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

2. 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.

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

5. How high and low does the patient go?

6. 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

7. 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

8. “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

9. 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

10. 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

11. 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

12. TREATMENT

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. Lithium levels Therapeutic 12-hour lithium levels:
in acute mania
in bipolar I maintenance
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

21. 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

22. 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.

23. 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

24. 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

25. 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

26. Divalproex (DEPAKOTE, DEPAKOTE-ER)
Target 12-hour blood level =
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

27. 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.

28. 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

29. 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

30. 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

31. 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 mg qhs (FDA approved in combo with fluoxetine)
QUETIAPINE (SEROQUEL):
Mania: mg qhs.
Bipolar depression: mg qhs.
Augmentation in MDD: mg qhs.
Bipolar maintenance may lower dose to maintain sleep/mood: mg qhs.

32. 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: mg BID-TID prn.
Nice option in intermittent severe irritability and mixed states
RISPERDAL CONSTA is a LAI (Long-Acting Injectable) mg q 2 weeks
ARIPIPRAZOLE (ABILIFY): D2 partial agonist, akathisia still common
Mania/mixed, BP maintenance: 5-30mg qd.
Augmentation in MDD: 1-15mg qd

33. ?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: mg daily
Weight-neutral, good metabolic profile
Must be taken with food for full absorption (350 cal) typically dinner

34. 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

35. 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

36. 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.