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Bipolar Disorder
BCPP Recertification
| Term | Definition |
|---|---|
| Manic Episode | At least 1 week (or any time if hospitalization is required) 3 of - these Grandiosity, Decreased sleep, flight of ideas, easily distracted, pressured speech, psychomotor agitation, risky activities. Significant social and occupational functioning. |
| Hypomanic Episode | Elevated, expansive irritable mood increased activity for at least 4 consecutive days. 3 of: Grandiosity, Decreased sleep, flight of ideas, easily distracted, pressured speech, psychomotor agitation, risky activities. No psychotic sx. Change in fx. |
| Bipolar I Disorder | Dx after one manic episode. Hypomanic or depressive episode may occur before or after the manic episode |
| Bipolar II Disorder | Occurrence of one hypomanic episode and at least one depressive episode. No history of mania. Depressive sx, or frequent alteration between depression and hypomania. |
| Cyclothymic Disorder | At least 2 years (1 year children/adolescents) periods of hypomanic and depressive symptoms that meet criteria for manic, hypomanic, depressive. Distress or impaired fx. 50% hypomania or depression. no periods greater than 2 months. |
| Bipolar and Related Disorders | Substance induced. Due to another medical condition. Short duration. Hypomania with insuff sx for depression. Hypomania without previous depression. Less than 2 years cyclothymia. |
| Bipolar Disorder with Anxiety | At least 2 anxious sx. Severity specified on # of sx. |
| Bipolar Disorder with mixed features | Manic or Hypomanic with mixed fx. full criteria for manic or hypomanic with at least 3 sx of depression. or visa versa. Criteria for full manic and depressive episodes, dx manic with mixed fx. |
| Rapid Cycling | 4 separate mood episodes in 12 months. Separated by full or partial remission or switch to opposite polarity. |
| Melancholic features | Anhedonia, decreased mood reactivity. 3 or more - despair, depression worse in morning, early awakening, psychomotor agitation or retardation, significant weight loss, excessive guilt. |
| Atypical features | Most during depression. 2 or more - weight gain/increased appetite, hypersomnia, leaden paralysis, rejection sensitivity |
| Psychotic features | Delusions or Hallucinations. Specify if mood congruent or not |
| Catatonia | with mania or depression 3 or more - stupor, waxy flexibility, staring, mutism, negativism, posturing, mannerisms, sterotypy, grimacing, echolalia, echopraxia, autonomic abnormalities, rigidity. |
| Peripartum onset | May occur during pregnancy or 4 weeks post delivery. Psychotic sx may or may not be present. Infanticide in 4% |
| Seasonal pattern | During last 2 years seasonal pattern of 1 type of episode. No non-seasonal episodes. full remission in seasonal pattern . |
| Specifiers for remission or episode | Partial or full remission. Severity mild, moderate, severe. |
| YMRS | Young Mania Rating Scale. Clinician rates. Screening and assessing symptom severity. zero to 4 and zero to 8. >25 severe mania, 19-24 moderate mania, <11 euthymia |
| CGI-BP | Clinical Global Impression Scale- Bipolar Version. clinician rated. rating of severity and change in baseline post tx. I = 0 - 7 not ill to very ill. II change from preceding phase, III change from worst phase. |
| MAS | Bech-Rafaelsen Mania Scale. clinician rates. presence and severity of sx. and response to medication. 0-4. 28 = severe mania, 20 = moderate mania, 15-19 = mild mania, <15 = hypomania. |
| CARS-M | Clinician administered rating scale for Mania. Clinician rated, severity of manic and psychotic sx. 0-5. > or = 26 severe mania, 16-25 moderate mania, 8-15 mild mania, 0-7 no or questionable mania |
| ASRM | Altman self rating mania scale. presence and severity of sx in last 7 days. can be used to help patients recognize and monitor sx. 0-4. > or = 6 high probability mania, hypomania, < or = 5 low probability |
| BSRS | Patient or clinician rated. severity of depression or mixed sx. 0-3. Max score is 60. |
| Risk Factos | Genetic, Neurophysiologic, psychosocial. Trauma, abuse, anxiety, conduct disorder, rapid onset of depressive symptoms, medication precipitated hypomania, family hx, >4 depressive episodes. |
| Genetics | Seven fold risk with first degree relative. 50% + family hx. monozygotic twins (40-80%) dizygotic twins (14-20%) SNPs CACNA1C (calcium channel) TRANK1 (tetratricopeptide, ankyrin repeat containing 1) ANK3 (ankyrin 3) ODZ4 (odd Oz/ten-m homologue 4) |
| Epigenetics | Environmental factors: Histone protein modification (acetylation, methylation), Covalent DNA modification, Regulation by non-coding RNA, Valproate has histone deacetylase inhibiting properties. |
| Prevalence | 2.6% adult population U.S. Bipolar I vs. 11 (0.6-1% vs. 0.4- 1.1%). Bipolar one equal, Bipolar II more women. |
| Clinical Course Statistics | 69% misdiagnosed. 1/3 of life in depressed state. 80% experience more than 4 episodes per lifetime. With tx. subsyndromal symptoms with greater morbidity. |
| Clinical Course Specifiers | Bipolar I - ~ 18 yo. Mania 60% of 1st episode. Bipolar II ~ 20 yo. greater chronicity inc episodes, inc depression, shorter euthymia. Rapid Cyclers - earlier onset, women, depressive morbidity, Mixed - ># of episodes > suicide, longer resolution. |
| Suicidality | Higher rates than other dx. 20 times higher than gen pop. upto 50% will attempt, 8-20% complete. Increase risk - inpt., female, bipolar II, SA, eating disorder, personality disorder. |
| Co-morbidities | Anxiety 56%, tx - Olanzapine, Quetiapine, VPA, Gabapentin, pregabalin. Short term BZD. No AD. SUD 60% alcohol, women. inc mixed, rapid cycle, sx severity. ADHD - 10 fold. worse prognosis, earlier onset, need concom mood stabilizer. Buprop, Modaf. |
| Medical Co-morbidities | DM, Obesity Dyslipidemia, decreased tx adherence, 10 yr less life expectancy compared to gen pop. biologic, lifestyle, medications. |
| Pathophysiology Structural | Increased ventricular dimension and amygdalal volume, decreased cortical volume and grey matter. White matter hyperintensities poor prog. |
| Pathophysiology Chemical | Neurotrasmitters. DA, NE, 5HT, Gaba deficiencies or excessive glutamate. Downregulation GABAergic interneurons, corrected by Clozapine, Olanzapine, Quetiapine, and VPA correct downregulation through DNA demethylation. |
| Pathophysiology Second Messengers (1) | BDNF - brain derived neurotropic factor - growth and plasticity.& GABA, DA, 5HT release. Polymorphisms increased severity. 2(Bcl-2) neuroprotective and anti-apoptotic protein. polymorphisms = glutamate toxicity. Lithium and VPA increase Bcl-2 . |
| Pathophysiology Second Messengers (2) | (GSK-3) opposes plasticity. polymorph = psychosis reduced Lithium response. (Lithium is inhibitor) A/cAMP = inc protein G. G coupled signal transduction =mood, appetite, wakefulness. C(PKC) excess = sx. mood stabilizers attenuate. Tamoxifen inhibits |
| Pathophysiology Messengers & Mitochondri | Calcium-2nd messenger in the phosphoisonsitide cycle, Lithiums sites of action. Ca++ Channel blocker - not good evidence. Hippocampal expression of genes related to mitochondrial proteins reduced. Mitoch dysfx. neg impact neuroplasticity, apoptosis. |
| Pathophysiology Neuroendocrine | HPA axis alterations, elevation in cortisol. chronic exposure reduces hippocampal size and promotes vulnerability to insults |
| Pathophysiology Immune | Pro-inflammatory illness. increased TNF-alpha, IL-4, IL-6, and CRP. leads to excessive glutamate, BDNF suppression, and monoamine neurotransmission disruption. |
| Pathophysiology Circadian | Hypothalamic Suprachiasmatic Nucleus genes - CLOCK and BMALI 1. Lithium improves sleep by altering expression of these and other genes. |
| Acute Treatment Mania | Lithium, Valproate, SGA, combination of first 2 with SGA may be most effective, especially with sever sx. or psychotic features. FGA's have anti-manic properties may be 2nd or 3rd line. BZD's anti-manic for short term |
| Acute Treatment Mania (2) | Refractory - ECT, Clozapine, Monotherapy with Gabapentin, Lamotrigine, Levetiracetam, Verapamil, Tiagibine and Topiramate not recommended for tx of acute manic episode. Mixed no response Li++ , VPA, Carbamazepine or SGA. Avoid antidepressants. |
| Acute Treatment Depression | Initially Lithium, Lamotrigine. Alt. Quetiapine, Olanzapine-Fluox, Lurasidone. Olan-fluox ,Luras FDA approved BP I, may use BPII. Quet 1st line data for BPII. Aripirazole , Ziprasidone neg results. Limited data for VPA, CBZ, Modafanil, or Pramiprexole |
| Acute Treatment Depression (2) | No AD monotherapy, may ppt. switching. higher risk TCA, SNRI, than Bupropion. Switch may not be seen for 10 wks, may appear as irritability, dysphoria. ECT may ppt. manic episode. De |
| Depressive Episode Mixed Features | Lurasidone, Olanzapine +/- Fluoxetine |
| Acute Mania or Depressed Episodes, Psychotic Features | More common in mania, tx with AP's, ECT. |
| Continuation/Maintenance | 2-4 months post acute. Maintenance least number of agents at minimum dose. Provides prophylaxis. FDA approval for Lithium , Lamotrigine, Risperidal Consta, Olanzapine, Ziprasidone, Quetiapine, Aripiprazole, for recurrence prevention |
| TMAP Frequent MRE Manic-Hypomanic- Mixed. Recurrent or Severe Mania | 1. Li, VPA, Olanzapine. 2. Aripiprazole. 3. CBZ or Clozapine. 4. Quetiapine, Risperidone, Ziprasidone. 5. FGA, OxCBZ or ECT |
| TMAP MRE Manic-Hypomanic-Mixed without Recent, recurrent or sever mania | 1. Li, VPA, Lamotrigine, Olanzapine. 2. Aripiprazole. 3. CBZ or Clozapine. 4. Quetiapine Risperidone, Ziprasidone. 5. FGA, OxCBZ, ECT. |
| TMAP MRE Depressed, recent and/or history of severe mania. | 1. Lamotrigine and antimanic. 2. Li. 3. Antimanic +Antidpressant, Olanzapine + Fluoxetine. 4. VPA, CBZ, Aripirazole, Clozapine, Olanzapine, Quetiapine, Risperidone, Ziprasidone. 5. FGA, OxCBZ, ECT |
| TMAP MRE Depressed, all others | 1. Lamotrigine. 2. Li. 3. Antimanic +Antidpressant, Olanzapine + Fluoxetine. 4. VPA, CBZ, Aripirazole, Clozapine, Olanzapine, Quetiapine, Risperidone, Ziprasidone. 5. FGA, OxCBZ, ECT |
| CANMAT 2013 Montherapy | |
| Lithium | Serum Mania = 0.8-1.2 or 1.2 to 1.5 severe. Maint. 0.6-1.0 drawn in AM 12 hrs post dose. Single daily dose min kidney changes, polyuria, inc. adherence. May unmask Brugada. Slower than VPA & SGA. SE's Acne, Psoriasis, Alopecia, Cardio change. |
| Lithium cont. | Amiloride for polyuria. Other SE's Hypothyroidism. N/V/D. Wt gain, Tremor, seizure, coma, delirium, confusion, =toxicity. Tx. HD Kayexalate. Permanent tox = memory, ataxia, dysarthria, tremor. Syndrome = (SILENT) |
| CBZ Drug Interactions | CYP450 3A4 substrates - Alprazolam, Aripiprazole, Citalopram, Simvastatin, Tacrolimus. 1A2 subtrates - Clozapine, Olanzapine. 3A4 inhibitor = azoles, Cimetidine, Fluoxetine, Grapefruit juice. 3A4 Inducer - Rifampin, Phenobarb, Phenytoin |
| CBZ Drug Interactions | AD's, AP's, Antiretrovirals reduced effectiveness. C/I - Nefazodone, Delaviridine, Lurasidone. Dec Aprip (70%) Quetiapine (80%), Haldol, Olanx, Risp (50-60%) Clozapine increased risk of agranulocytosis |
| CBZ Drug Interactions | Decreased levels of Apixiban, Dabigatran, Rivaroxaban, and Warfarin. Avoid oral anticoagulants, Warfarin preferred. Dec levels of hormonal contraceptives. |
| VPA Drug interactions | Carbapenems decrease VPA levels, dose increase does not fix. Lamotrigine - VPA increase AUC x2. Phenytoin - altered levels. Warfarin -decreased effect. |
| Lamotrigine Drug interactions | Estrogens - reduce Lamotrigine levels up to 50%. VPA - increased AUC |
| Lithium Drug Interactions | NSAIDS, ACE Inhibitors - increased Li levels - NSAIDS (16-60%) ACEI and ARB (30-40%- delayed 3 wks +). Diuretics (thiazide, osomotic - increase Li levels) Methylxanthines (30-60% Li level reduction) |
| Monitoring CBC | CBZ -Baseline, q2weeks x 2 months, then quarterly to annually. VPA - baseline, 2weeks after initiation or dose change then semi-annually or annually. Lamotrigine - baseline. Li - baseline and yearly |
| Monitoring ECG | CBZ - baseline. VPA & Lamotrigine - N/A. Li -baseline and annually if >40 yo, or cardiac concern, TMAP recommends for everyone |
| Monitoring LFT's | CBZ - baseline, q2weeks x2 mos. then qrtly to annually. VPA - baseline, 2 weeks after initiation or dose change, then semi to annually. Lamotrigine - baseline and annually. Li - N/A |
| Monitoring pregnancy | All - baseline and with suspicion for pregnancy |
| Monitoring TSH | CBZ baseline and annually, VPA & Lamotrigine N/A. Li Once or twice in first 6 months, then every 6-12 months. |
| Monitoring Renal Fx. | CBZ baseline and annually, VPA & Lamotrigine baseline. Li baseline, evey 2-3 months for 6 months, then semi to annually. |
| Monitoring Efficacy | 50% improvement in sx. for acute episode. Remission YMRS < or = 11, (7 proposed with no greater than 2 or 1 in specific items) Montgomery Asberg < or = 10. Hamilton < or = 7. Opposite pole worse - no remission. Early response not indicator. 8wk is. |
| Monitoring serum level | CBZ - 5 days after stable dose, autoinduction complete in several weeks. VPA - 50-125, measure free drug in protein binding change ( medically ill, old, malnourished) Lamotrigine N/A levels >20 more SE. Li - weekly until stable dose then qrtly to sa. |
| Monitoring serum electrolytes | CBZ -baseline, at 2 weeks then annual. VPA & Lamotrigine - N/A. Li - baseline & annually. |
| Monitoring Other | CBZ -Weight, HLA-B*1502 for rash, Asian. VPA weight, ammonia. Lamotrigine weight, rash. Li weight, serum CA++, Urine specific gravity, urinalysis, output, diet. |
| VPA MOA | GABA, Na+ and Ca++ channels, inositol, PKC, genes. Anti-kindling properties. Pkinetics - Glucuronidation and Mitochondrial beta-oxidation. Loading dose 20-30 mg/kg. Levels acute mania >72 or 94. Maint >50 SE's >125. Switch to ER decreased levels 8-20% |
| VPA SE's, C/I's | Hepatic dx. Urea cycle disorder, teratogenicity, suicidality, rash, SJS, TEN, Alopecia, Nause, Pancreatitis, weight gain, thrombocytopenia, Neuro- ataxia, diplopia, dizziness, sedation, tremor. 85-90 % protein bound, saturable in toxicity |
| Lamotrigine MOA | Sodium channels, presynaptic aspartate and glutamate, anti-kindling, Little to no effect on GABA, DA, AcetylCH, or NE. Slwo titration. SJS, TEN slow titration, max dose 200, w/VPA 100. |
| Lamotrigine Rash | Benign rash (7%) SJS/TEN (0.08%). Nearly all life threatening rashes occur within 2-8 weeks of initiation. Prodrome flu-like sx in up to 85%. Lesions face an upper torso. Re-challenge for non-life threatening not recommended but supported in lit. |
| Lamotrigine other SE | N/V/D, rare agranulocytosis. neurologic, may attenuate, less with ER. Serious (IR) ataxia, dizziness, diplopia, sedation, aseptic meningitis. |
| CBZ MOA | sodium channels, Blocks Calcium influx through NMDA receptor. decreases presynaptic aspartate and glutamate. Anti-kindling properties. |
| CBZ Pkinetics, Pgenetics | Metabolite - CBZ-10,11 epoxide associated with toxicity. Autoinduction starts in 3-5 days complete 3-5 weeks. Testing for HLA-B*1502 10X more likely SJS/TEN/DRESS. HLA-A*3101 moderate risk. |
| CBZ Dosing | Serum levels do not correlate well with efficacy. Usual range 4-12. Not routine, use in suspected toxicity, adherence issues, suspected toxicity. |
| CBZ Contraindications | Bone marrow suppression, hypersensitivity, MAOI, Nefazodone, Lurasidone. Delaviridine or other NNRTI. |
| CBZ Warnings/Precautions | Hypersensitivity rxn to CBZ confers 25-30% risk in OXC. Anemia, agranulocytosis, increased suicidality, teratogenicity. Avoid in hepatic porphyria. |
| CBZ AE's | Rash, Hyponatremia, (less than with OXC) Hematologic (risk 5-8X greater than in gen pop) Neurologic- ataxia, dizziness, somnolence, tremor, resolve later in tx. Levels over 12 nystagmus, ataxia, over 40 coma, seizure. arrhythmia rare. |
| SGA and FGA | vary in effectiveness. Caripiprazine FDA approved acute mixed or manic episodes BPI. FGA effective acute mania, lack efficacy in maint depression, may switch to depression. Clozapine data supports tx in resistance, manic respond better. dose less. |
| Other Agents (Not FDA Approved) | Oxcarbazepine, less hematologic se, more hyponatremia. Phenytoin - 3rd line. Tamoxifen (PKC inhibition) Tiagabine - weak antimanic, antidepressive, Topiramate and Zonisamide no better than placebo. Gabapentin, Levetiracetam not recommended neg data. |
| Lithium - Pregnancy | Pregnancy- risk of recurrence 50-71%, more than doubled if maint tx dcd. ECT for severe. No BZD. No once daily dosing. Avoid 1st trimester. Li - Ebsteins anomaly. less than believed. fetal echo - level 2 Ultsnd rec. |
| Lithium - Pregnancy | Li - floppy baby cyanosis, lethargy, prematurity, thyroid toxicity, increased birth weight. Taper before birth. |
| VPA - Pregnancy | AE 1-3.8% Avoid during pregnancy and 1st trim. Neural tube defects, skeletal abn, limb defects, CV defects, Cerebral hemorrhage, DD, IUGR, coagulopathy. Folate 4 mg daily preconcept & 1st trim. serum level less than 70. Decreased albumin, monitor free. |
| CBZ - Pregnancy | AE 3.3-6.7% vs.2-3% baseline. Spina bifida 2.5 fold risk. DD, lower IQ, Folate 4 mg daily preconceptually and 1st trim. Vitamin K last month. |
| Lamotrigine - Pregnancy | more favorable. low risk but inc.to 12.5% when used with VPA. Midline facial cleft 0.89% Clearance increases 50% monitor post partum or reduce to pre-pregnancy dose. |
| Lactation -CBZ, Li, LTG | CBZ compatible monitor baby LFT, CBC. level 15-65%mom. poss transient Hyperbili, Cholestasis. LTG unk. risk SJS/TENS? level 50% mom. Li. C/I. dehydration, abn kidney fx. Monitor hypotonia, hypothermia, cyanosis, levels, CBC renallabs conc 10-50% mom |
| Lactation VPA | Level 5-10% mom. rare AE, thrombocytopenia, anemia. long term unk. compatible, monitor LFT, CBC. |
| Elderly | New onset dec w/age. 6-8% dx after 60 yrs. Ave 25 yr delay from last episode. presentation similar, more premorbid psychosocial fx, prob, less sever psychopathology. Tx same lower doses |
| Children & Adolescents | 1.8% Depressive predominant, more time syndromal, and mixed or psychotic, freq. short periods lability, irritability. difficult d/d from ADHD, anxiety, PTSD, SA. Mania Hypomania risk 20-50% dep on genetics depression before Puberty. |
| Pharmacoeconomics |
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