What it is:A lifelong, recurrent mood disorder built around episodes of mania or hypomania, almost always punctuated by depressive episodes too. It is not "extreme mood swings" in the casual sense, it's a specific DSM-5 diagnosis with duration and symptom-count criteria, and it can't be explained by a substance or another medical/psychiatric condition.
The core problem:There are two distinct mood poles that each need their own treatment logic, plus a maintenance phase to prevent the next episode of either kind. That's three separate treatment problems living inside one diagnosis, which is exactly why bipolar pharmacotherapy feels more complicated than depression alone.
What you do about it:Medications are the backbone of care, essentially always. Psychotherapy alone is not considered sufficient. Pick a mood stabilizer (lithium, valproate, or an SGA) matched to the current episode, then keep the patient on something lifelong, because relapse risk after even one manic episode is over 90%.
Think of every drug class here through one lens: which mood pole is it treating, and is it also safe for maintenance?Some drugs are mania-only (oxcarbazepine), some are depression-only in the acute sense (lurasidone, lumateperone), and only a few (lithium, quetiapine, lamotrigine, valproate) do double or triple duty. Mapping each drug to FDA-approved phase (mania / depression / maintenance) is the single most testable organizing skill in this chapter.
DSM-5 splits bipolar and related disorders into five subtypes, but three of them carry almost all the clinical and testing weight.
May be preceded or followed by hypomania or major depressive episodes, but the manic episode alone is diagnostic. A single mixed episode also counts as Bipolar I.
At least one hypomanic episode anda current or past major depressive episode. Never a full manic episode, if one occurs, the diagnosis becomes Bipolar I.
Numerous periods of subsyndromal depressive and hypomanic symptoms that never meet full episode criteria, but persist chronically without a sustained euthymic period.
This is a classic trap. Bipolar II patients have more frequent and more severe depressive episodesthan Bipolar I patients, and their overall functional impairment can be equal or worse. They also have higher rates of suicidal thoughts and attemptsthan either Bipolar I or unipolar depression. "Bipolar II = lower lows, not lower stakes."
Etiology is multifactorial: developmental, genetic, neurobiological, and psychological factors all contribute, and multiple gene loci are involved. Heritability estimates run 60-80%, among the highest of any psychiatric illness, though no single gene explains it.
This is the framework your lecturer built the whole pathophysiology discussion around, and it explains almost every manic symptom from one starting point. Bipolar disorder may stem from a heightened sensitivity to reward-related stimuli. Even between episodes, people with bipolar disorder show emotional hypersensitivity to rewards, and reward hypersensitivity strongly predicts futuremania, even before a first episode.
That hypersensitivity drives overly ambitious goals (fame, money, achievement) and overestimation of success. It shows up neurologically as overactivation of the left lateral orbitofrontal cortex (LLOFC), the region linking emotion to decision-making. Mnemonic: "Let's Live Outrageously, Forget Consequences."
| State | LLOFC activity | Clinical picture |
|---|---|---|
| Bipolar I mania | Overactivation | Reward chasing, grandiosity, poor consequence-weighing |
| Bipolar depression (either type) / unipolar depression | Underactivation | Reduced reward sensitivity, ↓ motivation and pleasure, negative bias toward underestimating success |
Increased goal-directed activity typically appears days to weeks beforethe other manic symptoms as a prodrome, which is why it's considered the single most sensitive marker of mania. The other DIGFAST symptoms (grandiosity, flight of ideas, decreased sleep need, talkativeness) are downstream effects of that same reward-driven activation, not separate processes.
Mood in mania is classically non-reactive, meaning it stays elevated regardless of what's actually happening. A patient in mania who receives news of a death may stay euphoric instead of grieving. That mismatch between mood and reality, not "too much happiness," is the pathology. Mnemonic for the concept: MANIA= More Activity, Not Inherently Affective. The activity increase is the core lesion; the euphoria is optional.
Any workup for a first manic episode has to exclude organic causes before you call it primary bipolar disorder.
Episodes can occur back to back or with years of euthymia between them. What distinguishes mania, hypomania, and a mixed episode is duration, functional impairment, and whether psychotic features are present, not just symptom checklist overlap.
DSM-5 requires elevated or irritable mood plus increased energy, along with at least 3 of these 7 symptoms (4 if the mood is irritable only).
| Letter | Symptom | What it looks like |
|---|---|---|
| D | Distractibility | Can't stay on task, pulled off by irrelevant stimuli |
| I | Indiscretion / impulsivity | Spending sprees, sexual indiscretions, reckless business decisions |
| G | Grandiosity | Inflated self-esteem, unrealistic belief in one's own abilities |
| F | Flight of ideas | Rapid topic-jumping, often with pressured speech |
| A | Activity increase | Goal-directed activity surge - the most sensitive marker, its absence rules mania out |
| S | Sleep deficit | Feels rested after only a few hours, or goes days without sleep |
| T | Talkativeness | Pressured speech, hard to interrupt |
Mania:≥1 week of symptoms, or any duration if it requires hospitalization. Hypomania:≥4 days. Same symptom list, different clock. Memory aid: "1 fun week" of mania vs. the "2 blue weeks" needed for a major depressive episode.
Rapid cycling means ≥4 distinct mood episodes (manic, hypomanic, or depressive) within one year, affecting up to 43% of bipolar patients at some point and predicting a worse long-term course. It does notmean mood shifting over minutes to hours; that pattern points toward borderline personality disorder instead. Rapid cycling is associated with antidepressant use, which is one more reason antidepressants are used cautiously here.
Delusions, hallucinations, and suicide attempts are all more common in bipolar depression than in unipolar depression, which is one reason correctly identifying bipolarity in a depressed patient matters so much before reaching for an antidepressant.
Diagnosis requires a full medical, psychiatric, and medication history, physical exam, and labs to exclude organic causes (see secondary causes above) before applying DSM-5 criteria.
| Episode | DSM-5 criteria |
|---|---|
| Major depressive | ≥2 weeks of depressed mood or anhedonia, plus ≥5 of: depressed/irritable mood, ↓ interest/pleasure, appetite or weight change, insomnia or hypersomnia, psychomotor change, fatigue, guilt/worthlessness, poor concentration, thoughts of death or suicide |
| Mania | ≥1 week of elevated/irritable mood and energy, plus ≥3 DIGFAST symptoms (4 if irritable-only mood); marked functional impairment |
| Hypomania | ≥4 days of the same mood/energy change and ≥3 DIGFAST symptoms (4 if irritable-only), withoutmarked impairment |
None of these can be caused by a medical condition (e.g., hyperthyroidism) or a substance (e.g., an antidepressant-induced high). DSM-5 also allows specifiers like mixed features, anxious distress, rapid cycling, or melancholic features to further characterize an episode.
| Metric | Number |
|---|---|
| US adult prevalence | ~2.6% (6 million adults) |
| Lifetime prevalence, BP1 | 0.6-1% |
| Lifetime prevalence, BP2 | 0.4-1.1% (vs. ~20% for unipolar depression) |
| Untreated manic episode duration | ~13 weeks (median) |
| Untreated depressive episode duration | ~26 weeks (median), roughly double mania |
| Treated episode duration | Can resolve within days to weeks |
| Lifetime spent in an abnormal mood episode | Up to 50% (35% depressed, 10% hypomanic, 5% cycling, only 1% manic) |
| Recurrence risk after 1 MDE | ~50% |
| Recurrence risk after 1 manic episode | >90% |
Despite mania being the diagnostic hallmark, patients spend far more total time depressed than manic (35% vs. 1% of their lives, by one estimate). That's why acute depression and depression-prevention deserve just as much treatment attention as acute mania, even though mania gets more airtime in lecture and on boards.
Up to 50% of bipolar patients attempt suicide, and ~7% of Bipolar I patients die by suicide. That's a 60x higher ratethan the general population. Bipolar patients tend to use more lethal means, and about 1 in 3 attempts end in deathversus roughly 1 in 20 for unipolar depression. Bipolar II patients may have even higher attempt rates than Bipolar I. Suicide attempts cluster in depressive and mixed episodes, especially with severe depression or psychotic features, not during pure mania.
Ten goals worth internalizing as a checklist: (1) eliminate the current episode, (2) prevent recurrence, (3) restore baseline psychosocial function, (4) maximize adherence, (5) minimize adverse effects, (6) choose the best-tolerated option with fewest interactions, (7) minimize polypharmacy, (8) treat comorbid substance use, (9) minimize nicotine and stop caffeine ≥8 hours before bed, and (10) avoid known precipitating stressors or substances.
Treatment adherence is the single most important factor in achieving these goals; missed doses are the leading cause of nonresponse and relapse. Patients generally stay on a mood stabilizer (lithium, valproate, or an SGA) for life. During acute episodes, add medications as needed, then taper once the patient is euthymic and stable, but the maintenance backbone stays.
Patient and family education about symptoms, causes, and course is foundational. Address nutrition (regular protein and essential fatty acid intake), sleep, exercise, and stress reduction. Evidence supports adjunctive CBT, interpersonal and social rhythm therapy, group psychoeducation, family-focused therapy, and enhanced relapse-prevention/individual psychoeducation, particularly for depressive episodes and relapse prevention. Unlike unipolar depression, where therapy alone can be adequate, bipolar disorder's standard of care is medication-based; psychotherapy is an add-on.
Every acute presentation starts the same way regardless of pole: assess for secondary causes (substances, medical mimics), stop the offending agent if one is found (antidepressants in mania, antipsychotics/benzodiazepines/sedatives in depression if tolerated), treat any substance use, and layer in nutrition, sleep, exercise, and psychosocial support.
| Severity | Step | Regimen |
|---|---|---|
| Hypomania / mania | First | Optimize current mood stabilizer or initiate lithium, valproate, carbamazepine, or an SGA. Add a benzodiazepine (lorazepam or clonazepam) short-term for agitation/insomnia if needed. Oxcarbazepine is an alternative. |
| Second, if inadequate | Two-drug combo: lithium + an ASM or SGA, or ASM + ASM/SGA | |
| Severe mania | First | Optimize regimen or start a two/three-drug combo: lithium, valproate, or an SGA plus a benzodiazepine and/or antipsychotic. Do not combine antipsychotics.Lorazepam is recommended specifically for catatonia. Carbamazepine is an alternative. |
| Second, if inadequate | Three-drug combo: lithium + ASM + antipsychotic, or ASM + ASM + antipsychotic | |
| Third, if inadequate | ECT for mania with psychosis or catatonia, or add clozapine for treatment-refractory illness |
| Severity | Step | Regimen |
|---|---|---|
| Mild-moderate | First | Initiate or optimize lithium, quetiapine, or lurasidone. Alternative ASMs: lamotrigine, valproate. Alternative antipsychotics: fluoxetine/olanzapine combination, cariprazine, lumateperone. |
| Second, if inadequate | Consider carbamazepine or adding an antidepressant | |
| Severe | First | Optimize or start lithium, quetiapine, or lurasidone, plus fluoxetine/olanzapine combination. If psychosis present, add/optimize an antipsychotic (do not combine antipsychotics). Alternative ASM: lamotrigine or valproate. |
| Second, if inadequate | Three-drug combo: lithium + lamotrigine + antidepressant, or lithium + quetiapine + antidepressant | |
| Third/refractory | ECT, especially with psychosis, catatonia, or high suicide risk |
Severe acute mania:lithium or valproate plusan antipsychotic (aripiprazole, haloperidol, olanzapine, quetiapine, risperidone). Combination beats monotherapy for speed and depth of response. Lithium is preferred for "pure" non-mixed mania, including with psychosis. Mixed episodes:SGA and valproate are first-line, not lithium alone. Bipolar depression, first-line:quetiapine or lurasidone monotherapy. Maintenance, first-line:lithium, valproate, quetiapine, or lamotrigine, usually whichever agent resolved the acute episode. Lithium has the best evidence for reducing suicide riskof any bipolar medication and is the only one with established anti-suicide and neuroprotective effects, which is why it anchors maintenance therapy even when it isn't first pick acutely.
Adjunctive antidepressants may be no better than placebo for acute bipolar depression when added to a mood stabilizer, and they're generally considered third-line. TCAs and venlafaxine carry a higher risk of switching depression into mania than SSRIs do. Rules of thumb: never use as monotherapy, only add on top of a therapeutic mood stabilizer dose, avoid in patients with a history of mania triggered by a prior antidepressant or with frequent cycling, and plan to withdraw the antidepressant 2-6 monthsafter remission.
Grouped by drug class. Ranges are usual adult outpatient dosing; acute inpatient dosing for lithium, valproate, and carbamazepine runs higher and faster, see class detail below.
| Drug | Initial | Usual / target |
|---|---|---|
| Lithium | ||
| Lithium carbonate / citrate | 300 mg BID | 900-2400 mg/day divided BID-QID with meals ↓ suicide risk |
| Antiseizure medications | ||
| Divalproex / valproic acid / valproate sodium | 250-500 mg BID (or 20-30 mg/kg/day load) | 750-3000 mg/day (20-60 mg/kg/day) |
| Lamotrigine | 25 mg daily | 50-400 mg/day (target ~200 mg/day; halve with valproate) |
| Carbamazepine | 200 mg BID | 200-1800 mg/day divided BID-QID |
| Oxcarbazepine | 300 mg BID | 300-1200 mg/day divided BID |
| Second-generation antipsychotics | ||
| Aripiprazole | 10-15 mg daily | 10-30 mg/day mania + maintenance |
| Asenapine (sublingual) | 5-10 mg BID | 5-10 mg BID mania + maintenance |
| Cariprazine | 1.5 mg daily | 3-6 mg daily mania |
| Lumateperone | 42 mg daily | 42 mg daily bipolar depression |
| Lurasidone | 20 mg daily with food | 20-120 mg/day bipolar depression |
| Olanzapine | 2.5-5 mg BID | 5-20 mg/day mania + maintenance |
| Olanzapine/fluoxetine (Symbyax) | 6 mg / 25 mg daily | 6-12 mg olanzapine / 25-50 mg fluoxetine bipolar depression |
| Quetiapine | 50 mg BID | 50-800 mg/day mania + depression + maintenance |
| Risperidone | 0.5-1 mg BID | 0.5-6 mg/day mania |
| Ziprasidone | 40-60 mg BID | 40-160 mg/day mania |
| Benzodiazepines (short-term adjunct only) | ||
| Lorazepam / clonazepam | Titrate to response | Adjunct for agitation, insomnia, or catatonia (lorazepam); taper when no longer needed |
First-line for acute mania and for maintenance in both Bipolar I and II; second-line for acute Bipolar II depression. Mechanism isn't fully understood, but it enhances neuronal resilience and plasticity, modulates second-messenger systems, decreases serotonin reuptake while increasing post-synaptic 5-HT sensitivity, inhibits dopamine synthesis and receptor sensitivity, decreases CNS adrenergic activity, enhances GABA activity, and alters intracellular calcium handling. It's rapidly absorbed, not protein bound, not metabolized, and excreted unchanged by the kidney, so renal function is everything with this drug.
Onset:slower than antipsychotics or valproate for mania (6-10 days to respond, up to 3 weeks for full resolution). For depression, meaningful antidepressant effect can take 6-8 weeks. It produces a prophylactic response in up to two-thirds of patients and is uniquely proven to reduce suicide risk.
Dosing:start ~600 mg/day for prophylaxis, 900-1200 mg/day for acute mania. Give immediate-release BID-TID, extended-release once-twice daily; many patients transition to once-daily dosing once stable, which also cuts down on polyuria and reduces the structural/functional kidney changes seen more often with divided dosing.
| Context | Target trough (12h post-dose) |
|---|---|
| Maintenance | 0.6-0.8 mEq/L (up to 1.0-1.2 if needed; older adults 0.4-0.6) |
| Acute mania | 0.8-1.2 mEq/L (occasionally up to 1.5 mEq/L) |
Steady state takes ~5 days; check levels 1-2x weekly initially, then every 2 weeks once the desired level is reached, then every 3-6 months when stable. A reasonable outpatient trial is at least 4-6 weeks at therapeutic levels.
A benign fine hand tremoris common and dose-related, worse at peak concentration 1-2 hours post-dose; manage with a long-acting product, lower dose, or propranolol 20-120 mg/day. A coarse tremor is a toxicity warning sign, not just a nuisance side effect. Know the difference cold, it's a classic distractor pairing.
Other expected effects:GI/CNS effects worse at peak, help with food, lower dose, ER products, or bedtime dosing (diarrhea sometimes improves with a liquid formulation). Nephrogenic diabetes insipidus with polydipsia/polyuria develops in 20-40% of patients soon after starting and persists in 10-25%, but is typically reversible on discontinuation; manage nocturia with bedtime once-daily dosing, and manage true nephrogenic DI (urine output >3 L/day) with a loop or thiazide diuretic (cut the lithium dose 50% and watch lithium/potassium if using a thiazide; amiloride has less effect on lithium clearance). Hypothyroidism is more common in women and doesn't require stopping lithium, add levothyroxine and reassess if lithium is ever discontinued. Cardiac effects include T-wave flattening/inversion (up to 30% of patients), AV block, and bradycardia, get a baseline ECG and cardiology input if the patient is over 40 or has cardiac disease. Late, benign effects include reversible leukocytosis, acne, folliculitis, and weight gain.
Toxicity risk rises above 1.5 mEq/L(lower in older adults). Rough staging: 1.5-2.0mild-moderate (diarrhea, vomiting, drowsiness, muscle weakness, incoordination); 2.0-2.5moderate-severe (ataxia, blurred vision, tinnitus, ECG changes); >2.5-3.0severe/neurologic (arrhythmias, seizures, coma, permanent neurologic damage, kidney injury). If toxicity is suspected, stop lithium and send the patient to the ED immediately.Consider hemodialysis if lithium-naive with a level ≥4 mEq/L, or if previously stable on lithium with a level ≥2.5 mEq/L and moderate-severe neurologic toxicity; continue dialysis until the level is below 1 mEq/L drawn 8 hours after the last session.
Predisposing factors for toxicity:sodium restriction, dehydration, vomiting/diarrhea, age >50, heart failure, cirrhosis, interacting medications, heavy exercise, saunas, hot weather, and fever. Counsel patients to maintain steady sodium and fluid intake and avoid excess alcohol or caffeine.
Syndrome of Irreversible Lithium-Effectuated NeuroToxicity. Permanent neurologic damage, persistent memory impairment, ataxia, dysarthria, tremor, can follow either acute or chronic toxicity, even after the lithium level normalizes and the drug is stopped. It's rare but it's why toxicity is treated as an emergency rather than "just adjust the dose."
Interactions that raise lithium levels:thiazide diuretics, NSAIDs, ACE inhibitors, and salt-restricted diets. Neurotoxicity risk (without necessarily raising the level):antipsychotics, methyldopa, metronidazole, phenytoin, verapamil; calcium channel blockers as a class are best avoided with lithium for this reason. Less likely to interfere:acetaminophen, aspirin, loop diuretics. Lower levels:caffeine and theophylline enhance renal lithium elimination. Activated charcoal does not bind lithium, so it's useless in an overdose.
A patient stable on lithium for years starts a thiazide for new hypertension, then develops a GI illness with vomiting and diarrhea. A few days later: worsening tremor, ataxia, confusion, blurred vision. That's chronic toxicity from the thiazide plus volume depletion stacking on top of each other, not a dose that "was always too high." It's one of the most common ways this topic gets tested.
Pregnancy:lithium clearance increases 50-100%, monitor levels monthly, then weekly the month before delivery; reduce to prepregnancy dose at delivery and maintain hydration. First-trimester exposure raises the risk of Ebstein anomaly (roughly 1-10.78:1000) and neural tube defects (~13.4:1000); use the lowest effective dose to also limit "floppy infant" syndrome, neonatal hypothyroidism, and goiter. Breastfeeding on lithium is usually discouraged.
As effective as lithium and olanzapine for mania, and can outperform lithium specifically for rapid cycling, mixed states, and bipolar disorder with comorbid substance use. Reduces recurrence of manic, depressive, and mixed episodes.
Combinations:lithium plus valproate can be synergistic in treatment-refractory, rapid-cycling, or mixed-feature patients, and the combination is effective maintenance therapy for Bipolar I, but requires level monitoring of both drugs given the interaction potential. SGAs can be added for breakthrough mania but raise sedation and weight gain risk. Combining valproate with lamotrigine increases rash, ataxia, tremor, sedation, and fatigue, this pairing needs a dose adjustment (see lamotrigine below).
Dose-related adverse effects:GI upset, fine tremor, sedation, help with food, a slower titration, or switching to the ER formulation; bedtime dosing minimizes daytime sedation. Other effects: ataxia, lethargy, alopecia, pruritus, prolonged bleeding, transient LFT elevation, weight gain, hyperammonemia. Thrombocytopenia can occur at higher doses and usually normalizes with a dose reduction. Fatal necrotizing hepatitis is rare and idiosyncratic, mostly in children on multiple anticonvulsants. Life-threatening pancreatitis has also been reported.
Dosing:healthy inpatient adults in acute mania start at ~20 mg/kg/day divided q12h, adjusted 250-500 mg every 1-3 days as tolerated, max 60 mg/kg/day. Outpatients, hypomanic/euthymic patients, or older adults start lower (5-10 mg/kg/day) and titrate more slowly. ER divalproex can go once daily but has ~15% lower bioavailability than immediate-release.
Levels:target 50-125 mcg/mL drawn 12h post-dose. Cyclothymia and Bipolar II often respond at the lower end; more severe presentations may need up to 150 mcg/mL. Levels are most useful for checking adherence or toxicity, not for fine-tuning efficacy.
Avoid in pregnancy and in patients of childbearing potential when possible, this is the most teratogenic mood stabilizer, with a ~4% first-trimester neural tube defect risk. If used, add folic acid. Breastfeeding is compatible, but mother and infant need identical lab monitoring.
Carbamazepineis usually reserved for after lithium or divalproex failure, largely because of its interaction burden. Patients with a history of head trauma, anxiety, or substance use may respond particularly well. It has real acute antimanic effects, but long-term effectiveness and depression efficacy are less established than lithium's. Often combined with lithium, valproate, or antipsychotics for refractory mania.
It induceshepatic metabolism of antidepressants, other ASMs, antipsychotics, and oral contraceptives (patients need alternative contraception). CYP3A4 inhibitors added to carbamazepine (cimetidine, diltiazem, erythromycin, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, verapamil) can cause carbamazepine toxicity. Combining with valproate raises carbamazepine's freelevel, so the carbamazepine dose usually needs to come down. Never combine with clozapine, additive bone marrow suppression risk.
Dosing:inpatients start 400-600 mg/day divided with meals, increasing 200 mg/day every 2-4 days up to 1200-1600 mg/day; outpatients start lower and titrate more slowly. Levels can fallduring the first month from CYP3A4 autoinduction, requiring a dose bump. Check levels every 1-2 weeks for the first 2 months, then every 6-12 months at maintenance, target 6-10 mcg/mL (some need 12-14).
Required in patients of Asian ancestry before starting carbamazepine, to screen for elevated Stevens-Johnson syndrome/TEN risk.
Oxcarbazepineis a third-line mania option and is notrecommended for bipolar depression. Start 150-300 mg BID, increase 300-600 mg every 3-6 days to a max of 1200 mg/day. Watch for hyponatremia, more common with oxcarbazepine than carbamazepine, and stop immediately at the first sign of a skin reaction. It's a CYP2C19 inhibitor and 3A4/5 inducer, so it also reduces oral contraceptive efficacy, but unlike carbamazepine it does notautoinduce its own metabolism.
Has both antidepressant and mood-stabilizing properties and can augment lithium or valproate. It carries a low risk of switching a patient into mania, but it's less effective for acute maniathan lithium or valproate. Its real strength is maintenance, particularly preventing bipolar depression relapse in treatment-resistant Bipolar I and II. It is not FDA-approved for acute bipolar depression treatment, only for maintenance.
Common effects: headache, nausea, dizziness, ataxia, diplopia, drowsiness, tremor, and a maculopapular rash. Most rashes resolve with continued therapy, but some progress to Stevens-Johnson syndrome, discontinue immediately if the rash is diffuse, involves mucous membranes, or comes with fever or sore throat. Rash risk climbs with concomitant valproate, rapid dose escalation, or exceeding the recommended starting dose.
Valproate roughly doubles lamotrigine levelsby inhibiting its glucuronidation. When combining the two, dose lamotrigine at about half the standard doseand titrate even more slowly than usual.
Standard maintenance titration(no interacting drugs): 25 mg/day for weeks 1-2, 50 mg/day for weeks 3-4, 100 mg/day for week 5, then 200 mg/day. Usual range 50-300 mg/day, with 200 mg/day the typical target (100 mg/day if combined with valproate, 400 mg/day if combined with carbamazepine, since carbamazepine induces its clearance). Anyone who stops for more than a few days has to restart the full titration schedule from the beginning, don't just resume at the prior dose.
Both first-generation (fluphenazine, haloperidol) and second-generation antipsychotics (aripiprazole, asenapine, clozapine, lurasidone, quetiapine, risperidone, ziprasidone) work as monotherapy or add-on therapy for acute mania, especially when agitation, aggression, or psychosis are present. Quetiapine and lurasidonehave the strongest trial support as monotherapy or adjunctive treatment for bipolar depression; combined fluoxetine/olanzapinealso has depression evidence. For maintenance monotherapy: oral aripiprazole, olanzapine, sublingual asenapine, and long-acting injectable risperidone are all effective options. First-generation depot antipsychotics (haloperidol decanoate, fluphenazine decanoate) are useful maintenance choices specifically for nonadherent or treatment-resistant patients.
Controlled studies show lithium or valproate plusan antipsychotic outperforms any single agent alone for acute mania. Clozapine monotherapyhas real acute and long-term mood-stabilizing effects in refractory bipolar disorder, but demands regular WBC monitoring for agranulocytosis. Acute mania often needs a higher initial antipsychotic dose (e.g., olanzapine 20 mg/day); once mania is controlled, usually within 7-28 days, taper the antipsychotic and maintain on mood-stabilizer monotherapy where possible, to limit long-term exposure to obesity, type 2 diabetes, hyperlipidemia, hyperprolactinemia, and tardive dyskinesia.
Benzodiazepines(high-potency agents like clonazepam and lorazepam) are common short-term adjuncts, or alternatives, for acute mania, agitation, anxiety, panic, and insomnia, especially in patients who can't tolerate a mood stabilizer. IM lorazepam is useful for acute agitation, and lorazepam specifically is the agent recommended for catatonia. Taper gradually when no longer needed to avoid withdrawal. A history of substance use disorder is a relative contraindication to long-term use.
| Drug | What to check | Schedule / trigger |
|---|---|---|
| Lithium | Serum level (12h trough), renal function, thyroid function, ECG (if >40y or cardiac disease), electrolytes | Level 1-2x/wk initially → q2wks once stable → q3-6mo; renal q2-3mo x6mo then q6-12mo; thyroid 1-2x in first 6mo then q6-12mo |
| Valproate | Serum level (12h trough), CBC/platelets, LFTs, weight | Baseline, then closely during first 3-6mo especially if bruising/bleeding; d/c if platelets <100,000/mm³ or prolonged bleeding time |
| Carbamazepine | CBC with differential/platelets, LFTs, serum level, electrolytes (elderly), HLA-B*1502 (Asian ancestry) | Baseline, then q2wks x first 2mo, then q3mo if normal; d/c if platelets <100,000/mm³, WBC <3000/mm³, or marrow/liver dysfunction evidence |
| Oxcarbazepine | Serum sodium | Especially first 3 months, or with concomitant sodium-lowering drugs; watch for hypersensitivity if prior carbamazepine reaction (25-30% cross-reactivity) |
| Lamotrigine | Renal/hepatic function if impaired, skin exam | Rash risk window is 2-8 weeks after starting or after any dose increase |
| SGAs | Fasting glucose, lipids, weight/BMI | Baseline, then 6-12 months; monitor weight closely early in therapy |
| All patients | Mood chart (episode type, length, stressors), adherence, suicidal ideation, standardized rating scales | Every visit; missed doses are the top cause of relapse |