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Day # 49: Medication Algorithms for Bipolar Disorder

Today will kick off our discussion of medications for bipolar disorder. We will discuss different classes of medications, outline a general treatment algorithm, and provide other clinical pearls.

Today's Content Level: Intermediate


•As we discussed in our last post, there are nonpharmacological strategies that can improve the chances of recovery, reduce relapse, and improve the quality of life of patients with bipolar disorder.

•Having said this, however, it is important to stress that drug treatment is the mainstay of therapy for mania and hypomania.

Medication classes that are proven to be effective in treating mania include:

  • "Mood stabilizers"

  • Antipsychotics

  • +/-Benzodiazapines

Mood stabilizers = Lithium, Valproic acid (Depakote), Carbamazepine (Tegretol), and Lamotrigine (Lamictal). Oxcarbazepine (Trileptal) is sometimes used off-label.

Antipsychotics with FDA approval for Bipolar = Aripiprazole (Abilify), Asenapine (Saphris), Cariprazine (Vraylar), Clozapine (Clozaril), Lurasidone (Latuda) (for bipolar depression), Quetiapine (Seroquel) (for mania or bipolar depression), Olanzapine (Zyprexa), Risperidone (Risperdal), Ziprasidone (Geodon). First generation antipsychotics (ex: Haloperidol) are also sometimes used.

•Why do antipsychotics work in bipolar disorder? From Maudsley, "It is not helpful to think of antipsychotic drugs as only having "antipsychotic actions". Individual antipsychotics variously possess sedative, anxiolytic, antimanic, mood-stabilizing, and antidepressant properties. Some antipsychotics (quetiapine and olanzapine) show ALL of these activities."

•Benzodiazepines = not a "core" treatment for mania, but they are sometimes used during acute mania to rapidly help control certain manic symptoms before the mood stabilizers take effect. These symptoms include insomnia, agitation, or restlessness. Taper off benzodiazepines once stabilized.


•Now we will discuss treatment guidelines and a general algorithm for the treatment of acute mania, maintenance, acute depression, breakthrough depression, and mixed episode. Keep in mind that specific drug choice is made difficult by the small number of direct comparisons and so no one drug can be recommended over another on efficacy grounds. However, conclusions can be made from multiple meta-analyses which allow indirect comparison. These suggest that first-line antipsychotics should include olanzapine, risperidone, haloperidol, aripiprazole, and quetiapine. 1

Acute Mania

  • Lithium +/- Antipsychotic +/- Benzodiazepine.

  • Valproate +/- Antipsychotic +/- Benzodiazepine.

  • Antipsychotic alone.

  • Combination of mood stabilizer and antipsychotic is recommended in severe manic episodes.

  • Intramuscular antipsychotics may be the preferred initial treatment in patients with psychosis or acute agitation.

  • Also be sure to, if possible, taper and discontinue medications known to contribute to mania such as antidepressants, steroids, stimulants, etc.

  • Second line options include carbamazepine, oxcarbamazepine, lurasidone, and asenapine.

  • If using antipsychotic as an adjunct then taper after 3-6 months of stability and no psychotic symptoms.

"Breakthrough" Mania

  • Those who are on appropriate treatment but still develop manic episode.

  • Check medication serum levels if on mood stabilizer (ensures treatment adherence and helps with dose changes).

  • Add antipsychotic or benzodiazepine to the mood stabilizer.

  • Consider ECT if treatment refractory. Combination therapy (mood stabilizer + antipsychotic) should be considered before ECT. Some patients require more treatments of ECT (up to 20) than for depression.

Acute depression

Use of standard antidepressants may induce mania in those with or without diagnosis of bipolar disorder (6–8% of patients with MDD will switch to hypomania/mania). 2 Risk is higher with TCAs and younger patients. For this reason we typically avoid antidepressants with the exception of the approved combination of olanzapine + fluoxetine. Treatment options for acute depression include:

  • Lithium +/- lamotrigine

  • Valproic acid

  • Quetiapine (FDA approved for bipolar depression)

  • Olanzapine + fluoxetine (FDA approved for bipolar depression)

  • Also be sure to, if possible, taper and discontinue medications known to contribute to depression in these patients to include steroids, beta blockers, varenicline, statins, OCPs, hormone replacement, etc...

  • Second line options include Lurasidone (FDA approved for bipolar depression) or ECT. Controversial use of SSRIs, SNRIs, MAOIs, and TCAs.

"Breakthrough" depression

  • Ensure levels of medication are therapeutic (Ex: Lithium or Valproate).

  • Add second generation antipsychotic such as olanzapine or quetiapine.

  • Consider ECT if refractory.

Mixed episode

Patient is experiencing both mania and depression simultaneously or in quick sequence. Recommended treatments during this state include:

  • Olanzapine or quetiapine.

  • Valproic acid monotherapy.

  • Evidence that lithium is less effective in mixed episodes. 3

Maintenance Treatment

First-line medications for maintenance therapy are similar for both classes of bipolar disorder (I and II). The choice of medication for maintenance therapy should be guided by the patient's comorbidities and tolerance to the side effect profile (ex: avoid lithium in renal impairment and avoid valproate in liver disease). First-line options include:

  • *Lithium

  • Valproic acid

  • Lamotrigine

  • Olanzapine

  • Aripirprazole

  • Quetiapine

  • *Lithium has a one distinct advantage in that it is the only medication with robust evidence to show that it decreases the risk of suicide. 4 Some studies show a reduction of greater than 50%.


Now that we have a good baseline for the treatment of bipolar disorder we can start talking in detail about specific medications within the mood stabilizer class. We will discuss their mechanism of action, clinical indications, side effects, and prescriber tips. We previously discussed antipsychotic medications in great detail (see day 12, 15, 17, and 18) so feel free to check out those posts if you are not following the curriculum in order.

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