Bipolar Disorder Depression&Presentor – Kapil S. Kulkarni Moderator – Dr. J.P. Rawat
What is Bipolar Disorder?It is a mood disorder characterized by one ormore episodes of mania or hypomaniaoften with a history of one or more major depressive episodes.Mood episodes: Manic, Depressed, or Mixed
Correct diagnosis and treatment are essential as early aspossible in the course of the illness to prevent complications.and maximize response to treatment
Bipolar I disorder is characterized by one or moremanic or mixed mood episodesBipolar II disorder is characterized by one or more major.depressive episodes and at least one hypomanic episodeHypomania is an abnormally and persistently elevated,expansive, or irritable mood, but not of sufficient severity tocause significant impairment in social or occupational function.and does not require hospitalization
The lifetime prevalence of bipolar I disorder is estimated to be between 0.3% and 2.4%. The lifetime prevalence of bipolar II disorder ranges from 0.2% to 5%. Bipolar I disorder affects men and women equally. Bipolar II seems to be more common in women. Rapid cycling and mixed mania occur more often in women.
The mean age of onset of bipolar disorder is 20 yrs. Although onset may occur in early childhood to the mid-40s. If the onset of symptoms occurs after 60 years of age, then its probably secondary to medical causes. The most common comorbid conditions include anxiety, substance abuse, and eating disorder..
The precise etiology of bipolar disorder is unknown. -Genetically based -Environmental factors -Neurotransmitters
Genetic The lifetime risk of bipolar disorder in relatives of a bipolar patient is 40% to 70% for a monozygotic twin and 5% to 10% for another first-degree relative. Dizygotic twins have 20% to 25% chances and children of parent with bipolar disorder have 50% risk.Environmental HPA axis dysfunction due to environmental stress.Neurotransmitters NA, DA, 5HT and Glutamate are implicated.
Neurochemical The pathophysiology of bipolar disorder has been poorly understood. Imbalance of cholinergic and catecholaminergic neuronal activity Bipolar disorder is also related to inositol disterbance.
TheoriesAbnormal “programmed cell death”Studies in animal have shown that antidepressent, lithium and valproate indirectly regulate factors involved in cell survival. (BDNF, Bcl2 etc)“Kindling” Older hypothesis, same as in epilepsy, states that genetically predisposed persons experience minor neurological insult ( Due to excess of glucocorticoids, other acute or chronic stressors, drug abuse)
Theories These eventually result in mania. After first episode, sufficient neuronal damage persists which allow recurrence with or without minor environmental or behavioral stressors.This view also provides explanation to why anticonvulsants are useful in BMD.
Clinical Presentation1. Lack of energy2. Excessive lethargy3. Lack of initiative4. Hopelessness Depression5. Helplessness6. Worthlessness7. Suicidal tendancy
3-Thought ProcessesFlight of ideas (FOI)Easy distractibilityDelusions of grandeosity ManiaIdeas of reference
Clinical Presentation Suicidal ideations Negative thoughts Lack of initiative Depression Ideas of hopelessness Nihilistic delusion
Lab test to rule out other medical disorder. A mood disorder questionnaire. (YMRS, HDRS)
Bipolar I disorder (periods of major depressive, manic, and/or mixed episodes) Bipolar II disorder (periods of major depression and hypomania) Cyclothymic disorder (periods of hypomanic episodes and depressive episodes) Bipolar disorder, NOS
Bipolar I disorder diagnosis require one episode of mania, for at least 1 week or longer with elevated, expansive, or irritable mood , decreased need for sleep, excessive energy. If Bipolar disorder 1 diagnosed as MDD and the patient is treated by antidepressant this can precipitate mania or induce rapid cycling of mania.
The distinguishing feature of bipolar II disorder is depression with past hypomanic episodes.
Cyclothymic disorder is a chronic mood disturbance generally lasting at least 2 year.(1 year in children and adolescents) Characterized by mood swings including periods of hypomania and depressive symptoms. Hypomanic symptoms (grandiosity, decreased need for sleep, pressure of speech, flight of ideas, distractibility)
Patients with bipolar disorder have a high risk of suicide.
>= 2-week period of either depressed mood or loss of interest, associated with at least 5 of the following symptoms:•Depressed/sad mood• Decreased interest and pleasure in normal activities• Decreased appetite, weight loss• Insomnia or hypersomnia• Psychomotor retardation or agitation• Decreased energy or fatigue• Feeling of guilt or worthlessness• Impaired concentration and decision making• Suicidal thoughts or attempts
>= 1-week period of abnormal and persistent elevated mood (expansive or irritable), associated with at least 3 of the following symptoms (four if the mood is only irritable):• Inflated self-esteem (grandiosity)• Decreased need for sleep(insomnia)• Increased talking (pressure of speech)• Racing thoughts (flight of ideas)• Distractible (poor attention)• Increased activity (either socially, at work, or sexually) or increased motor activity or agitation• Excessive involvement in activities that are pleasurable but have a highrisk for serious consequences (buying sprees, sexual indiscretions, poorjudgment in business ventures)
At least 4 days of abnormal and persistent elevated mood (expansive or irritable); associated with at least 3 of the following symptoms (four if the mood is only irritable):• Inflated self-esteem (grandiosity)• Decreased need for sleep• Increased talking (pressure of speech)• Racing thoughts (flight of ideas)• Increased activity (either socially, at work, or sexually) or increased motor activity or agitation.• Excessive involvement in activities that are pleasurable but have a high risk for serious consequences (buying sprees, sexual indiscretions, poor judgment in business ventures)
Criteria for both a major depressive episode and manic episode (except for duration) occur nearly every day for at least a 1-week period.
Greater than 3 major depressive or manic episodes (manic, mixed, or hypomanic) in 12 months.
• Personality disorders• Alcohol and substance abuse or dependence• Anxiety disorders, including panic disorder,• Obsessive compulsive• Eating disordersMedical comorbidities include:• Migraine• Multiple sclerosis• Cushing’s syndrome• Brain tumor• Head trauma
• Reduce the symptoms of mania• Reduce the symptoms of bipolar depression• Prevent the recurrence of a manic or depressive episode• Avoid or minimize adverse treatment effects• Promote treatment adherence• Improve quality of life
Mood stabilizing agents are the cornerstone of treatment. Complete assessment and careful diagnosis to rule out non-psychiatric causes. Treatment is lifelong.
Interpersonal, family and group therapy. Cognitive-behavioral therapy (CBT). Electroconvulsive therapy (ECT). Psychoeducation.
Mood-stabilizing drugs are the usual first-choice treatments and include lithium, divalproate, carbamazepine, and lamotrigine. Atypical antipsychotics other than clozapine are also approved for treatment of acute mania Lithium, lamotrigine, olanzapine, and aripiprazole are approved for maintenance therapy. Benzodiazepines are used adjunctively for mania. Antidepressants may be used for bipolar depression, but usually along with a mood-stabilizing agent to prevent a mood switch to mania Mood-stabilizing drugs are considered the primary pharmacotherapy for relapse prevention.
First, 2 or 3 drug combination Lithium or valproate +benzodiazepine for short term t treatment of agitation or insomnia If psychosis is present consider atypical antipsychotic w with above Alternative, carbamazepine…….no response or tolerate c consider oxcarbazepineSecond if inadequate response ……then use 3 drugs c combination Lithium +Anticonvulsant +Atypical antipsychotic Anticonvulsant +Anticonvulsant +atypical antipsychoticThird if still inadequate response ……ECT
Hypomania First initiate and/or optimize- Mood stabilizing medication (lithium ,DVP, or a carbamazepine) c Consider adding BZD for short term of g g agitation or insomnia . Alternative Carbamazepine……if no response consider a antipsychotic Second if response is inadequate to above medication …. T Then consider2 drug combination Lithium +Anticonvulsant or atypical antipsychotic Anticonvulsant + Anticonvulsant or atypical a n antipsychotic
First - Mood stabilizing medication( lithium or lamotrigine)Alternative - Anticonvulsant (valproate ,carbamazepine or o oxcarbazepine )
First 2 or 3 drug combination - Lithium or Lamotrigine +antidepressant - Lithium + Lamotrigine If psychosis is present …..add on antipsychotic Alternative anticonvulsant : valproate ,Carbamazepine or o oxcarbazepineSecond if inadequate response …consider adding on atypical a antipsychotic (Quetiapine )Third if inadequate response …….3 drug combination Lamotrigine + Anticonvulsant +Antidepressant Llamotrigine + Lithium +AntidepressantForth if response is inadequate …….ECT
A first-line agent (Still Gold standard for BMD despite of side effect profile) Mechanism of action : Not well understood -Altered ion transport (Na, K, Ca, Mg) -Increased brain-derived neurotrophic factor(BDNF), -Inhibition of second messenger systems (adenyl y cyclase, ITP, Protein kinase C, Ca, Protein G)
Dosing and monitoring: 900- 1800 mg /day in acute phases 600- 900 mg /day in maintenance phase Has a narrow therapeutic index , periodic monitoring is recommended. Serum lithium concentration of 0.6 to 1.4 mMol/L.
Pharmacokinetics Half life is 18-24 hrs. Not protein bound. Bioavailability not affected by food. 98% drug is excreted unchanged in urine.
Adverse Effects Common : GIT upset, Tremor, and Polyuria, Polydipsia Nephrogenic : Lithium-induced Diabetes Insipidus (when urine volume exceed 3 L / day) Hypothyroidism Poor concentration, Acneiform rash, Alopecia, Worsening of Psoriasis, Weight gain ,Metallic taste, and Glucose dysfunction. Benign Leukocytosis Acute lithium toxicity …… serum concentration over 2 mEq/L
Acute Lithium Toxicity Early signs- (1.5-2.0 mMol/L)- Tremulousness, anorexia, nausea, vomiting, diarrhea, dehydration Further (>2.0mMol/L)- Neurological menifestations- Restlessness, muscle fasciculation, hypertonia, ataxia, Dysarthria, drowsiness, delirium. Cardiac problems- Hypotension, arrythmias, collapse. If levels too high (>2.5mMol/L)- Coma, seizure or permanent neurological damage
Lithium dosage should be reduced by 33% to 50% when used with thiazide Acute lithium toxicity … -Discontinue lithium -IV fluid to correct electrolyte imbalance -HemodialysisTremor ……………………Beta blockersLithium induced DI …….HCTZ, AmilorideHypothyroidism ………...LevothyroxineGI upset ………………….Take medication in divided doses with food.
Drug InteractionsLithium levels are increased by- ACE inhibitors, NSAIDS, SSRIs, Antiepileptics, Thiazide diuretics, CCB, methyldopa, Tetracyclines.Lithium levels are decreased by- Theophylline, CPZ, Antacids, Bicarbonates.
Mechanism of action : Uncertain - Modulates voltage sensetive Na ion transport - Enhance activity of GABA -Enhance BDNF Dosing and monitoring : 500 – 1000 mg /day The dosage is then titrated according to response, o tolerability, and serum concentration. Valproate is preferred over lithium for mixed I episodes and rapid cycling.
Adverse EffectsLoss of appetite, Nausea, Dyspepsia, Diarrhea, Tremor, andDrowsiness ,Weight gain, Alopecia.Hair loss can be minimized by supplementation with a vitamin containingselenium and zinc.Polycystic ovarian syndromeThrombocytopeniaDrug is usually stopped if the platelet count<100,000/mm3.RareHepatic toxicity and pancreatitis.
Drug interaction : It is a weak inhibitor of some of the drug by metabolizing liver enzymes. The risk of a dangerous rash due to lamotrigine is increased when given concurrently with divalproex. When divalproex is added to lamotrigine, the lamotrigine dosage should be reduced by 50%. Levels of valproate are decreased by- CBZ, Phenytoin, Rifampicin, Topiramate Levels increased by- CPZ, Clarithromycin, TCA and fluoxetine.
Use as mood stabilizing Mechanism of action -Block Na, Ca ion channels -Inhibit repetitive neuronal excitationDosing and monitoring : 400-600 mg /dayAdverse effect :Drowsiness, Dizziness, Ataxia, Lethargy, and Confusion.Aplastic anemiaAgranulocytosis ……rare but life threatening.Hyponatremia, exfoliative dermatitis.
Drug interactions Carbamazepine induces the hepatic metabolism of many drugs (Antiepileptic, antipsychotics, some antidepressants, oral contraceptives,…) ….need dose adjustment Carbamazepine is also an autoinducer. Carbamazepine can be slowed by enzyme-inhibiting drugs (antidepressants,macrolide ,azole antifungal )
Effective for the maintenance treatment of bipolar disorder More effective for depression relapse prevention than for mania relapse. Dosing and Monitoring 25 mg daily for the first 1 to 2 weeks, then titrate according to response upto 200 to 400 mg per day.
Adverse Effects : Maculopapular rash…..10% of patient Some rashes can progress to life-threatening Stevens-Johnson syndrome Dizziness, drowsiness, headache, blurred vision and nausea .Drug Interactions: DVP……..downward adjustment Carbamazepine …..upward adjustment
Used as adjunctive therapy, especially during acute mania episodes, to reduce anxiety and improve sleep.
Atypical antipsychotics act as mood stabilizers.They are used either alone or with combination with mood stabilizers in resistant cases.
Should be combined with a mood-stabilizing drug to reduce the risk of mood switch to hypomania or mania.TCA and SNRI…..switch mood to mania or hypomaniaSSRI are used.Bupropion …..the least one precipitate mania
The key issue is the relative risk of teratogenicity with drug use during pregnancy versus risk of bipolar relapse without treatment with consequent potential harm to both the pregnant patient and the fetus.Judgment depends on -history of the patient -whether the pregnancy is planned or unplanned.Lithium can cause “ floppy baby” syndrome, Ebestein anomaly.During first trimesterVPA and Carbamazepine …..neural tube defect (spinal bifida )Carbamazepine can cause …..fetal vitamin K deficiencyLamotrigine ……… with cleft palate