What is the recommended approach for lithium augmentation with antipsychotics in treatment-resistant depression or bipolar disorder?

From the Guidelines

Lithium augmentation with antipsychotics is a recommended approach for treatment-resistant depression or bipolar disorder, particularly when patients have not responded adequately to monotherapy, as it can help stabilize mood and address manic or psychotic symptoms. The combination of lithium and antipsychotics such as quetiapine, olanzapine, or risperidone is particularly effective in bipolar disorder, as seen in studies like Pavuluri et al. (2004b [ct]), where risperidone in combination with either lithium or valproate appeared to be effective in an open-label, prospective trial. When initiating lithium augmentation, it is typically started at 300mg once or twice daily and gradually titrated to achieve therapeutic blood levels between 0.6-1.2 mEq/L, with most clinicians targeting 0.8-1.0 mEq/L for augmentation purposes, as suggested by the practice parameter for the assessment and treatment of children and adolescents with bipolar disorder 1. Some key points to consider when using lithium augmentation with antipsychotics include:

• Regular monitoring of lithium levels every 3-6 months once stabilized, along with thyroid function, renal function, and electrolytes
• The combination works synergistically, with lithium enhancing serotonergic and dopaminergic neurotransmission while modulating intracellular signaling pathways, complementing the receptor-blocking actions of antipsychotics
• This approach typically requires 2-6 weeks to demonstrate clinical improvement, and should be maintained for at least 6-12 months after symptom resolution before considering any medication adjustments. It's also important to note that polypharmacy is common in the treatment of bipolar disorder, with some patients taking five or more drugs 1, and that comorbid disruptive behavioral disorders and ADHD can predict a poorer response to treatment 1.

From the FDA Drug Label

As adjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar I disorder. (1.2) Efficacy was established in two 6-week clinical trials in adults (14.2).

• The recommended approach for lithium augmentation with antipsychotics in treatment-resistant depression or bipolar disorder is to use it as an adjunct to lithium in the treatment of manic or mixed episodes associated with bipolar I disorder 2.
• Lithium is indicated in the treatment of manic episodes of Bipolar Disorder and as a maintenance treatment for individuals with a diagnosis of Bipolar Disorder 3.
• However, the provided drug labels do not explicitly address the use of lithium augmentation with antipsychotics in treatment-resistant depression.
• For treatment-resistant depression, the label mentions the use of Symbyax (olanzapine and fluoxetine in combination), but it does not provide information on lithium augmentation with antipsychotics 2.

From the Research

Lithium Augmentation with Antipsychotics

• Lithium augmentation with antipsychotics is a recommended approach for treatment-resistant depression or bipolar disorder, as it has been shown to be effective in long-term maintenance treatment 4.
• The atypical antipsychotics risperidone, olanzapine, quetiapine, and ziprasidone have been found to be effective in combination with mood stabilizers for the treatment of bipolar disorder 4.
• Lithium augmentation has also been used to enhance the effectiveness of tricyclic and other antidepressants, monoamine oxidase inhibitors, and combinations of antipsychotics and antidepressants in the treatment of refractory depression 5.

Clinical Evidence

• A study comparing lithium and quetiapine augmentation for treatment-resistant depression found that quetiapine was more clinically effective and cost-effective than lithium over 12 months 6.
• Lithium augmentation has been shown to increase serotonin neurotransmission and has been found to be effective in the continuation treatment phase to prevent early relapses in patients with major depressive disorder 7.
• Clinical practice guidelines recommend lithium as a first-line intervention for maintenance treatment of bipolar disorder and for the treatment of mania, with relatively modest support for the management of acute bipolar depression 8.

Mechanisms and Side Effects

• The mechanism of action of lithium augmentation is thought to involve a synergistic action of lithium and the antidepressant on brain serotonin pathways 7.
• Lithium augmentation has been associated with side effects such as peripheral weakness, severe fine tremor, and neurotoxicity, which can necessitate discontinuation of treatment 5.
• The atypical antipsychotics used in combination with lithium have relatively mild side effect profiles, although some combinations have been associated with excessive weight gain 4.