Bipolar Disorder Lecture Notes PDF

Bipolar Disorder AUSTIN DE LA CRUZ, PHARM.D., BCPP CLINICAL ASSOCIATE PROFESSOR UNIVERSITY OF HOUSTON COLLEGE OF PHARMACY INTEGRATED PSYCHIATRY MODULE- PHAR5368 MARCH 18, 2024 Objectives 1) Distinguish between the most common bipolar disorder subtypes 2) Compare the various antimanic agents and choo...

Bipolar Disorder AUSTIN DE LA CRUZ, PHARM.D., BCPP CLINICAL ASSOCIATE PROFESSOR UNIVERSITY OF HOUSTON COLLEGE OF PHARMACY INTEGRATED PSYCHIATRY MODULE- PHAR5368 MARCH 18, 2024 Objectives 1) Distinguish between the most common bipolar disorder subtypes 2) Compare the various antimanic agents and choose the appropriate pharmacological treatment based on a patient's clinical presentation and comorbidities 3) List appropriate monitoring parameters and be able to compare the most common treatment emergent adverse effects among the different agents Introduction Bipolar disorder is a common, chronic, an often-severe cyclic mood disorder characterized by recurrent fluctuations in mood, energy, and behavior Bipolar disorder differs from recurrent major depressive disorder (AKA unipolar depression) in that manic or hypomanic episodes occur during the course of illness Bipolar disorder is a lifelong illness with a variable course that requires both non-pharmacologic and pharmacologic treatments for mood stabilization Image available at:http://www.health.com/health/gallery/0,,20436786,00.html DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. Epidemiology Overall lifetime prevalence in the U.S. ~2.6% of the population 1% bipolar I 1.1% bipolar II Onset in late adolescent- early adulthood > 2/3 of those affected develop symptoms before 18 y/o Bipolar I= occurs equally in men and women Bipolar II= more common in women Stahl SM, et al. Stahl’s Essential Psychopharmacology. Prescribers Guide. 5th edition. Cambridge 2014. DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 Risk Factors- Mania Medications Medical Conditions Alcohol intoxication CNS Disorders (brain Bright light therapy tumor, strokes, head injury) Deep brain stimulation Infections (sepsis, HIV, Sleep deprivation neurosyphilis, encephalitis) Drug withdrawal Antidepressants DA-augmenting agents Hallucinogens Marijuana intoxication NE augmenting agents Electrolyte or metabolic abnormalities Endocrine or hormonal dysregulation (Addison's, Cushing disease, pregnancy) Steroids Thyroid preparations Xanthines Non-Rx weight loss agents St. Johns Wort DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. Somatic therapies Clinical Presentation 6 Course of Illness Bipolar is frequently not recognized or treated for many years Up to 69% of patients who seek treatment during the 1st year of onset are misdiagnosed Delays range from 8-13 years after onset of symptoms until initiation of appropriate medications risk of poor social functioning, hospitalizations, and greater lifetime suicide attempts Patients spend 1/3 of their life in a depressive state Women are more likely to experience depressive episodes, older age of onset, and better compliance with medications Men are more likely to experience mania and substance abuse Stahl SM, et al. Stahl’s Essential Psychopharmacology. Prescribers Guide. 5th edition. Cambridge 2014. DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 Course of Illness Kindling theory- external environmental stressors activate internal physiologic stress responses triggers 1st episode creates sensitivity to future episodes Acceleration of episode frequency is common with each subsequent episode becoming more difficult to treat More than half (~65%) of bipolar I patients have some degree of functional disability after the onset of their illness Individuals with bipolar disorder have 2.3x higher mortality rate DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. DSM-V Diagnostic Criteria Abnormal mood that is elevated, expansive, or irritable and increase in goal directed activity during a 1-week period (Mania) or 4 consecutive days (Hypomania) 3 criteria { o o o o Inflated self-esteem/grandiosity Decreased need for sleep Increased speech Flight of ideas/racing thoughts o Easily distracted o Increased goal directed activity o Engaging in abnormal/risky activities Mania: The disturbance causes significantly social/occupational function, hospitalization is required, or psychotic features are present (hallucinations/delusions) Hypomania: The disturbance in social/occupational functioning is not severe, hospitalization is not required, and there are no psychotic symptoms present Episode is not the result of a substance or caused by another medical condition DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing Subjective symptoms DIG-FAST Distractibility Indiscretion Grandiosity Flight of ideas Activity increase Sleep deficit Talkativeness Image available at: http://www.cbmcint.com/digging-extraordinary-out-of-the-ordinary/ Bipolar Disorder Subtypes 1. Bipolar I o Manic episode ± major depressive episode or hypomanic episode 2. Bipolar II o Major depressive episode + hypomanic episode 3. Cyclothymic Disorder o Chronic fluctuations between subsyndromal depressive and hypomanic episodes for at least 2 years 4. Unspecified bipolar and related disorder o Mood states do not meet full criteria for any bipolar disorder subtype A major depressive episode associated with bipolar disorder is the same used to diagnose MDD DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. Bipolar I Stahl SM, et al. Stahl’s Essential Psychopharmacology. 4thEdition. Cambridge 2013 Bipolar II Stahl SM, et al. Stahl’s Essential Psychopharmacology. 4thEdition. Cambridge 2013 Cyclothymic Disorder Stahl SM, et al. Stahl’s Essential Psychopharmacology. 4thEdition. Cambridge 2013 Bipolar I vs II Mania Bipolar I Bipolar II Required No Hypomania Required MDD Required Duration Psychosis Hospitalizations Lows: Highs Goldberg, Joseph. Available at: clinicaloptions.com No Bipolar Specifiers Bipolar Disorder.. o o o o o o o o o With anxious distress With mixed features With rapid cycling With melancholic features With atypical features With psychotic features With catatonia With peripartum onset With seasonal pattern Diagnosis should include episode type, severity, psychotic features, and other specifiers Example diagnosis: Bipolar I disorder, current episode depressed, severe, with mixed features American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing Bipolar Disorder 1 & 2 Pharmacological Treatment of Bipolar Disorder Initial Assessment Mental status exam Physical and neurological exam Complete family, social, and medical history 7-fold risk of developing bipolar disorder when a person has a first-degree relative with the illness Vital signs Laboratory evaluation (CBC, CMP, lipids, EKG, thyroid) Urine drug screen Rule out other potential causes Medication Selection Pharmacotherapy is the mainstay of treatment Considerations when choosing an agent: 1. Type of episode (I vs. II) 2. Medication risks vs. benefits o Adverse effects 3. Optimal medication administration 4. Precautions (pregnancy, elderly, etc.) 5. Adherence o Approximately 80% of patients experience >4 episodes in a lifetime 6. Adequate trial at adequate dose 7. Previous or family history of response DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 American Psychiatric Association. Am J Psychiatry 2004; 161:1–56 Mood Stabilizer Mood stabilizers are often used to describe a class of medications used to treat bipolar disorder: 1. Lithium 2. Valproic acid/ Divalproex sodium 3. Lamotrigine 4. Carbamazepine Mood stabilizers are primarily anti-manic agents, but still may treat both mania and depression without inducing either state DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 Image available at: http://www.multibriefs.com/briefs/exclusive/use_of_mood_stabilizers_for_bipolar_disorders.html#.WgxqgGhSyUk Lithium FDA approved for manic episodes & maintenance Evidence of effectiveness: Bipolar depression Unipolar depression (treatment resistant depression) Suicidal behavior Aggressive behavior Pros Cons Effective across multiple indications Poor response in mixed mania & rapid cycling Only mood stabilizer that Variable response >12) Dose range 300-2400 mg/day Image available at: https://www.istockphoto.com DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 -10 days) Lithium Drug Lithium Lithobid) Black Box Warning should be monitored to avoid toxicity Notes o Cognitive effects o Fine hand tremor o Weight gain o Polydipsia/polyuria o Hypothyroidism o Cardiac abnormalities o Acne o Stahl SM, et al. Stahl’s Essential Psychopharmacology. Prescribers Guide. 5th edition. Cambridge 2014. Stahl SM, et al. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4thEdition. Cambridge 2013 - - - Before Starting Lithium Lithium Induced Weight Gain Bowden, C. L., Grunze, H., Mullen, J., et al. (2005). A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. Journal of Clinical Psychiatry, 66(1), 111-121. DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. - Agents Affecting Lithium Levels Lithium Increased Lithium Not Changed Dunner, D.L. (2003). ASCP Model Psychopharmacology Curriculum, volumes 1 and 2. American Journal of Psychiatry. 160 (6), 1199-1200 Lithium Decreased Lithium Interactions Interaction -I, Clinical Concern Comments -60% - - -60% Warnings - effectuated neurotoxicity) Lithium may unmask Brugada syndrome Increased fetal risks- Ebstein’s anomaly DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 Image available at: https://medlineplus.gov/ency/article/007321.htm, http://patients.ambrygen.com/cardiology/about-the-diseases/brugada-syndrome/about Avoid Rapid Discontinuation Destabilization Early relapse Increased suicide risk Counsel patient’s numerous times Early symptom of mania is a change of thinking Goodwin, G. M. (1994). Recurrence of mania after lithium withdrawal: implications for the use of lithium in the treatment of bipolar affective disorder. The British Journal of Psychiatry, 164(2), 149-152. Lithium Toxicity Lithium is an extremely toxic medication if accidentally or intentionally taken in overdose Lithium toxicity occurs with levels >1.5 mEq/L (mmol/L), but elderly patients may experience toxicity at lower levels Severe lithium intoxication occurs >2 mEq/L (mmol/L), and there is a worsening in several key symptoms: GI (eg, vomiting, diarrhea, or incontinence) Coordination (eg, fine to coarse hand tremor, unstable gait, slurred speech, and muscle twitching) Cognition (eg, poor concentration, drowsiness, disorientation, apathy, and coma) DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. Risk Factors for Toxicity Risk factors for lithium toxicity include: Sodium restriction Dehydration Vomiting Diarrhea Age greater than 50 Heart failure Cirrhosis Drug interactions that decrease lithium clearance Heavy exercise, sauna baths, hot weather, and fever can promote sodium loss Patients should be cautioned to maintain adequate sodium and fluid intake (2.5-3 qt per day of fluids) DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. Valproic Acid (VPA) FDA approved for acute mania Also FDA approved for complex partial seizures & migraine prophylaxis Evidence of effectiveness: Bipolar Mixed Impulsivity/agitation/aggression Alcohol dependence Dosage forms: Valproic Acid (Depakene, Stavzor)- capsules, syrup Valproate Na+ (Depacon)- IV, oral solution Divalproex Sodium (Depakote)- enteric coated tablets Onset: as early as 3 days College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 VPA Drug Valproic Acid Black Box Warning Hepatotoxicity Pancreatitis Teratogenicity Notes Enhances GABA channels o o Tremor o Weight gain o Polycystic ovarian syndrome o o Hair loss Monitoring level - Stahl SM, et al. Stahl’s Essential Psychopharmacology. Prescribers Guide. 5th edition. Cambridge 2014. Stahl SM, et al. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4thEdition. Cambridge 2013 -your- - - -you- - -to- 2 P POS A VPA Interactions Interaction Clinical Concern Comments - Teratogenicity First trimester of gestation o Avoid use! “Valproate ate the folate” College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 Image available at: https://en.wikipedia.org/wiki/Spina_bifida Lamotrigine FDA approved for bipolar maintenance Very effective for depression dominant bipolar disorder Dose titration: Without VPA Week 1-2: 25mg Qdaily Week 3-4: 50mg Qdaily Week 5: 100mg Qdaily (200mg max) With VPA Week 1-2: 25mg QOD or 12.5mg Qdaily Week 3-4: 25mg Qdaily Week 5: 50mg Qdaily (100mg max) Onset: delayed (due to slow titration)= ~6 weeks Any break >5 days warrants re-titration College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 Lamotrigine Drug Lamotrigine Lamictal) Black Box Warning Toxic epidermal necrolysis Notes Metabolized primarily through Phase II i.e. glucuronidation) o Benign rash o Agranulocytosis o o Monitoring level Stahl SM, et al. Stahl’s Essential Psychopharmacology. Prescribers Guide. 5th edition. Cambridge 2014. Stahl SM, et al. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4thEdition. Cambridge 2013 - - - Lamotrigine Interactions Interaction Clinical Concern Comments Lamotrigine is primarily metabolized by UGTo College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 Image available at: https://www.ebmconsult.com/articles/valproate-valproic-acid-lamotrigine-interaction-rash 50% Carbamazepine FDA approved for acute mania or mixed episodes Also FDA approved for trigeminal neuralgia and seizures Auto-inducer Generates active metabolites that induces its own metabolism Auto-induction begins after 3-5 days of therapy and is complete in 3-5 weeks after a stable dose is maintained College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 Image available at: http://www.sciencedirect.com/science/article/pii/S1525505004002252 Carbamazepine Drug Carbamazepine Black Box Warning Notes o o Rash o Neurologico Hyponatremia o Fetal carbamazepine syndrome TEN Agranulocytosis } HLA-B1502 Monitoring level - Stahl SM, et al. Stahl’s Essential Psychopharmacology. Prescribers Guide. 5th edition. Cambridge 2014. Stahl SM, et al. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4thEdition. Cambridge 2013 -your- - - -you- - -to- Carbamazepine Interactions Interaction Clinical Concern Comments College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 - Suicidality in Bipolar Disorder Patients have a higher rate of suicide attempts compared with those with other psychiatric diagnoses Patients with bipolar disorder have a 20x higher suicide rate than the general population Up to 50% of patients will attempt suicide 8-20% complete suicide Life expectancy is ~10 years less than the general population Risk factors for increased suicidality: previous psychiatric admission, female sex, bipolar II disorder, heightened energy, comorbid substance use, eating disorder, and comorbid personality disorder College of Psychiatric and Neurologic Pharmacists. Psychiatric Pharmacotherapy Review 2020-2021 Substance Use Disorder Alcohol and substance abuse is common among patients with bipolar disorder (~60.7%) Substance use can have a significant impact on the age of onset, course of the illness, and response to treatment Patients with substance use disorders are more likely to: have an earlier onset of their illness mixed states higher rates of relapse a poorer response to treatment comorbid personality disorders increased suicide risk more psychiatric hospitalizations Bipolar patients often abuse substances such as alcohol, marijuana, or cocaine during episodes, which can result in further impairment DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 11 e. New York, NY: McGraw-Hill; 2020. Standardized Rating Scales There are multiple clinician rated and self-rated scales used to assess mania and depression in the context of bipolar disorder The same scales used for major depressive disorder are used to measure depressive symptoms in bipolar disorder PHQ-9 Montgomery-Asberg Depression Rating Scale Hamilton Depression Rating Scale Bipolar Disorder Mood Disorder Questionnaire Young Mania Rating Scale Image available at: http://adhd-institute.com/assessment-diagnosis/rating-scales/ Young Mania Rating Scale (YMRS) Clinician rated; 15–30-minute scale Uses: widely used in research for screening and assessing symptom severity of mania at baseline and over time The most frequently utilized rating scale to assess manic symptoms. Scale is based on the subjective report of the patient’s clinical condition over the previous 48 hours 11 item scale – (0-4- and 0-8-point scale) Scoring: > 25: severe mania 19-24: moderate mania