1231-42. What percentage of patients respond to an augmentation to their original SSRI? Augmenting Antidepressants Random (equipoise) design between bupropion and buspirone Unblinded, no placebo Recall: patients had a choice: switch or augment Many of these patients had a partial response to citalopram Medication Augmentation after the Failure of SSRIs for Depression. Trivedi MH et al. NEJM 2006, 354:1243-52. Augmentation of SSRI Medication Augmentation after the Failure of SSRIs for Depression. Trivedi MH et al. NEJM 2006, 354:1243-52. QIDS = Quick Inventory of Depressive Symptoms Conclusions from STAR*D Citalopram treatment requires relatively high dose (40-60mg/d) and at least 8 weeks Switching to Bupropion-SR, Sertraline, or Venlafaxine XR equally efficacious (remit rate for all: about 25%) Augmentation with Bupropion (39% remission rate) slightly better than buspirone (33%) Overall, remission rates rather disappointing but the study demonstrates up to date methodology that can be applied to “real world” practices Current Issues in Depression Sequenced treatment alternatives to relieve depression (STAR*D) – Still to come Step Three: One of the following options: switch to mirtazapine (Remeron) or nortriptyline OR Augment with lithium or Cytomel (T3) Step Four: Switch to tranylcypromine (Parnate) or venlafaxine (Effexor) XR + mirtazapine (Remeron) Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:28-40. Major Depressive Disorder Overview: Other Antidepressants Mirtazapine (Remeron): sedation and weight gain Venlafaxine (Effexor): Mixed NE and 5HT activity, increases BP, similar side effect profile to ssri’s Duloxetine (Cymbalta): Also mixed NE and 5HT activity Buproprion (Wellbutrin): low rate of sexual side effects or weight gain, associated with increase rate of seizures, not for use in patients with eating disorders, prior seizure d/o Nefazodone (Serzone)5-HT2 blocker, often recommended for anxious depression, black box warning for liver failure, low rate of sexual se’s Trazodone (Desyrel) – usually prescribed as a hypnotic (ie, sleep aid) Major Depressive Disorder Overview: Tricyclic Antidepressants and MAOI’s TCA’s (tricyclic antidepressants): anticholinergic side effects, tremor, weight gain, sexual side effects, cardiac conduction delay (quinidine like effect), NE reuptake inhibitors Examples [not a complete list]: amitriptyline (Elavil), doxepin (Sinequan), imipramine (Tofranil), desipramine (Norpramin), nortriptyline (Pamelor, Aventyl), maprotiline (Ludiomil) MAOI’s (monoamine oxidase inhibitors): important: dietary restrictions! (b/o hypertensive crisis), new patch* side effects: sedation, sexual side effects, weight gain phenelzine (Nardil), trancylopramine (Parnate), [selegiline (Eldepryl) for Parkinson’s] Current Issues in Bipolar Disorder EPIDEMIOLOGY OF BIPOLAR DISORDER Prevalence: 1.8 to 3.6 million Americans Morbidity (untreated): 14 year cumulative loss of productivity Suicide rate: 10-20% 9.2-year reduction in life expectancy 1-3% prevalence in general population (recent estimates suggest higher prevalence) Altemus. In: Schulkin. Hormonally Induced Changes in Mind and Brain. 1993 McEachron. In: Schulkin. Hormonally Induced Changes in Mind and Brain. 1993 EPIDEMIOLOGY OF BIPOLAR DISORDER Genetic: Bipolar disorder tends to run in families. 80-90% of individuals with bipolar disorder have a relative with either depression or bipolar disorder (which is 10-20 times higher than that found in the general population). Triggers: trauma, social stress, sleep deprivation, antidepressants (without accompanying mood stabilizers) Altemus. In: Schulkin. Hormonally Induced Changes in Mind and Brain. 1993 McEachron. In: Schulkin. Hormonally Induced Changes in Mind and Brain. 1993 Misdiagnosis of Bipolar Disorder in 1994 Years to diagnosis: 8 Number of clinicians before diagnosis: 3.3 48% not diagnosed with BP until seeing more than 3 mental health professionals Lish JD et al. J Affect Disord 1994; 31: 281-294. The DMDA survey of bipolar members. Altemus. In: Schulkin. Hormonally Induced Changes in Mind and Brain. 1993 McEachron. In: Schulkin. Hormonally Induced Changes in Mind and Brain. 1993 Misdiagnosis of Bipolar Disorder in 2000 Mean number of clinicians seen before diagnosis: 4 Mean number of diagnoses received before bipolar diagnosis made: 3.5 Percentage of respondents misdiagnosed: 69% More than one-third reported a lapse of 10 years or more between first seeking treatment and then receiving appropriate treatment. Hirschfeld RM et al. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry 2003;64:45-59. Bipolar Disorder in Primary Care Of 108 consecutive anxious and depressed patients in primary care clinic, Using DSM-IV criteria in a semi-structured interview by family physician, 25% were diagnosed with bipolar disorder: BP I (2.8%), BP II (18.5%), BP III (3.7%) Manning JS et al. Compr Psychiatry 1997; 38: 102-108. On the Nature of Depressive and Anxious States in a Family Practice Setting: The High Prevalence of Bipolar II and Related Disorders in a Cohort Followed Longitudinally. Bipolar Disorder in Primary Care Of 1146 patients who were screened from a waiting room of a primary care clinic, Using the Mood Disorders Questionnaire, PRIME-MD, and medical record review 112 (9.8%) screened positive for bipolar disorder In these 112, primary care providers recognized: some mental disorder/psychiatric symptoms in 67.7% depression or depressive symptoms in 49.0% bipolar disorder in 0% Das AK et al. JAMA 2005; 293:956-963. Screening for Bipolar Disorder in a Primary Care Practice. Subtypes of Bipolar Disorder Bipolar I: Depression with Classic Mania Bipolar II: Depression with Hypomania Bipolar III: Antidepressant Associated Hypomania -?A less penetrant type of bipolar disorder? -Not in DSM-IV Major Depressive Disorder Dysthymic Disorder Cyclothymic Disorder Bipolar I Disorder Bipolar II Disorder Diagnostic Criteria [Depressive episodes] Hypomanic episodes Manic episodes Mixed episodes Rapid cycling specifier Bipolar Disorder: DIG FAST Mnemonic D – Distractibility I – Insomnia G – Grandiosity (or inflated self esteem) F – Flight of Ideas (or racing/crowded thoughts) A – Activities (increased goal directed activities) S- Speech (pressured) T- Thoughtlessness (impulsivity, ie, increased pleasurable activities with potential for negative consequences: sex, money, traveling, driving) DSM-IV Diagnostic Criteria Hypomanic Episode: A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 4 days. B. During the period of the mood disturbance, three or more of the following symptoms (four if the mood is only irritable): APA Diagnostic and Statistical Manual. 1994 DSM-IV Diagnostic Criteria Hypomanic Episode: 1) inflated self-esteem or grandiosity 2) decreased need for sleep (eg, feels rested after only 3 hours of sleep) 3) more talkative than usual or pressure to keep talking APA Diagnostic and Statistical Manual. 1994 DSM-IV Diagnostic Criteria Hypomanic Episode: (continued) 4) flight of ideas or subjective experience that thoughts are racing 5) distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli) 6) increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation APA Diagnostic and Statistical Manual. 1994 DSM-IV Diagnostic Criteria Hypomanic Episode: (continued) 7) excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) APA Diagnostic and Statistical Manual. 1994 DSM-IV Diagnostic Criteria Hypomanic Episode: (continued) C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. D. The disturbance in mood and the change in functioning are observable by others. APA Diagnostic and Statistical Manual. 1994 DSM-IV Diagnostic Criteria Hypomanic Episode: (continued) E. The episode is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features. F. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism) [video] APA Diagnostic and Statistical Manual. 1994 DSM-IV Diagnostic Criteria Manic Episode: A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. Same as for hypomanic episode DSM-IV Diagnostic Criteria Manic Episode: (continued) C. The symptoms do not meet criteria for a Mixed Episode. D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. DSM-IV Diagnostic Criteria Manic Episode: (continued) E. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism). [video] DSM-IV Diagnostic Criteria Mixed Episode: Rapidly alternating moods (sadness, irritability, euphoria) accompanied by criteria for both a Manic Episode and a Major Depressive Episode. Duration of 1 week. Frequently includes agitation, insomnia, appetite dysregulation, psychotic features, and suicidal thinking. Symptoms are not due to the direct effects of a substance, or a general medical condition. [video] DSM-IV Diagnostic Criteria Rapid Cycling specifier Four or mood episodes per year. Considered more treatment-refractory. Probably not a separate illness but a phase in the evolution of bipolar disorder that may last years. Often associated with clinical or subclinical hypothyroidism (up to 60%). Associated with antidepressant monotherapy. Responds better to valproate or carbamazepine than to lithium. DIAGNOSTIC CONSIDERATIONS Rarely see patients in manic or hypomanic episode. When ill, majority of time is spent depressed (30/1). Patients usually do not view hypomanic episodes as pathologic (nor are they). Patients frequently do not have classic presentations. High levels of psychiatric co-morbidity: anxiety disorders, substance abuse disorders, ADHD, personality disorders. Collateral information from family or friends can be critical. Treatment Implications The course of bipolar disorder may be worsened with antidepressants, especially TCA’s. Patients frequently benefit from treatment with mood stabilizers and/or low-dose atypical neuroleptics. Patients should be educated about common triggers of manic or depressive episodes: sleep deprivation, street drugs (particularly amphetamines, cocaine, hallucinogenics), psychosocial stress. Summary 1) While the STAR*D study demonstrates the efficacy of ssri monotherapy (citalopram), the dosage should be high (40-60mg/d) and of sufficient duration (eight weeks) 2) Switching to Bupropion-SR up to 400mg/d, Or Sertraline up to 200mg/d Or Venlafaxine XR up to 375mg/d Was equally efficacious (remit rate for all: about 25%) Summary (continued) 3) Augmentation with Bupropion up to 400mg/d (39% remission rate) Was slightly better than buspirone up to 60mg/d (33% remission rate) 4) Be alert for further results of the STAR*D study Summary (continued) 5) Bipolar disorder in the primary care population is more common than previously thought. 6) Correct diagnosis requires a high index of suspicion and familiarity with various presentations of hypomanic or manic or mixed episodes. 7) Antidepressant monotherapy can lead to induction of mania or rapid cycling. The End: Questions and Comments