University:
West Coast University
Course:
PHAR 835 | IPC Neurology/Psychiatry
Academic year:

2024
Views:

284

Pages:

84
Author:

Asal A.

Pharmacotherapy of Bipolar Disorder Attendance: Parna Haghparast, PharmD, BCPS Assistant Professor West Coast University Some Slides has been adopted from Dr. Pondrom’s lecture • 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 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 Depression Chelsea’s Story (cont.) • • • • • • • fadinggutty so Mona as Fyotenergy talkfast rateofspeakingisfast tactivity insomer What is Chelsea’s diagnosis? • Issuesw Introduction BD to meAdherence Don'twanttoacceptthat theyhave substanceuselHigh suicideBRIM • 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 • Previous name: manic-depressive illness • Approx. 2/3 of patients with BD do not receive appropriate treatment • The symptoms, course, severity, and response to treatment differ among individuals • (Hypo)manic and depression episode occurs during the course of the illness • Is a lifelong illness with no biomarkers to help with diagnosis • Suicide and substance use is high in this population • Lifetime prevalence of bipolar disorder in the US is • Bipolar I disorder = 0.6% • Bipolar II disorder= 0.4% • 1.4% for sub- threshold manifestations of bipolar disorders e.g. cyclothymia and • Subthreshold BP (e.g. cyclothymia—hypomania + mild depression for at least 2 years) is more common than BDI and BDII • Broader bipolar spectrum of bipolar disorders= 2.4% • Similar rates among men and women • Depression and mixed presentation may occur more frequently in females • The incidence of death by suicide among patients with bipolar disorder as high at 20% more than the general public • Higher rate of suicide in BP II than BP I • Non-adherence with pharmacologic treatment and substance use are major factors in relapse and hospitalizations • Medication non-adherence: 20% to 60% of patients • Intolerance of ADR • Failure to recognize the disorder • Reluctance to acknowledge BD Time to Diagnosis • Time between onset of symptoms and correct diagnosis – average 9 years • Time to diagnosis is longer in patients with comorbidities and depressive onset polarity • Onset: late adolescence/early adulthood around the age of 20 (with 1/3 to 2/3 of patients experiencing sx as a child or adolescent) • An earlier age of onset has been associated with greater comorbidity and bipolar I • Onset of illness more commonly begins with depression • Depressive symptoms tend to be longer than (hypo)manic phase • Examples of differential diagnosis for bipolar disorder include • Personality disorder • Major depressive disorder • ADHD • A later-in-life onset of mania might be suggestive of an underlying medical cormorbidiy Secondary Causes of Mania Medical conditions CNS disorders Infections • Brain tumors, strokes, MS, SLE, • Encephalitis, neurosyphillis, sepsis, HIV Endocrine or hormonal dysregulation • Addison’s, Cushing’s, hyper/hypothyroidism Electrolyte or metabolic abnormalities • Ca++/Na+ fluctuations • Hyper- or hypoglycemia Vitamin and nutritional deficiencies Secondary Causes of Mania Medications or drugs that induce mania Alcohol intoxication Drug withdrawal states Antidepressants DA-augmenting agents Hallucinogens Marijuana intoxication – psychosis, paranoia, anxiety, restlessness NE-augmenting agents Steroids Thyroid preparations OTC weight-loss agents and decongestants Herbal product Predominant Polarity Predominant polarity determined by the pole that patient spends at least 2/3 of their episodes in. E.g. Pre-domoniantly depressive means patient spends 2/3 of their episodes in depression Depressive pre-dominant clinically correlates to: • • • • • Greater delayed diagnosis, Depressive index episode, Bipolar disorder type II Higher rates of suicidal acts Shorter duration of euthymia. Predominantly manic is clinically correlated with: • • • • • Earlier illness onset Manic/psychotic index episode, Greater prevalence of comorbid substance abuse, and Longer duration of euthymia Associated with bipolar type I Be cautious in using AD without a mood stabilizer in patients with pre-dominant manic episodes or those with rapid cyclers Iweek Bipolar I: É pof Bipolar II: -At least 1 episode of mania + MDD -Mania lasts at least 7 days -Mania should include elevated energy/increased activity -Mania may include psychosis and/or may require hospitalization -Tends to be predominantly manic senseof Better mayor -At least 1 episode of hypomania + MDD -Hypomania lasts at least 4 days -Tends to be predominantly depression -Tends to occur a little later in age compared to Bipolar I (ex. Mid 20s vs around 18-20) needIepisodofmanatobeBD just Don't needDepression Bipolar Ivs. Bipolar II cyclothymia inthemidd foratleast3 ways No Armada Dos ammonia as go highas BDI Copepression Estimated time spent in each episode Mood 32% 53% Depressed Manic Cycling/Mixed 9% 6% Asymptomatic as you Over 12 year period, n=146 Unipolar Depressio n Bipolar Disorder Bipolar I Manic • • Hypomani a OR Depressio n Bipolar II Hypomani a Major depressive episode Cyclothymi a Chronic fluctuations between subsyndromal depressive and hypomanic episodes (2 yrs for adults) Unspecifie d bipolar MDD Does not meet any criteria 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 5year period. If a manic episode develops, the diagnosis is changed to bipolar I Dysthymia Chronically (at least 2 years) of mild depression mania DSM-5 Diagnosis r highenergy a talktioness 3insoma123hr TakeupwiFanenergy can't sleep setality stopping knowthey Getting high rapidspeech 6 racingthought Flightoifdeas 8 selfthan 7 affordI DSM-5 Bipolar Disorder Specifiers Rapid Cycling Bipolar Disorder Poorer prognosis of BD, more challenging to manage Defined as: • 4 or more episodes/yr (manic, mixed, depression) • Considered a separate episode if there is at least 2 months euthymia between the same pole (e.g. two depressive or two manic phases) Frequent mood shifts: Unlike the typical pattern of bipolar disorder, where episodes may be separated by months or years, rapid cyclers move between mood states much more frequently. More common in women Address risk Factors: • Substance use (discontinue stimulants) • Hypothyroidism (address thyroid issues) • Antidepressant use (try to avoid AD in rapid cyclers) Often may require combination of two drugs • Tend to experience more depressive than manic episodes but AD Monotherapy with one mood stabilizer is without a mood stabilizer can exacerbate the rapid cyclers often ineffective This Photo by Unknown Author is licensed under CC BY-NC Mixed Features Mixed episode is having both poles in the same day or at the same time Mixed Features • • • • • Psychotic features may be present • • Agitation is frequent in patients who have mixed features Mixed features Manic Episode • • Abnormally and persistently Elevated, Expansive, or Irritable mood At least 1 week (or any duration, if hospitalization is necessary) • • • • • Inflated self-esteem / grandiosity Decreased Need for Sleep More talkative / pressured speech Flight of ideas / racing thoughts Distractibility Exclusions • Due to substance or general medical condition Marked impairment • • Occupational functioning Usual social activities/relationships Distinct period of: Plus 3 or more of the following: • • • Increase in goal-directed activity Psychomotor agitation Excessive involvement in pleasurable activities that have high potential for painful consequences Bipolar Mania Etiology • BD runs in families • • • • Etiology • • • • • • Treatment of Bipolar Disorder Treatment Goals • • Alleviate current acute manic, hypomanic or depressive episode • • • • • 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 r Mood stabilizers: The mainstay of bipolar drug therapy • Lithium – the “Gold Standard” • Anticonvulsants – carbamazepine, oxcarbazepine, valproate, lamotrigine • Atypical Antipsychotics z Antidepressants Sedative / hypnotics Acute Mania Lithium Valproic Acid Oxcarbazepine Carbamazepine Antipsychotics totroughlay 0 6 1.2 U F Afterinitiating I ordog 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) the Know Calculation Example: lamotrigine 300 mg Li Carbonate= 8 mEq Li ion 8mEq of Li ion= 5 ml Li Citrate syrup = Étoinducerits metabolize owns Patient is taking Lithium Carbonate 300 mg TID. The doctor is going to switch the patient to Lithium Citrate syrup. How many ml of lithium citrate should the patient take daily? The Lithium will be given in three divided doses. What should each dose be? 1. Lithium carbonate TDD= 900 mg/day 2. 300 mg Li Carbonate= 8mEq 900 mg Lithium Carbonate= x= 24mEq 3. 8mEq=5 ml 24 mEq=X X= 15 ml/day 4. 5 ml TID Side Effects 1. Occurs early in therapy, transient (often dose related) 1. GI side effects 2. CNS side effects 2. Not dose related, occurring w/ long term treatment 3. Associated with toxic levels Cardiovascular: •Can cause benign and reversible cardiac effects. If significant preexisting cardiac disease, consult cardiologist and ECG first •Edema, hypotension, bradycardia, arrythmia Musculoskeletal: GI: •muscle irritability, muscle weakness Diarrhea, nausea, vomiting, xerostomia Neuro: Ophthalmic: Weight gain: •Fine tremor, somnolence, delirium, memory problems •visual field scotoma •Due to fluid retention, consumption of high calorie beverages as a results of polydipsia or decreased metabolic rate due to hypothyroidism Renal Leukocytosis •Polydipsia, polyuria, diabetic insipidus, electrolyte abnormalities •Reversible Hypothyroidism Managing Side Effects • • • XR formulation or change capsule to 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 0.8 to 1.2 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 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 tremor seizurepong confusion gross app Signs of LithiumToxicity Labstocheck Realthyroid 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 Target: Trough Li+ plasma levels 0.8-1.2 mEq/L for acute treatment 0.6-1.0 mEq/L for maintenance EE In renally impaired patients: start at lower dose, titrate to desired level, response 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. Drug Interactions • Use with SSRI can increase risk of: • Dizziness • Confusion • Diarrhea • Agitation • Tremor • Serotonin syndrome • Haloperidol & lithium • Encephalopathic syndrome similar to NMS É RENAL DRUG INTERACTIONS Effect on Lithium Concentrations NSAID’s Increase Li Diuretics (esp thiazides) Increase Li ACEIs prig Metronidazole lipalpchecklevellstatwllow Increase Li Increase Li trenadolttioss EECasinopIGBremIdl example lithium Counselling Points sptraedthydratted ptneedsalIPL.it of hypertention Pain Ambdopite Inol tramadol 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 193 7 main tee matter • 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 CNS • • • • • • Sedation Tremor Dizziness Ataxia Asthenia (weakness) Headache • • • • • • • BBW GI Misc. Life-Threatening Abdominal pain Nausea/ vomiting Diarrhea Reduced appetite Constipation Dyspepsia Weight gain • Alopecia • Polycystic ovaries • Elevated ammonia levels • Hyperandrogenism • Hyperinsulinemia • Rare hepatotoxicity • Rare pancreatitis 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 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 • CYP3A4 inducer and CYP2C19 inhibitor 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 Common • Sedation, dizziness, confusion, unsteadiness, headache • Nausea, vomiting, diarrhea • Blurred vision • Benign leucopenia • Rash Life Threatening or Dangerous Side Effects: • Rare aplastic anemia (bone marrow doesn’t make enough blood cells) agranulocytosis (ANC < 100) • Rare severe dermatologic reactions (Stevens-Johnson syndrome)—greater risk in Asian ancestry (test for HLAB*1502) • Rare cardiac problems Monitoring • Initiation: • CBC, LFT, SCr, TSH • During tx: • CBC every 2-4 weeks x2 months then every 3-6 mos • LFT, SCr, TSH every 612 months 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 nonhormonal contraceptive method or barrier method of contraception during treatment 3. Oral side effects may include nausea, vomiting, constipation, pruritus, dry mouth, asthenia (general feeling of weakness and lack of energy), 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 • Used off-label • Less data supporting its use vs carbamazepine for bipolar d/o • Typically recommended as third line for mania Efficacy • Initial trials suggested oxcarbazepine has mood-stabilizing effects similar to carbamazepine, with the advantages of milder adverse effects, no autoinduction of liver enzymes, and potentially fewer drug interactions Side Effects….similar to carbamazepine • Abdominal pain, nausea and vomiting • Ataxia, dizziness, headache, somnolence, abnormal vision • Hyponatremia (greater incidence than carbamazepine) Interactions: • Oxcarbazepine is CYP 2C19 enzyme inhibitor and a 3A4 enzyme inducer (lower induction compared to CBZ) Administration: IR: With or without food ER: Empty Stomach Oxcarbazepine Drug-Drug Interactions • • • • • • Oral contraceptives Lamotrigine Phenobarbital Valproate Verapamil Fosphenytoin, Phenytoin • Selegiline Usual Dosage Range • 1200 – 2400 mg/day (typically 1/3 higher than carbamazepine for similar results) Monitoring Parameters • Sodium • Liver function tests • CBC Lamotrigine • 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 features • May be combined with lithium or VPA • NOT effective for acute mania • Slow dose titration to reduce risk of SJS/TEN • Has data for rapid cyclers 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 • Valproate • • • • • SE VA Leto venire Allora sedatin Summary of Mood StabilizersCANMAT, 2018 Recommendations • Lithium • Acute bipolar mania • Acute bipolar depression • Maintenance (GOLD STANDARD) • Depakote • Acute bipolar mania • Acute bipolar depression (2nd line) • Maintenance • Lamotrigine • Acute bipolar depression • Maintenance • CBZ • Acute bipolar mania (2nd line) • Maintenance (2nd line) • Oxcarbazepine • Acute Mania (adjunct to DVP/Li)—2nd line • Adjunct oxcarbazepine use as maintenance requires further supporting data clozapine tagging pomania Atypical Antipsychotics Block D2 and 5HT-2A receptors GoDon'tgofor 1stgen Haldoll Antipsychotic Efficacy • • • • • AP are combined with DVP or lithium has greater efficacy than DVP /Li monotherapy SGAs for Mood Disorders Drug Mania Aripiprazole X Asenapine X BPDepression X Brexpiprazole Cariprazine Major Depression (Adjunct) X X X (mono-) X Lumateperone X (mono- or adjunct) Lurasidone X (mono- or adjunct)-off label Off-label Combo-FLX (Symbyax ®) X Combo-FLX –Symbyax ®(treatment resistant) X Olanzapine X Quetiapine X Risperidone X Paliperidone (>6 mg) Ziprasidone Off-label off-label-monoX (mono-) Off-label SGAs for Mood Disorders-Comprehensive list--FYI Drug Mania Mixed Aripiprazole X X Asenapine X BPDepression BP -Maintenance X X X X Lumateperone X (mono-) X X (mono- or adjunct) Lurasidone X (mono- or adjunct)-off label Off-label Off-label X X Quetiapine X X Risperidone X X LAI (Rispedal Consta) off-labelmonoX (mono-) Off-label Off-label X X (adjunct)-mono (offlabel) Ziprasidone Combo-FLX (Symbyax ®) X Off-label (in combination DVP/Li) X Olanzapine Paliperidone (>6 mg) X X Brexpiprazole Cariprazine Major Depression (Adjunct) Combo-FLX –Symbyax ®(treatment resistant) X (in combo DVP/Li) X Off-label Summary-SGA Mania • Olanzapine • Quetiapine • Aripiprazole • Cariprazine • Risperidone • Ziprasidone • Asenapine • Paliperidone (>6 mg) All SGA with the exception of lurasidone, lumateperone and clozapine can be used for mania BP Depression • Olanzapine • Quetiapine • Cariprazine • Lurasidone • Lumateperone Mixed Episodes • Olanzapine • Quetipine • Ziprasidone • Cariprazine • Aripiprazole • Risperidone All Bipolar Drugs: AP + mood stabilizers MDD Bipolar Depression Mania Bipolar depression + Mania Abilify Lurasidone All SGA (except lurasidone, lumateperone and clozapine) Olanzapine Seroquel Lumateperone Haldol Quetiapine Olanzapine/fluoxeti Cariprazine ne (Symbyax) CBZ Lithium Brexpiprazole Oxcarbazepine Divalproex Cariprazine Lamotrigine • Combination therapy • AP + anticonvulsant +/-AD • 2 anticonvulsants • E.g. Li + DVP • Don’t combine CBZ and OXBZ • Dose adjust: 1. DVP + lamotrigine 2. CBZ + lamotrigine • 1 AP + 1 mood stabilizer is preferred over 2 AP or 2 mood stabilizer combinations 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 • 1st line: 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 Approach to Therapy Acute Mania • • • • • • Assess for secondar causes of mania Manic Episode 2-3 Drug Combination • Lithium, Valproate or SGA + antipsychotic for agitation or insomnia • Lorazepam is recommended for catatonia • Do not combine antipsychotics 3-Drug Combination for Inadequate Response • Li + anticonvulsant + antipsychotic • Anticonvulsant + Anticonvulsant + Antipsychotic Treatment-Refractory • Consider ECT for mania with psychosis or catatonia • Consider clozapine Acute depressive episode • • • • • *controversial Mixed features Rapid Cyclers- Treatment approach Treatment • DVP, lamotrigine or CBZ have data (monotherapy or as adjunct to Li) • Combination therapy preferred • Avoid AD monotherapy 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. 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 3. The use of antidepressants in major depressive episode with mixed features may not alleviate depressive symptoms and may pose a potential hazard for exacerbating subthreshold mania symptoms that accompany depression. 1. TCAs and SNRIs may carry the highest risk of causing a treatment-emergent affective switch, while bupropion and some SSRIs may have a lower risk of affective switch Special Populations Pregnancy • High risk of postpartum episodes • Benefit/Risk ratio • Teratogenic medications Children/Adolescents Geriatrics • Few controlled studies • Lithium, VPA, CBZ • Aripiprazole, Risperidone, Quetiapine • Dose adjustments for renal clearance • Dementia patients may be more sensitive to side effects of mood stabilizers and antipsychotics Summary • • • • • BP is a life long 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 combined Collect/Assess • • • • • • • • • • • • • • Plan/Implement • • • • • • • • Follow-Up: Monitor and Evaluate • • • • • • Follow-Up/Monitoring • • •

Pharmacotherapy of Bipolar

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