bipolar disorder in primary care: A COLLABORATIVE approach Leslie Walker MD Case western reserve university dept of psychiatry April 2018

Objectives Distinguish bipolar I disorder, bipolar II disorder, and major depressive disorder Safely manage patients on lithium and anticonvulsants. Safely manage and watch for long-term sequelae of antipsychotics.

diagnosis IMPAIRED FUNCTION due to EPISODIC CYCLING of these factors at the same time: MOOD ENERGY LEVEL and NEED FOR SLEEP COGNITIVE SPEED

How high and low does the patient go?

Screening in Primary care Has there EVER been a time when you were not your usual self and … 7+ symptoms plus 3 yes answers at the SAME TIME, plus moderate- severe problems caused by these symptoms Also asks about FH and if a HCP ever said you had manic-depressive illness or bipolar disorder

A positive screen does not = bipolar disorder. REFER for comprehensive diagnostic evaluation Detailed history from both patient and an outside informant who has seen the patient over time – are symptoms episodic or chronic? Review FH: psychiatric illness, SUDs, suicide Review PMH and SH for other causes of “mood swings” Are all 3 features abnormal at the same time, episodically, for days-months? Mood Energy and need for sleep Cognitive speed

“mood swings” do not = bipolar disorder Emotion dysregulation Immaturity PTSD and Developmental Trauma Personality Disorders Hormones Testosterone/anabolic steroid use or low T PMDD, pregnancy, postpartum, perimenopause Medications: steroids, stimulants, beta agonists, dopamine agonists Substance intoxication, withdrawal, abuse, dependence Interpersonal conflict, domestic violence, bullying Brain injuries, neurologic diseases, early dementia

Bipolar I disorder Manias and Major Depressive Episodes Prevalence 1%, F=M Often have psychotic symptoms, usually mood-congruent “Classic mania” Widely spaced psychotic manias Euthymic between episodes Quite typical bipolar I Chronic residual mood and cognitive symptoms, especially depression Multiple medications to stabilize mood and prevent psychotic symptoms Comorbid alcohol/drug abuse Prominent anxiety and attention problems

Bipolar II disorder Long episodes of major depression (often months-years) Brief episodes of hypomania and/or mixed states (days-weeks) Prevalence 2-5%, F>M We consider Bipolar II Disorder if: No or only a brief response to antidepressants Extremely rapid response to an antidepressant Elevated moods followed by a very rapid “crash” into depression Long history of irrational irritability and/or severe anxiety, often with antidepressants on board

Mixed states LOW MOOD – depressed or irritable HIGH energy – pacing, agitation, too wired to sleep HIGH cognitive speed – racing thoughts, can’t stop thinking, rapid/pressured speech May follow starting or increased dose of antidepressants EPISODIC states (vs. chronic symptoms in anxiety disorders, PTSD) Higher suicide risk during these states

TREATMENT

Treatment goals in bipolar disorder ACUTE Safety Treat psychotic symptoms Stabilize sleep and mood including a CORE bipolar maintenance medication ?Taper off meds that fuel cycling (antidepressants, stimulants) MAINTENANCE CORE mood stabilizer Adjust acute meds as needed Taper BDZ? Reduce dose of sedating antipsychotics? Monitor side effects, weight, labs and adjust as needed

Maintenance treatment Social Rhythm Therapy: Sleep, meals, social interactions Plan for disruptions Recovery/Sobriety Address residual anxiety or attention sx Support/education for patient and family Relapse anticipation: watch for herald symptoms

Anticipate pregnancy High relapse rate (85%) if meds stopped in pregnancy - usually depression 37% relapsed if meds were continued (Viguera et al 2008) High risk (66%) of postpartum illness if meds stopped during pregnancy 23% relapsed if meds were continued (Wesseloo et al 2016) Depression or mania in pregnancy ↑risk of adverse events for mom and baby High risk of postpartum psychosis if bipolar I disorder! DO NOT STOP MEDICATIONS WITHOUT CLEAR RISK/BENEFIT DISCUSSION www.womensmentalhealth.org

Work as a team Don’t change psychiatric medications without collaborating, especially in pregnancy Alert psychiatrist to medical changes or psychiatric symptoms Forward labs/weights Educate patients about long-term risks and why monitoring is so important Actively support smoking cessation, sobriety, healthy diet, exercise strategies

FDA-APPROVED medications for bipolar disorder MANIA/MIXED MAINTENANCE BIPOLAR DEPRESSION LITHIUM DIVALPROEX Chlorpromazine Loxapine inhaled (REMS) Olanzapine: 13+ (M, adjunct) Quetiapine: 10+ (M, adjunct) Quetiapine XR (M, adjunct) Ziprasidone (M, adjunct) Risperidone: 10+ (M, adjunct) Aripiprazole: 10+ (M, adjunct) Asenapine: 10+ (M, adjunct) Cariprazine (M) LITHIUM: 12+ LAMOTRIGINE Olanzapine (M) Quetiapine (adjunct) Ziprasidone (adjunct) Risperidone LAI (M, adjunct) Aripiprazole: 10+ (M, adjunct) Asenapine (M, adjunct) Olanzapine + fluoxetine (Symbyax): 10+ Quetiapine Quetiapine XR Lurasidone: 10+ M = monotherapy Adjunct = added to lithium or valproate REMS = Risk Evaluation & Mitigation Strategy

Antidepressants are not approved in bipolar disorder. Don’t beat placebo in bipolar depression. May cause “switching” to hypomania or mania. May fuel cycling – faster cycling, more mixed states. If they are required for treating comorbid anxiety disorders (ie OCD or severe anxiety disorders): First establish an effective CORE mood stabilizer regimen Then watch carefully for switching or faster cycling with an AD

lithium Use Li carbonate ER unless pt has had gastric bypass qhs dosing often better tolerated than BID Monitor at 6-12 mo intervals: 12-hour lithium level thyroid and renal functions weight

Lithium levels Therapeutic 12-hour lithium levels: 1.0-1.2. in acute mania 0.8-1.0 in bipolar I maintenance 0.6-1.0 in bipolar II maintenance Li levels are elevated by: Dehydration Regular daily NSAIDs Thiazide diuretics, ACEIs and Angiotensin II Type 1 antagonists Li levels may be lowered by: aminophylline, theophylline, and possibly caffeine

ACUTE Lithium toxicity Levels >1.5 can cause toxicity. If >2.0 and significant sx, consider admit to a monitored unit for hydration. CNS (tremor, imbalance, confusion, coma) GI (nausea, vomiting, diarrhea) Cardiovascular (T-wave flattening, arrhythmias) Renal Level >4.0 usually requires urgent hemodialysis

Lithium in pregnancy & postpartum Ebstein’s anomaly less common than previously thought. Lithium levels decrease as blood volume increases throughout pregnancy. Check lithium level every 2-3 months and adjust dose accordingly. Hold lithium during labor & maintain good hydration. After labor, restart lithium at PRE-PREGNANCY dose. Breastfeeding not recommended due to risk of toxicity in newborn and risk of sleep disruption in mom.

anticonvulsants Affect transmission through ion channels on the membranes of neurons to make them more or less excitable Typically started during/after depressive episode: LAMOTRIGINE (LAMICTAL) Typically started during/after manic episode: DIVALPROEX (DEPAKOTE) Off-label carbamazepine (Tegretol) Farther off-label oxcarbazepine (Trileptal) Way off-label: gabapentin, topiramate, newer anticonvulsants

Lamotrigine (LAMICtAL) FDA-approved for bipolar maintenance Often initiated during/after bipolar depression Safest monotherapy option in pregnancy No blood monitoring required Usually weight-neutral, well-tolerated REQUIRED dose initiation schedule due to risk of SJS

STEVENS-JOHNSON SYNDROME 10% get brief itchy drug rash which usually resolves within days with diphenhydramine 1/1000 go on to SJS, TEN, or similar multiple-organ illness Typically occurs within first 2 weeks or first 6 months of LAM treatment SJS/TEN can occur with any anticonvulsant esp CBZ, other drugs including sulfonamide antibiotics

Divalproex (DEPAKOTE, DEPAKOTE-ER) Target 12-hour blood level = 80-120 Dose qhs to minimize daytime sedation and help with sleep Side Effects: Metabolic (WEIGHT GAIN, osteoporosis) CNS (sedation, tremor, dizziness) GI (nausea, diarrhea, elevated transaminases) Hair loss TERATOGENIC IN PREGNANCY Baseline labs: Pregnancy test, LFTs, CBC, weight Once therapeutic level established, check LFTs, CBC, weight q 6mo Older patients: DEXA scan q 1-2 yrs Doubles the levels of lamotrigine; watch for other drug interactions

Antipsychotics in bipolar disorder Required for psychotic mania or depression, at least temporarily Frequently used for agitation/sedation/sleep in mania and hypomania, often in conjunction with high-dose benzodiazepines for inpatients Increasingly used for bipolar depression and maintenance, even without psychotic symptoms Black box warning on entire class for increased risk of death in elderly dementia patients Must monitor AIMS (Abnormal Involuntary Movement Scale), weight, lipids, HbA1c regularly.

Antipsychotics TYPICAL or First-Generation Antipsychotics (FGAs): D2 blockers Haloperidol (Haldol), fluphenazine (Prolixin), thioridazine (Mellaril), chlorpromazine (Thorazine) Some also prescribed for nausea/vomiting: prochlorperazine (Compazine), droperidol (Inapsine), metoclopramide (Reglan) ATYPICAL or Second-Generation Antipsychotics (SGAs): Brief D2 blockers and 5HT-2A blockers Some D3 blockers Lower rates of EPS and TD but may have more metabolic SE

D2 BLOCKERS & EXTRAPYRAMIDAL SYMPTOMS (EPS) Antipsychotic threshold = 65% D2 receptor occupancy EPS threshold = 80% D2 receptor occupancy Acute EPS (dystonic reactions): diphenhydramine 50mg IV/IM/po Tremor, rigidity: reduce dose if possible, add anticholinergics if necessary Akathisia: reduce dose/taper off, clonazepam or beta blockers temporarily

D2 antagonistS & tardive dyskinesia (TD) Higher risk with longer use and higher dose Women and older individuals may be more at risk Early sx: tongue/mouth, patient may be unaware Tongue dyskinesia, tongue thrusting, lips puckering, grimacing Later sx: limbs, neck, torso dyskinesia, writhing, choreoathetoid movements Taper off if possible but watch for withdrawal-emergent worsening Clozapine, quetiapine are best options if antipsychotic needed in TD Expensive new drugs available to treat moderate-severe TD

two SGAs APPROVED in all bipolar mood states Highly sedating, high risk of increased appetite and weight OLANZAPINE (ZYPREXA): Mania: 5-30mg qhs. Bipolar depression 2.5-15mg qhs (FDA approved in combo with fluoxetine) QUETIAPINE (SEROQUEL): Mania: 600-800mg qhs. Bipolar depression: 300-600mg qhs. Augmentation in MDD: 150-300mg qhs. Bipolar maintenance may lower dose to maintain sleep/mood: 25-200mg qhs.

LESS-SEDATING MODERATE potency SGAs Higher risk of EPS including akathisia; watch for TD even when tapering off RISPERIDONE (RISPERDAL): can increase PRL and affect menses/fertility Mania: 4-8mg qhs or divided dose. Agitation/irritability: 0.25-2mg BID-TID prn. Nice option in intermittent severe irritability and mixed states RISPERDAL CONSTA is a LAI (Long-Acting Injectable) 12.5-50mg q 2 weeks ARIPIPRAZOLE (ABILIFY): D2 partial agonist, akathisia still common Mania/mixed, BP maintenance: 5-30mg qd. Augmentation in MDD: 1-15mg qd

?Best options to avoid weight gain/metabolic sx ZIPRASIDONE (GEODON) BP mania/mixed: 40-80mg BID or all qhs if sedating May be helpful with anxiety LURASIDONE (LATUDA) BP depression: 20-120mg daily Weight-neutral, good metabolic profile Must be taken with food for full absorption (350 cal) typically dinner

New atypical antipsychotics ASENAPINE (SAPHRIS): sublingual tablets Mania/mixed: 5-10mg BID. BP Maintenance: 5-10mg BID or qhs Can be sedating, may help with anxiety, may have less weight gain CARIPRAZINE (VRAYLAR) D3>D2 Manic/mixed: 1.5-3mg daily Positive trial in bipolar depression, may have lower risk of metabolic SE

Benzodiazepines (Off-label in bipolar disorder) Agitation/Decreased Need for Sleep in acute mania Sleep disruption/regulation in maintenance Or Z-drugs (off-label) if effective and tolerance doesn’t develop Anxiety CBT is best, but BDZ may be preferable to antidepressants in anxiety disorders such as GAD and Panic Disorder BDZ should not fuel mood cycling or mixed states Risk of tolerance/dependence (esp alprazolam) Watch for overlap with alcohol

RESOURCES FOR PATIENTS/FAMILIES Mondimore FM. Bipolar Disorder: A Guide for Patients and Families. 3rd edition (2014). Federman, Thomson. Facing Bipolar: The Young Adult’s Guide to Dealing with Bipolar Disorder (2010). Miklowitz D. The Bipolar Disorder Survival Guide. 2nd edition (2010). For kids: Campbell, Lewis. Sometimes My Mommy Gets Angry. Chan. Why is Mommy Sad? A Child’s Guide to Parental Depression. Leslie.s.walker@case.edu