Drug Selection and Use
Choice of drug treatment for bipolar disorders Bipolar Disorders Bipolar disorders are characterized by episodes of mania and depression, which may alternate, although many patients have a predominance of one or the other. Exact cause is unknown, but heredity... read more 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.
(See also Bipolar Disorders Bipolar Disorders Bipolar disorders are characterized by episodes of mania and depression, which may alternate, although many patients have a predominance of one or the other. Exact cause is unknown, but heredity... read more .)
For severe manic psychosis, in which immediate patient safety and management is compromised, urgent behavioral control usually requires a sedating 2nd-generation antipsychotic Second-generation antipsychotics Antipsychotic drugs are divided into conventional antipsychotics and 2nd-generation antipsychotics (SGAs) based on their specific neurotransmitter receptor affinity and activity. SGAs may offer... read more , sometimes supplemented initially with a benzodiazepine such as lorazepam or clonazepam 2 to 4 mg IM or orally 3 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, cariprazine, 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). 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. Patients with a family history of typical bipolar disorders are more likely to respond to lithium.
Whether lithium or another mood stabilizer is being used, breakthroughs are more likely in patients who have mixed states Mixed features Bipolar disorders are characterized by episodes of mania and depression, which may alternate, although many patients have a predominance of one or the other. Exact cause is unknown, but heredity... read more , rapid-cycling forms of bipolar disorder (usually defined as ≥ 4 episodes/year), comorbid anxiety Overview of Anxiety Disorders Everyone periodically experiences fear and anxiety. Fear is an emotional, physical, and behavioral response to an immediately recognizable external threat (eg, an intruder, a car spinning on... read more , substance use disorder Substance Use Disorders Substance use disorders are a type of substance-related disorder that involve a pathologic pattern of behaviors in which patients continue to use a substance despite experiencing significant... read more , or a neurologic disorder.
Lithium carbonate is started at 300 mg orally 2 or 3 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 Hypothyroidism Hypothyroidism is thyroid hormone deficiency. It is diagnosed by clinical features such as a typical facial appearance, hoarse slow speech, and dry skin and by low levels of thyroid hormones... read more 
) and often exacerbates acne Acne Vulgaris Acne vulgaris is the formation of comedones, papules, pustules, nodules, and/or cysts as a result of obstruction and inflammation of pilosebaceous units (hair follicles and their accompanying... read more 
and psoriasis Psoriasis Psoriasis is an inflammatory disease that manifests most commonly as well-circumscribed, erythematous papules and plaques covered with silvery scales. Multiple factors contribute, including... read more 
. 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, 3 times a day), or using slow-release forms. Once dosage is established, the entire dose should be given after the evening meal. This once-daily dosing may improve adherence and possibly reduce renal toxicity. 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:
Older patients
Patients with decreased creatinine clearance
Those with sodium loss (eg, due to fever, vomiting, diarrhea, or use of diuretics)
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
Hypothyroidism Hypothyroidism Hypothyroidism is thyroid hormone deficiency. It is diagnosed by clinical features such as a typical facial appearance, hoarse slow speech, and dry skin and by low levels of thyroid hormones... read more
, particularly when there is a family history of hypothyroidismRenal 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 Hypothyroidism Hypothyroidism is thyroid hormone deficiency. It is diagnosed by clinical features such as a typical facial appearance, hoarse slow speech, and dry skin and by low levels of thyroid hormones... read more 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 Choice of drug treatment for bipolar disorders can be difficult because all drugs have significant adverse effects, drug interactions are common, and no drug is universally effective. Selection... read more ).
Lithium references
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
2. Pawar AS, Kattah AG: Lithium-induced nephropathy. N Engl J Med 378 (11):1042, 2018. doi: 10.1056/NEJMicm1709438
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 3 times a day (extended-release formulation can be used); target blood levels are between 50 and 125 mcg/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 mcg/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 Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common... read more 
, 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 Second-generation antipsychotics Antipsychotic drugs are divided into conventional antipsychotics and 2nd-generation antipsychotics (SGAs) based on their specific neurotransmitter receptor affinity and activity. SGAs may offer... read more , such as
Aripiprazole (10 to 30 mg orally once/day)
Cariprazine (1.5 to 3.0 mg once/day)
Lurasidone (20 to 120 mg once/day)
Olanzapine (usually 5 to 10 mg orally twice a day)
Quetiapine (200 to 400 mg orally twice a day)
Risperidone (usually 2 to 3 mg orally twice a day)
Ziprasidone (40 to 80 mg orally twice a 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 Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal fat), hypertension, abnormal fasting plasma glucose or insulin resistance, and dyslipidemia. Causes... read more (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 Drug Treatment of Depression Several drug classes and drugs can be used to treat depression: Selective serotonin reuptake inhibitors (SSRIs) Serotonin modulators (5-HT2 blockers) Serotonin-norepinephrine reuptake inhibitors... read more (eg, selective serotonin reuptake inhibitors Selective Serotonin Reuptake Inhibitors (SSRIs) Several drug classes and drugs can be used to treat depression: Selective serotonin reuptake inhibitors (SSRIs) Serotonin modulators (5-HT2 blockers) Serotonin-norepinephrine reuptake inhibitors... read more [SSRIs]) are sometimes added for severe depression, but their effectiveness is controversial; they are generally not recommended as monotherapy for depressive episodes, though there is evidence than an SSRI (specifically sertraline) may be safe and effective as monotherapy for bipolar II depression (1 Antidepressants references Choice of drug treatment for bipolar disorders can be difficult because all drugs have significant adverse effects, drug interactions are common, and no drug is universally effective. Selection... read more ). A series of small studies have indicated that tranylcypromine may be more effective than other antidepressants in the treatment of bipolar depression (2 Antidepressants references Choice of drug treatment for bipolar disorders can be difficult because all drugs have significant adverse effects, drug interactions are common, and no drug is universally effective. Selection... read more ).
Antidepressants references
1. Gitlin MJ: Antidepressants in bipolar depression: An enduring controversy. Int J Bipolar Disord 6:25, 2018. doi: 10.1186/s40345-018-0133-9
2. Heijnen WT, De Fruit J, Wiersma AI, et al: Efficacy of tranylcypromine in bipolar depression: A systematic review. J Clin Psychopharmacol 35: 700-705, 2015. doi: 10.1097/JCP.0000000000000409
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 Attention-Deficit/Hyperactivity Disorder (ADD, ADHD) Attention-deficit/hyperactivity disorder (ADHD) is a syndrome of inattention, hyperactivity, and impulsivity. The 3 types of ADHD are predominantly inattentive, predominantly hyperactive/impulsive... read more and autism spectrum disorders Autism Spectrum Disorders Autism spectrum disorders are neurodevelopmental disorders characterized by impaired social interaction and communication, repetitive and stereotyped patterns of behavior, and uneven intellectual... read more (1 Precautions during pregnancy references Choice of drug treatment for bipolar disorders can be difficult because all drugs have significant adverse effects, drug interactions are common, and no drug is universally effective. Selection... read more ).
Extensive study of the use of 1st-generation antipsychotics and tricyclic antidepressants during early pregnancy has not revealed causes for concern. There is evidence that 2nd-generation antipsychotics are safe as well with the possible exception of risperidone (2 Precautions during pregnancy references Choice of drug treatment for bipolar disorders can be difficult because all drugs have significant adverse effects, drug interactions are common, and no drug is universally effective. Selection... read more ). The same appears to be true of selective serotonin reuptake inhibitors Selective Serotonin Reuptake Inhibitors (SSRIs) Several drug classes and drugs can be used to treat depression: Selective serotonin reuptake inhibitors (SSRIs) Serotonin modulators (5-HT2 blockers) Serotonin-norepinephrine reuptake inhibitors... read more (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 references
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
2. Huybrechts KF, Hernandez-Diaz S, Patorno E, et al: Antipsychotic use in pregnancy and the risk for congenital malformations. JAMA Psychiatry 73(9):938-946, 2016. doi: 10.1001/jamapsychiatry.2016.1520
