David N. Osser, MD

A recent study found a 5.1% prevalence rate of tardive dyskinesia (TD) in patients with bipolar disorder (n = 1074) treated at Mayo Clinic and other sites in the Bipolar Disorder Biobank research collaborative.

 Investigators considered this rate a likely underestimate because milder cases may not have been diagnosed or reported. This study served as a sobering reminder of the significant frequency of this disfiguring and sometimes disabling adverse effect, which can be irreversible.

The study results were consistent with previously identified TD rates from second-generation antipsychotics (SGAs) found in meta-analyses—for example, a study by Carbon and colleagues

 that found an annualized rate of 2.6% per year. Risk factors that increase the rate include use in mood disorders, older individuals, women, those with alcohol use disorder, those with diabetes and cigarette dependence, and those who use anticholinergic drugs.

Additionally, a second meta-analyses by Carbon et al found a significantly greater risk of TD in participants who were actively taking a first-generation antipsychotic (FGA) compared with an SGA.

 The investigators analyzed 41 studies, which included 11,493 participants on antipsychotic medications and demonstrated an overall prevalence of TD in 25.3% of participants. Participants taking FGAs had a 30.0% prevalence of TD, while participants taking SGAs had a 20.7% prevalence of TD. The rate was 7.2% in the small number of studies (N = 4) involving patients who had only been on SGAs.

There are now 10 SGAs that are US Food and Drug Administration (FDA)–approved for acute mania, bipolar depression, and/or maintenance treatment in bipolar disorder, and their use has increased 4-fold in recent years.

 Notably, it still seems common for haloperidol to be used in managing severe mania; this puts those patients at greater risk for later TD even if they are switched to and maintained on SGAs.

The patients in the new study were on antipsychotics for a mean of 18 years, and the mean dose was equivalent to about 6 mg of haloperidol;
78% of their trials were with SGAs. Bipolar I disorder was associated with greater risk, probably because individuals with bipolar I disorder were more likely to receive antipsychotics.

The widely accepted Schooler and Kane criteria for diagnosing TD require ruling out other potential causes of the movements, some of which are poorly fitting dentures or other dental problems, parkinsonian symptoms, restless leg syndrome, and Huntington and Wilson diseases.

 Then, using the Abnormal Involuntary Movement Scale, there should be 1 body area with a score of at least 3 (moderate severity) or 2 areas with mild movements (score of 2). The patient should have been taking an antipsychotic for at least 3 months.

There are alternative FDA-approved treatments for long-term maintenance of patients with bipolar disorder that would involve minimal risk of this adverse effect, including lithium and lamotrigine. (Reminder: Valproate and carbamazepine have not been approved for maintenance treatment.) Informed consent discussions of treatment options should certainly include the potential risk of TD with antipsychotics, but it seems (from consulting on many bipolar cases) that this often does not occur. There are other significant adverse effects from SGAs including drug-induced parkinsonism, akathisia, dystonias, significant weight gain, prolactin elevation,

 hyperlipidemia, hyperglycemia, onset of type 2 diabetes, and more.

Regarding treatment of TD, we now have 2 FDA-approved options: deutetrabenazine and valbenazine. They are expensive, and in some settings—including certain VA hospitals—they still require off-formulary approval. According to 1 meta-analysis of efficacy, valbenazine seemed to have somewhat more efficacy with a number needed to treat (NNT) of 4 versus a NNT of 7 for deutetrabenazine,

 but the other analysis concluded that both had NNTs of 5.

 There have been no head-to-head comparisons. Deutetrabenazine has a short half-life and requires twice-daily dosing. Adverse effects of the 2 agents in studies of patients with TD seem comparable.

This article originally appeared on Psychiatric Times.

1. Gardea-Resendez M, Taylor-Desir MJ, Romo-Nava F, et al. Clinical phenotype of tardive dyskinesia in bipolar disorder. 

2. Carbon M, Kane JM, Leucht S, Correll CU. Tardive dyskinesia risk in first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. 

3. Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis. 

4. Rhee TG, Olfson M, Nierenberg AA, Wilkinson ST. 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. 

5. Schooler NR, Kane JM. Research diagnoses for tardive dyskinesia. 

6. Osser DN. Prolactin monitoring in first-episode psychotic patients. 

7. Solmi M, Pigato G, Kane JM, Correll CU. Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials. 

8. Citrome L. Valbenazine for tardive dyskinesia: a systematic review of the efficacy and safety profile for this newly approved novel medication—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? 

9. Citrome L. Deutetrabenazine for tardive dyskinesia: a systematic review of the efficacy and safety profile for this newly approved novel medication—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? 

Articles

A recent study highlights the significant frequency of the adverse effect.

Examining the Risk of Tardive Dyskinesia from Antipsychotics

Patients with bipolar disorder frequently receive polypharmacy, with up to 20% of patients getting 4 or more bipolar medications.

 Problematic drug-drug interactions occur often, impacting effectiveness or safety. They can be pharmacokinetic or pharmacodynamic. Yet these interactions receive little attention in the various practice guidelines and algorithms for the psychopharmacologic management of bipolar disorder. Some of these will be summarized here and in a subsequent article.

The antipsychotics that may cause weight gain—especially olanzapine, quetiapine, and clozapine—can cause even more weight gain when added to valproate.

Lithium is well known to interfere with the synthesis and release of thyroid hormones and, in the brain’s effort to compensate for this, thyroid-stimulating hormone will increase. Periodic monitoring is required. What is not so well known is that carbamazepine (CBZ) decreases T4, possibly by induction of the UGT metabolizing enzyme, which exacerbates or hastens the onset of hypothyroidism.

 Thus, the combination of lithium and CBZ may present additive risks. Quetiapine also has some evidence of causing thyroid dysfunction.

Lithium and anticonvulsants—especially valproate and CBZ—produce a metabolic-type or action tremor (ie, it is worse when doing an action like extending the arms—similar to benign familial essential tremors and tremors associated with hyperthyroidism, electrolyte abnormalities, and alcohol intoxication and withdrawal). When these medicines are used in combination, the severity or likelihood of tremor increases.

Antipsychotics—especially the older neuroleptics and risperidone/paliperidone—produce Parkinsonian tremors (resting tremors—slower than metabolic tremors, rhythmic, typically 4 to 6 beats per second).

 Lithium seems to increase antipsychotic-induced Parkinsonian tremors by a not-well-understood mechanism.

Antipsychotics that raise prolactin (eg, risperidone, paliperidone, and most first-generation antipsychotics) increase osteoporosis risk through a pharmacodynamic effect. For this reason and others, guidelines now recommend routine monitoring of prolactin change with all antipsychotics.

 Selective serotonin reuptake inhibitors (SSRIs), which are usually not recommended in bipolar patients but often used, also increase osteopenia by a different mechanism involving serotonin. With use of both agents, one can expect an additive harmful effect on bone metabolism.

CBZ also causes osteoporosis through its effect to induce the metabolism of vitamin D. Thus, the combination of CBZ with the prolactin-inducing antipsychotics or with SSRIs, or all three in combination, may produce additive bone harms over the long term.

 But here’s some good news: Lithium may protect from osteoporosis. The use of lithium in combination with antipsychotics and/or SSRIs could reduce the risk associated with the other agents. Better still: Use lithium alone for your patients with bipolar disorder if you can.

Watch out for drug-drug interactions with combinations involving ziprasidone, haloperidol, citalopram, escitalopram, quetiapine, risperidone, and lithium.

1. de Leon J, Spina E. Possible pharmacodynamic and pharmacokinetic drug-drug interactions that are likely to be clinically relevant and/or frequent in bipolar disorder. 

2. Osser DN. Neuroleptic induced pseudoparkinsonism. In: Joseph AB, Young RR, eds. 

Movement Disorders in Neurology and Neuropsychiatry, 2nd Edition

3. Osser DN. Prolactin monitoring in first-episode psychotic patients. 

4. Hindley G, Gall N. QT interval prolongation. In: Taylor DM, Gaughran F, Pillinger T, eds. 

The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Up to 20% of patients with bipolar disorder have 4 or more medications, so it is important to be aware of these common drug-drug interactions.