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Evidence based medicine approach to the diagnosis and treatment of Bipolar Depression

Evidence based medicine approach to the diagnosis and treatment of Bipolar Depression. Nadia Robertson August 23, 2007. Clinical Scenario. 22 YO WF with no past psychiatric history who presents with worsening depressive symptoms over past six weeks. Presenting Symptoms:

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Evidence based medicine approach to the diagnosis and treatment of Bipolar Depression

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  1. Evidence based medicine approach to the diagnosis and treatment of Bipolar Depression Nadia Robertson August 23, 2007

  2. Clinical Scenario • 22 YO WF with no past psychiatric history who presents with worsening depressive symptoms over past six weeks. • Presenting Symptoms: • Depressed mood, impaired motivation and focus, increased irritability, hypersomnia and weight loss. • Pertinent Negatives: • Denied manic symptoms including periods of elevated mood, decreased need for sleep, increased productivity. • Family History: • Two first degree relatives (mother/sister) with Bipolar I disorder.

  3. Clinical Question • What is the evidence to support various symptoms as predictors of a bipolar diathesis when patient’s present with first depressive episode?

  4. Searching the Literature • Searched Pubmed, Cochrane Database, Ovid EBM reviews • Keyword searching: • Depression and predicting bipolarity. • Bipolar Depression

  5. Why is this important? • Sharma V, Khan M, Smith A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005 Feb;84(2-3):251-7. • Study looked at 61 patients diagnosed with treatment resistant unipolar depression • Following diagnostic re-evaluation with Structured Clinical Interview for DSM-IV (SCID): *80% were found to show evidence of bipolarity. *Prompted a frequent change in medication to mood stabilizers. *“Soft Bipolar Spectrum” may underlie some treatment resistance.

  6. Perlis RH, Brown E, Baker RW, Nierenberg AA. Clinical features of bipolar depression versus major depressive disorder in large multicenter trials. Am J Psychiatry. 2006 Feb;163(2):225-31. • Pooled together 477 patients with Bipolar I and 367 patients with MDD from two previous double blind, randomized trials that were separately studying patients with these two disorders. • Bipolar I patients had to meet DSM-IV criteria for bipolar I disorder and depression according to structured clinical interview for DSM-IV, baseline Montgomery Asberg Depression Rating Scale (MADRS) total score >20 • Demographic and illness characteristics compared between patients in the studies. • Forward stepwise logistic regression performed to determine best predictors of MDD vs bipolar depression.

  7. Bipolar Depression 8 years earlier onset Increased FH Bipolar Increase # of depressive episodes Increase score for fear and tension/edginess MDD Increased somatic sx: GI, GU, PULM, MSK Increased insomnia Cognitive symptoms more prevalent Results

  8. Predicting diagnosis…. • Clinical features/rating scale items then placed back into a stepwise logistic regression with diagnosis as the outcome. • Model correctly classified 86.9% of the total patients. -69% probability of predicting bipolar disorder when it was bipolar disorder. -94.9% probability of predicting MDD when actual dx was MDD.

  9. Bipolar Spectrum • Goal of researchers is to identify a validated bipolar spectrum concept and reduce underrecognition of bipolarity. • Unipolar-----“Bipolar Spectrum”----Bipolar • Depressive mixed state has been proposed as a condition that should be covered within the bipolar spectrum.

  10. Depressive mixed state • Depressive mixed state (DMX): major depressive episode plus 3 or more intra-MDE hypomanic symptoms. -irritability -psychomotor agitation -talkativeness -racing thoughts -distractibility Depressive mixed state has been shown to be a strong predictor of BP-II disorder.

  11. Benazzi F, Akiskal H. Psychometric delineation of the most discrimant symptoms of depressive mixed states. Psychiatry Research. 2006; 141: 81-88 • Goal: Find the most discriminant clinical symptoms suggestive of DMX. • 602 MDE outpatients were given following: • Structured Clinical Interview for DSM-IV • Global Assessment of Functioning scale • Family History Screen • Hypomania Interview Guide • Sensitivity, specificity, positive predictive value, negative predictive value were used to assess the predicting power for DMX of the individual symptoms.

  12. Refresher on terminology… • Sensitivity: refers to the proportion of people with disease who have a positive test result. • Specificity: refers to the proportion of people without disease who have a negative test result. • Positive predictive value (PPV): probability that a person who is identified as ill by a test actually has an illness. • Negative predictive value (NPV): probability that a person who is identified as not ill by a test actually is not ill. • NPV/PPV are affected by prevalence of a disorder.

  13. Sensitivity, specificity, positive predictive value, and negative predictive value of intra-MDE hypomanic symptoms (present in more than 15% of individuals) for depressive mixed state (DMX3), in the entire bipolar-II and major depressive disorder sample (n = 602) Table 2: Intra-MDE hypomanic symptoms rate SE% SP% PPV% NPV% Irritable mood, 50.3% 76.1 75.6 75.9 75.9 Distractibility, 73.2% 90.7 44.3 62.1 82.6 Racing thoughts, 66.7% 88.0 54.6 66.1 82.0 Psychomotor agitation27.7% 51.3 96.0 92.8 66.2 Talkativeness, 18.6% 33.4 96.3 90.1 58.9 (SE=sensitivity, SP=specificity, PPV=positive predictive value, NPV=negative predictive value, MDE=major depressive episode).

  14. Discussion • Based on results, irritability represents an initial, quick screen that can be used to assess for diagnosis of DMX. • Symptoms of irritability and psychomotor agitation are more likely present in bipolar spectrum disorders (BP II and DMX) than in other mood disorders.

  15. Benazzi F, Akiskal H. Irritable-hostile depression: further validation as a bipolar depressive mixed state. J Affect Disord. 2005 Feb;84(2-3):197-207. Study Design: -348 bipolar II and 254 unipolar MDD outpatients were interviewed with SCID, Hypomania Interview Guide, and the Family History Screen. -Irritability defined with DSM criteria with various features of hostility and anger. -Hypothesis: Irritable-hostile depression would be linked to a bipolar depressive mixed state. -Exclusion criteria: substance abuse and borderline personality

  16. Results • MDE with irritability was present in 59.7% of BP-II and 37.4% of MDD. • Sensitivity (80.2%), specificity (64.2%) for irritability predicting depressive mixed state in BP-II. • Sensitivity (66.3%), specificity (86.1%) for irritability predicting depressive mixed state in MDD. • In BP-II sample: irritability was associated with more depressive mixed states, more psychomotor agitation, more weight gain, increased eating, more leaden paralysis. • In MDD sample: irritability was associated with more atypical depressions, more bipolar family history, more hypersomnia.

  17. Discussion • Strong associations linking irritable-hostile depressions to multiple parameters of bipolarity. • Irritability is likely to be associated with clustering of hypomanic symptoms (depressive mixed state) and external bipolar validators. • Limitations: -Did not use validated instrument to measure irritable affect. -Unintended bias from one interviewer.

  18. Treatment Implications • Given strong association between irritability and many intradepressive hypomanic symptoms (depressive mixed state) and external bipolar validators, suggest treatment may require an initial or concurrent mood stabilizing agent.

  19. Back to the patient… • Based on clinical features of irritability, talkativeness, hypersomnia and significant family history, patient is initiated on a mood stabilizer. • Does addition of an antidepressant confer added benefit to mood stabilizer?

  20. Sachs, GS, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression.N Engl J Med. 2007 Apr 26;356(17):1711-22. Epub 2007 Mar 28. • Study is part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). • Study was necessary because: -Limited data available to support use of antidepressants in bipolar depression. -Belief that antidepressants can induce mania has not been shown in placebo controlled studies.

  21. Methods • Subjects with bipolar I or II disorder were treated for up to 26 weeks with adjunctive use of standard antidepressants to treatment with mood stabilizers. • Had to meet criteria for major depressive episode associated with bipolar disorder.

  22. Methods • Randomization: -Mood stabilizer + adjunctive antidepressant -Mood stabilizer + placebo • Monitored with Clinical Monitoring Form: includes Structured Clinical Interview for DSM-IV and symptoms subscales for depression and mood elevation. • Primary Outcome: Euthymia for 8 consecutive weeks. • Treatment effectiveness response rate: 50% improvement from baseline scores.

  23. Study limitations • Possible that other antidepressant would have different outcome. • Primary outcome reflects 8 week time period. • Study subjects were allowed to receive psychosocial intervention – which may confound effectiveness of antidepressant. • Unlikely to include patients who had recent manic episode as clinicians may not have wanted to enroll in study.

  24. Patient update • Consistent with STEP-BD results, patient was initiated on mood stabilizer alone without antidepressant augmentation. • At follow-up, patient is tolerating lithium well with goal level 0.5-0.7. Her hypersomnia, irritability, and depressed mood have shown improvement since initiation of treatment.

  25. References Angst J. The bipolar spectrum. The British Journal of Psychiatry (2007) 190: 189-191. Angst J, Gamma A. A new bipolar spectrum concept: a brief review. Bipolar Disord 2002: 4 (Suppl 1): 11-14. Benazzi F, Akiskal H. Irritable-hostile depression: further validation as a bipolar depressive mixed state. J Affect Disord. 2005 Feb;84(2-3):197-207. Benazzi F, Akiskal H. Psychometric delineation of the most discrimant symptoms of depressive mixed states. Psychiatry Research. 2006; 141: 81-88. Benazzi F. Symptoms of depression as possible markers of bipolar II disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006 May;30(3):471-7. Epub 2006 Jan 19. Perlis RH, Brown E, Baker RW, Nierenberg AA. Clinical features of bipolar depression versus major depressive disorder in large multicenter trials. Am J Psychiatry. 2006 Feb;163(2):225-31. Sachs, GS, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression.N Engl J Med. 2007 Apr 26;356(17):1711-22. Epub 2007 Mar 28. Sharma V, Khan M, Smith A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005 Feb;84(2-3):251-7. Thase ME. Bipolar depression: diagnostic and treatment considerations.Dev Psychopathol. 2006 Fall;18(4):1213-30. Review.

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