Drug Selection and Use
Choice of drug can be difficult because all drugs have significant adverse effects, drug interactions are common, and no drug is universally effective. Selection should be based on what has previously been effective and well-tolerated in a given patient. If there is no prior experience (or it is unknown), choice is based on the patient’s medical history (vis-à-vis the adverse effects of the specific mood stabilizer) and the severity of symptoms.
For severe manic psychosis, in which immediate patient safety and management is compromised, urgent behavioral control usually requires a sedating 2nd-generation antipsychotic, sometimes supplemented initially with a benzodiazepine such as lorazepam or clonazepam 2 to 4 mg IM or orally three times a day.
For less severe acute episodes in patients without contraindications (eg, renal disorders), lithium is a good first choice for both mania and depressive episodes. Because its onset is slow (4 to 10 days), patients with significant symptoms may also be given an anticonvulsant or a 2nd-generation antipsychotic.
For patients with depression, lamotrigine may be a good choice of anticonvulsant.
For bipolar depression, the best evidence suggests using quetiapine or lurasidone alone or the combination of fluoxetine and olanzapine.
Once remission is achieved, preventive treatment with mood stabilizers is indicated for all bipolar I patients (bipolar I is defined by the presence of at least one full-fledged manic episode and usually depressive episodes). If episodes recur during maintenance treatment, clinicians should determine whether adherence is poor and, if so, whether nonadherence preceded or followed recurrence. Reasons for nonadherence should be explored to determine whether a change in mood stabilizer type or dosing would render treatment more acceptable.
Lithium
As many as two thirds of patients with uncomplicated bipolar disorder respond to lithium, which attenuates bipolar mood swings but has no effect on normal mood.
Whether lithium or another mood stabilizer is being used, breakthroughs are more likely in patients who have mixed states, rapid-cycling forms of bipolar disorder (usually defined as ≥ 4 episodes/yr), comorbid anxiety, substance use disorder, or a neurologic disorder.
Lithium carbonate is started at 300 mg orally two or three times a day and titrated, based on steady-state blood levels and tolerance, to a range of 0.8 to 1.2 mEq/L (0.8 to 1.2 mmol/L). Levels should be drawn after 5 days at a stable dose and 12 hours after the last dose. Target drug levels for maintenance are lower, about 0.6 to 0.7 mEq/L (0.6 to 0.7 mmol/L). Higher maintenance levels are more protective against manic (but not depressive) episodes but have more adverse effects. Adolescents, whose glomerular function is excellent, need higher doses; older patients need lower doses.
Lithium can cause sedation and cognitive impairment directly or indirectly (by causing hypothyroidism) and often exacerbates acne and psoriasis. The most common acute, mild adverse effects are fine tremor, fasciculation, nausea, diarrhea, polyuria, polydipsia, and weight gain (partly attributed to drinking high-calorie beverages). These effects are usually transient and often respond to decreasing the dose slightly, dividing the dose (eg, three times a day), or using slow-release forms. Once dosage is established, the entire dose should be given after the evening meal. This dosing may improve adherence. A beta-blocker (eg, atenolol 25 to 50 mg orally once a day) can control severe tremor; however, some beta-blockers (eg, propranolol) may worsen depression.
Acute lithium toxicity is manifested initially by gross tremor, increased deep tendon reflexes, persistent headache, vomiting, and confusion and may progress to stupor, seizures, and arrhythmias. Toxicity is more likely to occur in the following:
Thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin may contribute to hyperlithemia. Lithium blood levels should be measured every 6 months and whenever the dose is changed.
Long-term adverse effects of lithium include
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Hypothyroidism, particularly when there is a family history of hypothyroidism
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Renal damage involving the distal tubule that appears after ≥ 15 years of lithium treatment
Therefore, thyroid-stimulating hormone (TSH) levels should be monitored when lithium is started and annually thereafter if there is a family history of thyroid dysfunction or every other year for all other patients. Levels should also be measured whenever symptoms suggest thyroid dysfunction (including when mania recurs) because hypothyroidism may blunt the effect of mood stabilizers. Blood urea nitrogen (BUN) and creatinine should be measured at baseline, 2 or 3 times during the first 6 months, and then once or twice a year. Cumulative dose is a risk factor for renal damage so the minimal effective dose for effective prophylaxis should be used (1–3).
Lithium references
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1. Presne C, Fakhouri F, Noël LH, et al: Lithium-induced nephropathy: Rate of progression and prognostic factors. Kidney Int 64 (2):585–592, 2003. doi: 10.1046/j.1523-1755.2003.00096.x.
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2. Pawar AS, Kattah AG: Lithium-induced nephropathy. N Engl J Med 378 (11):1042, 2018. doi: 10.1056/NEJMicm1709438.
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3. McKnight RF, Adida M, Stockton S, et al: Lithium toxicity profile: A systematic review and meta-analysis. Lancet 379 (9817):721-728, 2012. doi: 10.1016/S0140-6736(11)61516-X.
Anticonvulsants
Anticonvulsants that act as mood stabilizers, especially valproate and carbamazepine, are often used for acute mania and for mixed states (mania and depression). Lamotrigine is effective for mood-cycling and for depression. The precise mechanism of action for anticonvulsants in bipolar disorder is unknown but may involve gamma-aminobutyric acid mechanisms and ultimately G-protein signaling systems. Their main advantages over lithium include a wider therapeutic margin and lack of renal toxicity.
For valproate, a loading dose of 20 to 30 mg/kg is given, then 250 to 500 mg orally three times a day (extended-release formulation can be used); target blood levels are between 50 and 125 μg/mL (347 and 867 micromol/L). This approach does not result in more adverse effects than does gradual titration. Adverse effects include nausea, headache, sedation, dizziness, and weight gain; rare serious effects include hepatotoxicity and pancreatitis.
Carbamazepine should not be loaded; it should be started at 200 mg orally twice a day and be increased gradually in 200-mg/day increments to target levels between 4 and 12 μg/mL (17 and 51 micromol/L; maximum, 800 mg twice a day). Adverse effects include nausea, dizziness, sedation, and unsteadiness. Very severe effects include aplastic anemia and agranulocytosis.
Lamotrigine is started at 25 mg orally once a day for 2 weeks, then 50 mg once a day for 2 weeks, then 100 mg a day for 1 week, and then can be increased by 50 mg each week as needed up to 200 mg once a day. Dosage is lower for patients taking valproate and higher for patients taking carbamazepine. Lamotrigine can cause rash and, rarely, the life-threatening Stevens-Johnson syndrome, particularly if the dosage is increased more rapidly than recommended. While taking lamotrigine, patients should be encouraged to report any new rash, hives, fever, swollen glands, sores in the mouth and on the eyes, and swelling of the lips or tongue.
Antipsychotics
Acute manic psychosis is being increasingly managed with 2nd-generation antipsychotics, such as
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Risperidone (usually 2 to 3 mg orally twice a day)
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Olanzapine (usually 5 to 10 mg orally twice a day)
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Quetiapine (200 to 400 mg orally twice a day)
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Ziprasidone (40 to 80 mg orally twice a day)
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Aripiprazole (10 to 30 mg orally once/day)
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Cariprazine (1.5 to 3.0 mg once/day)
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Lurasidone (20 to 120 mg once/day)
In addition, evidence suggests that these drugs may enhance the effects of mood stabilizers after the acute phase.
Although any of these drugs may have extrapyramidal adverse effects and cause akathisia, risk is lower with more sedating drugs such as quetiapine and olanzapine. Less immediate adverse effects include substantial weight gain and development of the metabolic syndrome (including weight gain, excess abdominal fat, insulin resistance, and dyslipidemia); risk may be lower with the least sedating 2nd-generation antipsychotics, ziprasidone and aripiprazole.
For extremely hyperactive psychotic patients with poor food and fluid intake, an antipsychotic given IM plus supportive care in addition to lithium or an anticonvulsant may be appropriate.
Antidepressants
Specific antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs]) are sometimes added for severe depression, but their effectiveness is controversial; they are generally not recommended as sole therapy for depressive episodes, though there is evidence than an SSRI (specifically sertraline) may be safe and effective as monotherapy for bipolar 2 depression (1).
Antidepressants
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Drug |
Starting Dose* |
Therapeutic Dosage Range |
Precautions |
SSRIs |
Cause discontinuation symptoms† if stopped abruptly (less likely with fluoxetine) |
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Citalopram |
20 mg once/day |
20–40 mg |
Lower potential for drug interactions because it has less effect on CYP450 isoenzymes Risk of QT-interval prolongation that limits doses to ≤ 40 mg/day |
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Escitalopram |
10 mg once/day |
10–20 mg |
Lower potential for drug interactions because it has less effect on CYP450 isoenzymes |
|
Fluoxetine |
10 mg once/day |
20–60 mg |
Has very long half-life Less likely to cause discontinuation symptoms† The only antidepressant proven effective in children |
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Fluvoxamine |
50 mg once/day |
100–200 mg |
Can cause clinically significant elevation of theophylline, warfarin, and clozapine blood levels Has potential for interactions between its active metabolites and HCAs, carbamazepine, antipsychotics, or type 1C antiarrhythmics Has CYP450 profile similar to fluoxetine |
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Paroxetine |
20 mg once/day 25 mg CR once/day |
20–50 mg 25–62.5 mg CR |
Has potential for interactions between its active metabolites and HCAs, carbamazepine, antipsychotics, or type 1C antiarrhythmics Has CYP450 profile similar to fluoxetine Of SSRIs, may cause the most weight gain |
|
Sertraline |
50 mg once/day |
50–200 mg |
Of SSRIs, has highest incidence of loose stools |
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Vilazodone |
10 mg orally once/day for 7 days, then increase to 20 mg daily for 7 days |
10–40 mg (titrate by 5–10 mg every 7 days) |
May increase risk of bleeding if the drug is taken with aspirin, other NSAIDs, or other drugs that affect coagulation Should not be stopped abruptly; reduce dose gradually |
Serotonin modulators (5-HT2 blockers) |
Cause discontinuation symptoms† if stopped abruptly |
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Mirtazapine |
15 mg once/day |
15–45 mg |
Causes weight gain and sedation Has fewer sexual adverse effects than SSRIs and serotonin- norepinephrine reuptake inhibitors |
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Trazodone |
50 mg three times a day |
150–300 mg |
May cause priapism and sedation May cause orthostatic hypotension |
Serotonin- norepinephrine reuptake inhibitors |
Cause discontinuation symptoms† if stopped abruptly |
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Desvenlafaxine |
50 mg once/day |
50–100 mg |
May increase BP or HR (control BP before initiating the drug and monitor BP and HR while patients are taking the drug) |
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Duloxetine |
20 mg twice a day |
60–120 mg |
Modest dose-dependent increase in systolic and diastolic BP May cause mild urinary hesitancy in males Less potential for drug-drug interactions because it has less effect on CYP450 isoenzymes |
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Levomilnacipran |
20 mg once/day for 2 days, then 40 mg once/day |
40–120 mg (increase dose in increments of 40 mg/day at intervals of ≥ 2 days; not to exceed 120 mg/day) |
May increase BP or HR (control BP before initiating the drug and monitor BP and HR while patients are taking the drug) May increase risk of bleeding if the drug is taken with aspirin, other NSAIDs, or anticoagulants Can affect urinary hesitation or retention (caution required in patients with obstructive urinary disorders; stop the drug if symptoms develop) |
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Venlafaxine |
25 mg three times/day 37.5 mg XR once/day |
75–375 mg 72–225 mg XR |
Modest dose-dependent increase in diastolic BP Dual norepinephrine and 5-HT reuptake effect at about 150 mg Rarely, increase in systolic BP (not dose-dependent) If stopped, should be tapered slowly Less potential for drug-drug interactions because it has less effect on CYP450 isoenzymes |
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Vortioxetine |
5–10 mg once/day |
10–20 mg |
May increase risk of bleeding if the drug is taken with aspirin, other NSAIDs, or other drugs that affect coagulation or bleeding |
Norepinephrine- dopamine reuptake inhibitor |
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Bupropion |
100 mg twice/day 150 mg SR once/day 150 mg XL once/day |
200–450 mg |
Contraindicated in patients who have bulimia or who are seizure-prone May interact with HCAs, increasing the risk of seizures May cause dose-dependent recent memory loss |
Heterocyclics |
Contraindicated in patients with coronary artery disease, certain arrhythmias, angle-closure glaucoma, benign prostatic hypertrophy, or esophageal hiatus hernia Can cause orthostatic hypotension leading to falls and fractures, potentiate the effect of alcohol, and raise the blood level of antipsychotics Cause discontinuation symptoms† if stopped abruptly With significant overdose, potentially lethal |
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Amitriptyline |
50 mg once/day |
150–300 mg |
Causes weight gain |
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Amoxapine |
50 mg twice/day |
150–400 mg |
Can have extrapyramidal adverse effects |
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Clomipramine |
25 mg once/day |
100–250 mg |
Lowers seizure threshold at doses of > 250 mg/day |
|
Desipramine |
25 mg once/day |
150–300 mg |
— |
|
Doxepin |
25 mg once/day |
150–300 mg |
Causes weight gain |
|
Imipramine |
25 mg once/day |
150–300 mg |
May cause excessive sweating and nightmares |
|
Maprotiline |
75 mg once/day |
150–225 mg |
Increased risk of seizures with rapid dose escalation at high doses |
|
Nortriptyline |
25 mg once/day |
50–150 mg |
Effective within the therapeutic window |
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Protriptyline |
5 mg three times/day |
15–60 mg |
Has long half-life (74 hours) |
|
Trimipramine |
50 mg once/day |
150–300 mg |
Causes weight gain |
MAOIs |
Serotonin syndrome possible when taken with an SSRI Hypertensive crisis possible when taken with other antidepressants, sympathomimetic or other selective drugs, or certain foods and beverages With significant overdose, potentially lethal |
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Isocarboxazid |
10 mg twice/day |
30–60 mg |
Causes orthostatic hypotension |
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Phenelzine |
15 mg three times/day |
45–90 mg |
Causes orthostatic hypotension |
|
Selegiline, transdermal |
6 mg once/day |
12 mg |
Can cause application site reactions and insomnia |
|
Tranylcypromine |
10 mg twice/day |
30–60 mg |
Causes orthostatic hypotension Has amphetamine-type stimulant effects and modest abuse potential |
Melatonergic antidepressant |
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Agomelatine (5-HT2C receptor antagonist) |
25 mg once/day at bedtime |
25–50 mg |
Should be stopped immediately if symptoms or signs of potential liver injury develop or if serum aminotransferases increase to > 3 times the upper limit of normal |
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* All drugs are given orally except for transdermal selegiline. |
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† Discontinuation symptoms include nausea, chills, muscle aches, dizziness, anxiety, irritability, insomnia, and fatigue. |
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BP= blood pressure; CR = continuous release; CYP450 = cytochrome P-450 system; HCAs = heterocyclic antidepressants; HR = heart rate; 5-HT = 5-hydroxytryptamine ( serotonin); MAOIs = monoamine oxidase inhibitors; NSAID = nonsteroidal anti-inflammatory drug; SR = sustained release; SSRI = selective serotonin; XL = extended release; XR = extended release. |
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Antidepressants reference
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Gitlin MJ: Antidepressants in bipolar depression: An enduring controversy. Int J Bipolar Disord 6:25, 2018. doi: 10.1186/s40345-018-0133-9.
Precautions During Pregnancy
Lithium use during pregnancy has been associated with an increased risk of cardiovascular malformations (particularly Ebstein anomaly). However, the absolute risk of this particular malformation is quite low. Taking lithium during pregnancy appears to increase the relative risk of any congenital anomaly by about 2-fold, a risk similar to the 2- to 3-fold increased risk of congenital anomalies associated with use of carbamazepine or lamotrigine and is substantially lower than the risk associated with use of valproate.
With valproate, risk of neural tube defects and other congenital malformations appears to be 2 to 7 times higher than that with other commonly used anticonvulsants. Valproate increases the risk of neural tube defects, congenital heart defects, genitourinary anomalies, musculoskeletal abnormalities, and cleft lip or palate. Also, cognitive outcomes (eg, IQ scores) in children of women who took valproate during pregnancy are worse than those with other anticonvulsants; risk appears to be dose-related. Valproate also appears to increase risk of attention-deficit/hyperactivity disorder and autism spectrum disorders (1).
Extensive study of the use of 1st-generation antipsychotics and tricyclic antidepressants during early pregnancy has not revealed causes for concern. The same appears to be true of selective serotonin reuptake inhibitors (SSRIs), except for paroxetine. Data about the risks of 2nd-generation antipsychotics to the fetus are sparse as yet, even though these drugs are being more widely used for all phases of bipolar disorder.
Use of drugs (particularly lithium and SSRIs) before parturition may have postpartum effects on neonates.
Treatment decisions are complicated by the fact that with unplanned pregnancy, teratogenic effects may already have taken place by the time practitioners become aware of the issue. Consultation with a perinatal psychiatrist should be considered. In all cases, discussing the risks and benefits of treatment with patients is important.
Precautions during pregnancy reference
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1. Tomson T, Battino D, Perucca E: Valproic acid after five decades of use in epilepsy: Time to reconsider the indications of a time-honoured drug. Lancet Neurol 15 (2): 210–218, 2016. doi: 10.1016/S1474-4422(15)00314-2.
