Bipolar Disorder Information PDF

Pharmacotherapy of Bipolar Disorder Attendance: Parna Haghparast, PharmD, BCPS Assistant Professor West Coast University Some Slides has been adopted from Dr. Pondrom’s lecture  Suggested Readings Book: Hayg...

Pharmacotherapy of Bipolar Disorder Attendance: Parna Haghparast, PharmD, BCPS Assistant Professor West Coast University Some Slides has been adopted from Dr. Pondrom’s lecture  Suggested Readings Book: Haygood J, Drayton SJ. Bipolar Disorder. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023. Accessed August 07, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3097&sectionid=264560892 Guidelines: 1. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. doi:10.1111/bdi.12609 2. Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Acute and long-term treatment of mixed states in bipolar disorder. World J Biol Psychiatry. 2018;19(1):2-58. doi:10.1080/15622975.2017.1384850 Objectives  43-year-old married librarian Long history of depression – feeling depressed for a month since starting a new job Concerned her new boss and colleagues thought her work was poor and slow, and that she was not friendly. No energy or enthusiasm at home Instead of playing with her children or talking to her husband, she watched TV for hours, overate and slept long hours She gained six pounds in just three weeks, which made her feel even worse about herself Cried many times through the week “The depression is back” Thought often of death but has never attempted suicide Chelsea’s Story  Her memory about history of depression is a little fuzzy, Husband provides collateral information: She had first become depressed in her teens and had at least five different periods of depression as an adult Episodes involved depressed mood, lack of energy, deep feelings of guilt, loss of interest in sex and some thoughts that life wasn’t worth living Also sometimes had periods of “too much” energy, irritability and racing thoughts. These episodes of excess energy could last hours, days or a couple of weeks. Chelsea’s Story Chelsea’s Story (cont.) What is Chelsea’s diagnosis?  Introduction Cyclic mood disorder where patients sequentially experience different types of episodes with or without a period of normal mood (euthymia) between episodes Can have mood fluctuations that continue for months, or after one episode, they can sometimes go years without the recurrence of any type of mood episode The symptoms, course, severity, and response to treatment differ among individuals Manic or hypomanic episode occurs during the course of the illness Is a lifelong illness Lifetime prevalence of bipolar disorder in the US is 4.4% Subthreshold BP (e.g. cyclothymia) is more common than BDI and BDII Similar rates among men and women Depression and mixed presentation may occur more frequently in females Onset: late adolescence/early adulthood (with 1/3 to 2/3 of patients experiencing sx as a child or adolescent)  Bipolar Disorder Unspecified Bipolar I Bipolar II Cyclothymia bipolar Hypomania Major Chronic fluctuations Does not Manic OR Hypomania depressive between meet any Depression episode subsyndromal criteria depressive and hypomanic episodes (2 yrs for adults) For bipolar I disorder, 90% of individuals who experience a manic episode later have multiple recurrent MDD, manic, or hypomanic episodes alternating with a normal mood state 5% to 15% of pts with bipolar II disorder will develop a manic episode over a 5-year period. If a manic episode develops, the diagnosis is changed to bipolar I DSM-5 Diagnosis DSM-5 Bipolar Disorder Specifiers  Rapid Cycling Bipolar Disorder Poorer prognosis of BD Address risk Factors: Substance use Hypothyroidism Antidepressant use (try to avoid AD in rapid cyclers) Often may require combination of two drugs This Photo by Unknown Author is licensed under CC BY-NC Mixed Features  Mixed Features Agitation is frequent in patients who have mixed features Mixed features Bipolar I vs. Bipolar II Manic Episode Distinct period of: Abnormally and persistently Elevated, Expansive, or Irritable mood At least 1 week (or any duration, if hospitalization is necessary) Inflated self-esteem / grandiosity Increase in goal-directed activity Decreased Need for Sleep Psychomotor agitation Plus 3 or more of More talkative / pressured speech Excessive involvement in pleasurable the following: Flight of ideas / racing thoughts activities that have high potential for Distractibility painful consequences Due to substance or general medical condition Exclusions Occupational functioning Marked impairment Usual social activities/relationships Course of Illness Frequently not recognized and treated for many years Onset in late adolescence, early adulthood Average age at onset: 21 yrs old Onset of mania after age 60 is rare Rapid cycling: 4 or more mood episodes per year Alcohol & substance abuse / dependence is common among patients with bipolar disorder (as high as 40-45% of patients)  Course of Illness Continued Adherence with medications is best predictor of level of functioning Medication non-adherence: 20% to 60% of patients Intolerance of ADR Failure to recognize the disorder Reluctance to acknowledge BD Approx. 2/3 of patients with BD do not receive appropriate treatment Non-adherence with pharmacologic treatment and substance use are major factors in relapse and hospitalizations Effective maintenance treatment, early in the course of illness, has been shown to reverse cognitive impairment and preserve brain plasticity, particularly in those who remain episode free improved prognosis and minimization of illness progression Generally, those with rapid cycling have poorer prognosis. Factors associated w/ rapid cycling must be addressed (stimulant and antidepressant discontinuation and treating hypothyroidism Monotherapy with one mood stabilizer is often ineffective Estimated time per episode Mood Depressed 32% Manic 53% Cycling/Mixed 9% Asymptomatic 6% Over 12 year period, n=146 Etiology BD runs in families Etiology  Difficulty in Diagnosing Episodes of mania or depression may be induced or caused by medical illness, medications, or substance intoxication or withdrawal The timely diagnosis and treatment of bipolar disorder may be difficult due to Frequent episodes of depression, Comorbid conditions A complete medical, psychiatric, and medication history; physical examination; and laboratory testing are important tools to rule out any organic causes of mania or depression Secondary Causes of Mania Medical conditions CNS disorders Infections Electrolyte or metabolic Brain tumors, strokes, MS, Encephalitis, neurosyphillis, abnormalities SLE, sepsis, HIV Ca++/Na+ fluctuations Hyper- or hypoglycemia Endocrine or hormonal dysregulation Vitamin and nutritional Addison’s, Cushing’s, hyper/hypothyroidism deficiencies Secondary Causes of Mania Medications or drugs that induce mania Drug withdrawal DA-augmenting Alcohol intoxication Antidepressants states agents Marijuana intoxication – NE-augmenting Hallucinogens Steroids psychosis, paranoia, agents anxiety, restlessness OTC weight-loss Thyroid agents and Herbal product preparations decongestants  Treatment of Bipolar Disorder Treatment Goals Alleviate current acute manic, hypomanic or depressive episode  Approach to treatment Individualize treatment plan Clinical presentation, frequency of episodes and severity varies among pts Non-Pharmacological + pharmacological Adherence to treatment is VERY IMPORTANT for stabilization Patients and family members should be educated about the disease state Patients should be on maintenance therapy (mood stabilizer) for life Acute pharmacological treatment varies depending on type of episode pt is experiencing e.g. (hypo)mania vs depression Maintenance medication dose can be either titrated or switched to another medication w/ efficacy in that polarity during an acute episode or another medication added to maintenance therapy Once pt stabilizes, the added medication can be tapered off. Nonpharmacologic Therapy Ensure good nutrition, exercise, adequate sleep, stress reduction, and psychosocial therapy (e.g. CBT)  ECT for non-responders with: severe mania depression, psychotic features, mixed episodes or rapid cycling  Pharmacologic Therapy Drug choice is dependent on presenting episode Mood stabilizers: The mainstay of bipolar drug therapy Lithium – the “Gold Standard” Anticonvulsants – carbamazepine, Antidepressants Sedative / hypnotics oxcarbazepine, valproate, lamotrigine Atypical Antipsychotics General Approach to Treatment Acute Mania Assess for secondar causes of mania Acute Mania Lithium Valproic Acid Carbamazepine Oxcarbazepine Antipsychotics Manic Episode Lithium, Valproate or SGA + antipsychotic 2-3 Drug for agitation or insomnia Combination Lorazepam is recommended for catatonia Do not combine antipsychotics 3-Drug Combination Li + anticonvulsant + antipsychotic for Inadequate Anticonvulsant + Anticonvulsant + Antipsychotic Response Consider ECT for mania with psychosis or catatonia Treatment-Refractory Consider clozapine Acute depressive episode *controversial LITHIUM  FDA approved for mania and maintenance therapy for BDI and BDII May be used for prevention of bipolar depression as well (6-8 week delay in antidepressant effect) Key Lithium Info Onset of action: 5 to 10 days Effective in preventing both manic and depressive episodes (magnitude of prophylactic efficacy greater against mania vs depression)  Side Effects Cardiovascular: Musculoskeletal: Can cause benign and reversible GI: muscle irritability, muscle weakness cardiac effects. If significant pre- existing cardiac disease, consult Diarrhea, nausea, vomiting, cardiologist and ECG first xerostomia 1. Occurs early in therapy, transient (often Edema, hypotension, bradycardia, arrythmia dose related) 1. GI side effects Neuro: Ophthalmic: Weight gain: 2. CNS side effects Fine tremor, somnolence, delirium, visual field scotoma Due to fluid retention, consumption 2. Not dose related, occurring w/ long memory problems of high calorie beverages as a results term treatment of polydipsia or decreased metabolic rate due to hypothyroidism 3. Associated with toxic levels Renal Leukocytosis Polydipsia, polyuria, diabetic Reversible insipidus, electrolyte abnormalities Hypothyroidism Managing Side Effects XR formulation or change to capsule/liquid (if diarrhea) For fine tremors  switch to XR, lower dose or add beta blocker e.g. propranolol Dosing Bipolar disorder, manic episode extended-release tablets: 1800 mg/day ORALLY in 2 to 3 divided doses desired serum lithium level 1 to 1.5 mEq/L immediate-release tablet and capsule formulations: 600 mg ORALLY 3 times daily desired serum lithium level 1 to 1.5 mEq/L Bipolar disorder, maintenance therapy extended-release tablets: 900 to 1200 mg/day ORALLY in 2 to 3 divided doses desired serum lithium level 0.6 to 1.2 mEq/L immediate-release tablet and capsule formulations 300 mg ORALLY 3 to 4 times daily desired serum lithium level 0.6 to 1.2 mEq/L Rapid discontinuation increases the risk of relapse and possibly suicide; may need to be tapered slowly over 3 months after long-term maintenance Signs of Lithium Toxicity Lithium Level (mmol/L) Side Effects 1.0 – 1.5 Fine tremor, nausea 1.5 – 2.0 Cogwheeling tremor, N/V, somnolence 2.0 – 2.5 Ataxia, confusion 2.5 – 3.0 Slurred speech (dysarthria), gross tremor > 3.0 Delirium, seizures, coma, death In renally impaired patients: start at lower dose, Target: Trough Li+ plasma levels titrate to desired level, response 1.0-1.5 mEq/L for acute treatment 0.6-1.2 mEq/L for maintenance  NARROW THERAPEUTICS INDEX Monitoring Parameters 30 min prior to next dose (8-12 after last dose) Check levels 4-7 days after initiation or dose change BBW: Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic levels. Facilities for prompt and accurate serum lithium determinations should be available before initiating therapy.  Effect on RENAL DRUG Drug Interactions Lithium INTERACTIONS Concentrations NSAID’s Increase Li Use with SSRI can increase risk of: Dizziness Confusion Diuretics (esp Increase Li Diarrhea thiazides) Agitation Tremor ACEIs Increase Li Serotonin syndrome Haloperidol & lithium Metronidazole Increase Li Encephalopathic syndrome similar to NMS  Counselling Points 1. It is used to treat bipolar disorder 2. Activities requiring mental alertness or coordination until drug effects are realized, as drug may cause dizziness, somnolence, and vision changes 3. Side effects may include diarrhea, nausea, ataxia, hand tremor, muscle irritability or weakness, frequent urination, or low urine output, dehydration, or low blood pressure 4. Maintain adequate fluid intake, salt intake, and a normal diet, especially during stabilization period 5. Toxicity include: course tremor, confusion, seizures, delirium 6. If changes made to any of your medications, ask your doctor about drug-drug interactions 7. If you need medications for pain, it is preferred to use acetaminophen over Advil, Aleve, ASA, Naproxen Low plasma sodium levels are associated with lithium retention; high levels with lithium elimination. Anticonvulsants -Divalproex sodium (also known as sodium valproate) -Carbamazepine -Oxcarbazepine -Lamotrigine  Valproate (Depakote ®) Valproate has antimigraine, mood-stabilizing, and anti aggressive effects Comparable in efficacy to lithium and olanzapine for mania FDA approved: BDI manic episode Can be used for acute bipolar depression (CANMAT, 2018) off label As adjunct (in combination w/ lurasidone)—as one of the 1st line options Monotherapy (2nd line) Can be used as maintenance therapy (CANMAT, 2018)- off label Potentially more effective than lithium in certain sub-types Multiple prior episode Mixed features (more effective than Li) Co-morbid substance use BBW: Hepatotoxicity Pancreatitis Teratogenic effect (Peg Cat D) Combinations When combined with lithium, CBZ, antipsychotics or BZDs, it can augment its antimanic effect Depakote + lithium Synergistic effect for those that are tx resistant, rapid cyclers, mixed features Depakote + antipsychotics Effective for breakthrough mania if there is incomplete or partial response to monotherapy OR quicker time to tx response Depakote + CBZ Synergistic effect but drug interact together (reduces CBZ level) makes monitoring levels essential for both agents Dosing Delayed Release: Initial 500 mg BID (titrate based on level)---at Charter XR: Initial, 25 mg/kg/day orally once (titrate to effect) Trough Level 50-125 mcg/ml (may require up to 150 mcg/ml) Draw 30 min before morning dose (after 3-5 days of initiation or dose change) Adverse Effects BBW CNS GI Misc. Life-Threatening Sedation Abdominal pain Alopecia Rare hepatotoxicity Tremor Nausea/ vomiting Polycystic ovaries Rare pancreatitis Dizziness Diarrhea Elevated ammonia Ataxia Reduced appetite levels Asthenia (weakness) Constipation Hyperandrogenism Headache Dyspepsia Hyperinsulinemia Weight gain Valproate Monitoring parameters Platelets, liver function tests Plasma levels to assist monitoring of efficacy, side effects, and compliance Drug Interactions Lamotrigine: increased half-life of LTG ↓VPA levels: CBZ, Phenytoin, ethosuximide, phenobarbital, rifaminpin ↑VPA levels: Felbamate, chlorpromazine, fluoxetine, fluvoxamine, topiramate, cimetidine, erythromycin, ibuprofen Pregnancy Category D Neural tube defects BBW: do not use Depakote in those in child bearing age unless have failed other therapies  Counselling Points 1. For female patients: Avoid pregnancy during therapy and use effective contraception 2. Avoid activities requiring mental alertness or coordination until drug effects are realized, as drug may cause drowsiness 3. take with food to minimize gastric irritation 4. Side effects include: headache, weight gain, hair loss, sedation, headache Carbamazepine (Tegretol ®, Equetro ®) FDA approved for manic or mixed episodes in BDI In clinical practice also used for maintenance (data for routine maintenance is not strong) Data supporting its use for acute bipolar depression is lacking NOT first line (reserved for after tx failure w/ divalproex and lithium) Due to interactions and safety May be combined with lithium, valproate, or antipsychotics for treatment-resistant patients experiencing a manic episode May also be used for mixed features or rapid cyclers Carbamazepine PK Is a strong inducer of CYP3A4. Can increase the metabolism of certain oral contraceptives (through CYP3A4 induction), leading to significantly lower concentrations Many interactions due to Inducing CYP1A2, 2B6, 2C9/19 Dosing 200 mg BID – increase in 200 mg/day increments 600 – 1600 mg/day Rapid cyclers may need 1000 – 2000 mg/day Target Concentration Serum level: 4-12 mcg/mL Adverse Effects/Monitoring Life Threatening or Common Monitoring Dangerous Side Effects: Sedation, dizziness, Rare aplastic Initiation: confusion, unsteadiness, anemia, CBC, LFT, SCr, TSH headache agranulocytosis During tx: Nausea, vomiting, (ANC < 100) CBC every 2-4 weeks diarrhea Rare severe x2 months then every Blurred vision dermatologic reactions 3-6 mos Benign leucopenia (Stevens-Johnson LFT, SCr, TSH every 6- syndrome)—greater Rash 12 months risk in Asian ancestry (test for HLA- B*1502) Rare cardiac problems  Counselling Points 1. Avoid activities requiring mental alertness or coordination until drug effects are realized, as drug may cause dizziness and drowsiness 2. Instruct female patient of reproductive potential using hormonal contraceptives to use an alternative non- hormonal contraceptive method or barrier method of contraception during treatment 3. Oral side effects may include nausea, vomiting, constipation, pruritus, dry mouth, asthenia, ataxia (lack of coordination), blurred vision, low blood pressure, or confusion 4. IR (tablets): Take with food; ER (capsules): with or without food 5. Avoid alcohol, grapefruit juice, or grapefruit  Oxcarbazepine (Trileptal ®) Introduction Side Effects….similar to carbamazepine Used off-label Abdominal pain, nausea and vomiting Ataxia, dizziness, headache, somnolence, abnormal vision Less data supporting its use vs carbamazepine for bipolar d/o Hyponatremia (greater incidence than carbamazepine) Typically recommended as third line for mania Efficacy Interactions: Initial trials suggested oxcarbazepine has mood-stabilizing effects Oxcarbazepine is CYP 2C19 enzyme inhibitor and a similar to carbamazepine, with the advantages of milder adverse 3A4/5 enzyme inducer effects, no autoinduction of liver enzymes, and potentially fewer drug Administration: interactions IR: With or without food ER: Empty Stomach Oxcarbazepine Drug-Drug Monitoring Usual Dosage Range Interactions Parameters Oral contraceptives 1200 – 2400 mg/day Sodium Lamotrigine (typically 1/3 higher Liver function tests Phenobarbital than carbamazepine CBC for similar results) Valproate Verapamil Fosphenytoin, Phenytoin Selegiline  FDA approved for BDI maintenance Clinically also used for BDII Often used in clinical practice for acute and prevention of bipolar depression (off-label) Has long dose titration Beneficial in rapid cycling and mixed Lamotrigine features?? May be combined with lithium or VPA NOT effective for acute mania Slow dose titration to reduce risk of SJS/TEN  Dosing for Maintenance (Patients not taking enzyme-inducing drugs or valproic acid): 25 mg/day orally for 2 weeks, then 50 mg/day for 2 weeks, then 100 mg/day for 1 week, then maintain at 200 mg/day; (Added to valproic acid regimen) 25 mg/day orally every other day for 2 weeks, then 25 mg/day for 2 weeks, then 50 mg/day for 1 week, then maintain at 100 mg/day (Added to enzyme-inducing antiepileptic drug regimen without valproic acid) 50 mg/day orally for 2 weeks, then 100 mg/day for 2 weeks in divided doses, then 200 mg/day for 1 week in divided doses, then 300 mg/day for 1 week in divided doses, then may increase up to the usual maintenance dose of 400 mg/day in divided doses Adverse Effects Self-limiting rash Higher than recommended initial dose Drug-Drug Interactions  Summary of Mood Stabilizers- CANMAT, 2018 Recommendations Lithium Lamotrigine Acute bipolar mania Acute bipolar depression Acute bipolar depression Maintenance Maintenance (GOLD STANDARD) CBZ Depakote Acute bipolar mania (2nd line) Acute bipolar mania Maintenance (2nd line) Acute bipolar depression (2nd line) Oxcarbazepine Maintenance Acute Mania (adjunct to DVP/Li)—2nd line Lamotrigine Adjunct oxcarbazepine use as maintenance requires CBZ further supporting data Oxcarbazepine BD I and II Lithium Lamotrigine (clinically nut not FDA approved for BPII) Mixed features/rapid cyclers Lamotrigine CBZ Depakote +/- lithium (synergistic effect) Atypical Antipsychotics Block D2 and 5HT-2A receptors Antipsychotic Efficacy AP are combined with DVP or lithium has greater efficacy than DVP /Li monotherapy  SGAs for Mood Disorders Drug Mania Mixed BP- BP -Maintenance Major Depression Depression (Adjunct) Aripiprazole X X X X Asenapine X X Brexpiprazole X Cariprazine X X X (mono-) X Lumateperone X (mono- or adjunct) Lurasidone X (mono- or Off-label Off-label adjunct) (in combination DVP/Li) Olanzapine X X Combo-FLX X Combo-FLX –Symbyax (Symbyax ®) ®(treatment resistant) Quetiapine X X X X X Risperidone X X LAI (Rispedal Consta) Off-label Paliperidone (>6 mg) off-label- Off-label Off-label mono- Ziprasidone X (mono-) X X (adjunct)-mono (off- Off-label label) Summary-SGA Mania BP Depression Mixed Episodes Olanzapine Olanzapine Olanzapine Quetiapine Quetiapine Quetipine Aripiprazole Cariprazine Risperidone Cariprazine Lurasidone Ziprasidone Risperidone Lumateperone Cariprazine Ziprasidone Aripiprazole Asenapine Paliperidone (>6 mg) All SGA with the exception of lurasidone, lumateperone and clozapine can be used for mania CANMAT, 2018 Recommendations List of drugs recommended are in order of recommendation unless patient has had previous non-response/tolerability issues  Acute Mania 1. Choose first line monotherapy OR first line combination switch among first line agents multiple times before moving to 2nd line tx 2. Common combinations AP + Li/DVP 2nd line: Li + DVP +/- AP Typically not recommended but common in clinical practice: 2 AP +/- mood stabilizer Acute Bipolar Depression Quetiapine (level 1), followed by lithium, lamotrigine, lurasidone (level 2) The drugs that start with an “ L”---for low mood Adj Antidepressants (NOT MONOTHERAPY) are 2 line Risk of switch to manic episode, rapid cycling and weak efficacy Avoid antidepressants or use cautiously in pt w/: History of antidepressant-induced mania/ hypomania, Current or predominant mixed features, Recent rapid cycling  Maintenance Generally, medications that have been found to be effective in the acute phase should be continued during the maintenance phase.: Exception: long term AD use generally not recommended If continuing the drug used during acute phase for maintenance, a dose reduction may be needed Many AP have strong data for prevention of mania (rather than depressive episode) Risk of recurrence is reduced when an AP is combined with lithium/divalproex.  Maintenance 1st line Lithium Quetiapine +/- DVP/Li Depakote Lamotrigine Aripiprazole +/- DVP/Li 2nd line (Monotherapy) Olanzapine Risperidone LAI CBZ Paliperidone Mixed features  Approach to Pharmacological Therapy 1. If therapy with one or a combination of the first-line agents (lithium, divalproex and/or an atypical antipsychotic) at optimal doses is inadequate or not tolerated, the next step is to switch to or add on an alternate first-line agent 2. Because there are multiple first-line agents with substantial efficacy data and relative safety and tolerability, the use of second- and third-line agents is only recommended after unsuccessful trials of multiple first-line strategies Special Populations Pregnancy Children Elderly  Summary BP is a life loneg psychiatric disorder that requires life long term treatment Poor adherence to medications is a risk factor for relapse BP I vs BP II Psychotherapy + pharmacological therapy Pharmacological therapy Mood stabilizers Lithium DVP Lamotrigine CBZ Oxcarbazepine SGA Medications used depend on current mood episode (depression vs mania) Medications can be used monotherapy or compbined Collect/Assess Plan/Implement Follow-Up: Monitor and Evaluate Follow-Up/Monitoring QUESTIONS??