Exploring psychotherapeutic issues and agents in clinical practice
Aripiprazole (Abilify®) is an antipsychotic drug that was first approved by the U.S. Food and Drug Administration (FDA) in 2002 for the treatment of schizophrenia, with subsequently approved indications for the treatment of bipolar disorder and agitation associated with schizophrenia, bipolar disorder, or autism. The drug was also approved in 2007 for adjunctive use with antidepressant agents for the treatment of major depression. A colleague recently sent me a copy of a published letter written by two neurologists (Friedman & Tarsy, 2010) who expressed concern that the FDA approval of aripiprazole for use in treating depression may result in an increase in the number of cases of tardive dyskinesia (TD). In this month’s column, I comment on certain statements made in the letter, emphasizing the importance of understanding the pharmacology that is unique to particular drugs and the need to consider the relative safety of a particular drug in the context of all other treatment options.
Antipsychotic Drug-Induced Motor Syndromes
Dopamine is the major neurotransmitter within the basal ganglia, the involuntary motor system of the brain. Blocking dopamine receptors in the basal ganglia can cause extrapyramidal (i.e., Parkinsonian) symptoms, acute dystonia, akathisia, TD, and neuroleptic malignant syndrome (NMS). Extrapyramidal symptoms, including resting tremor, muscle rigidity, shuffling gait, stooped posture, blunted facial expression, and drooling, are similar to Parkinson’s disease. Acute dystonia is a sudden and severe prolonged muscle contraction, usually involving an isolated muscle or group of muscles. Akathisia is characterized by a subjective and objective experience of restlessness, anxiety, and mild motor agitation. NMS is a rare, serious, and potentially fatal reaction to dopamine receptor-blocking drugs. The motor and behavioral symptoms of NMS include muscular rigidity and dystonia, akinesia (i.e., immobility), mutism, obtundation, and agitation. Autonomic symptoms of NMS include fever, sweating, tachycardia, and hypertension. Patients with NMS can develop increases in muscle and liver enzymes and kidney failure. TD is characterized by abnormal, involuntary, irregular motor movements involving muscles of the head, limbs, or trunk. Alterations in dopamine function, including postsynaptic dopamine receptor sensitivity and changes with cholinergic and noradrenergic systems within the basal ganglia, have been implicated in the development of TD.
The Pharmacological Diversity of Antipsychotic Drugs
In their letter, Friedman and Tarsy (2010) state the following: “Antipsychotics all share the property of blocking dopamine receptors in the brain. Almost all, including the ‘atypical antipsychotics,’ have been associated with extrapyramidal side effects” (para. 1). This is an overly simplistic statement about the pharmacology of antipsychotic drugs, especially the group of so-called “atypical” second-generation antipsychotic drugs, including clozapine (Clozaril®), risperidone (Risperdal®), olanzapine (Zyprexa®), quetiapine (Seroquel®), ziprasidone (Geodon®), aripiprazole, paliperidone (Invega®), iloperidone (Fanapt®), asenapine (Saphris®), and lurasidone (Latuda®).
Second-generation antipsychotic drugs are pharmacologically diverse, which is why they do not have a uniform side effect profile and are not uniformly associated with similar rates of Parkinsonian symptoms, akathisia, dystonias, or dyskinesias. Compared with the dopamine receptor blocking effects of older first-generation antipsychotic drugs, second-generation antipsychotic drugs modulate D2 receptor function in various ways. They also have significantly greater effects on blocking or modulating serotonin type-2 receptors, along with having variable effects on other neurotransmitters and receptors, compared with first-generation antipsychotic drugs. Because of these unique properties, second-generation antipsychotic drugs are generally less likely to be associated with the development of adverse motor effects, including TD, although some risk remains.
Second-generation antipsychotic drugs do not have a uniform therapeutic profile. All treat psychosis, but not all possess antidepressant effects. How can a single drug, such as aripiprazole, be effective for treating agitation, psychosis, mania, or depression, whereas antidepressant drugs, for example, cannot effectively treat mania or psychosis? To explain this phenomenon, the pharmacology and dose-related pharmacological effects of aripiprazole must be understood. Its pharmacology is complicated, with aripiprazole being a partial agonist at dopamine D2, D3, and D4 receptors; a partial agonist at serotonin 5HT1A, 5HT2C, and 5HT7 receptors; and an antagonist at serotonin 5HT2A and 5HT6 receptors (Shapiro et al., 2003). These receptor effects distinguish aripiprazole from first-generation antipsychotic drugs and other second-generation antipsychotic drugs. The effective doses for treating depression with aripiprazole in clinical trials are lower (typically ≤10 mg per day) than for treating psychosis, mania, and agitation, which usually require doses >15 mg per day (Pae, Forbes, & Patkar, 2011). At lower doses, the pharmacological effects of aripiprazole mimic some of the receptor effects of antidepressant drugs. At higher doses, aripiprazole’s partial agonist receptor effects become more functionally antagonist, which likely explains the anti-manic and antipsychotic properties.
Aripiprazole and the Relative Risk of Tardive Dyskinesia
Friedman and Tarsy (2010) further state: “Aripiprazole, the most recently approved atypical antipsychotic has recently been implicated as a cause of TD in patients never exposed to other dopamine receptor-blocking agents and at the low doses recommended for treating depression” (para. 3). Friedman and Tarsy (2010) cited two published case reports describing three patients—two patients were taking 15 mg per day and one patient was taking 5 mg per day (Friedman, 2010; Lungu et al., 2009). Case reports can be useful for detecting “signals” of potentially positive or negative drug effects, but they are difficult to interpret, subject to various forms of bias, and cannot be used to definitively establish causality. Regarding abnormal motor symptoms, multiple studies have consistently demonstrated that various neurological abnormalities, including dyskinesias, Parkinsonian symptoms, and neurological soft signs, are present in drug-naïve individuals with first-episode psychosis prior to receiving any antipsychotic medications (Torrey, 2002).
Friedman and Tarsy (2010) go on to state:
The addition of aripiprazole into the depression arena, assisted by mass market advertising, especially on television, may lull unsuspecting non-psychiatrists into believing that this drug, and possibly similar drugs in the future, are as risk-free in terms of TD as the selective serotonin reuptake inhibitors. (para. 3)
Unfortunately, the authors do not mention that literature exists describing the association of antidepressant drugs, including selective serotonin reuptake inhibitors, with Parkinsonian symptoms, akathisia, dystonias, and dyskinesias (Gerber & Lynd, 1998; Lee, Lin, Chang, Chong, & Cheng, 2013; Schillevoort et al., 2002).
Friedman and Tarsy (2010) then state, “In a recent review of studies using comparable doses of antipsychotics, the annualized incidence of TD was estimated to be 3.9% for atypical antipsychotics compared with 5.5% for conventional antipsychotics—only a modest improvement” (para. 4).
These rates were derived from a review (Correll & Schenk, 2008) of 12 long-term prospective incidence trials and four cross-sectional prevalence studies. None of the 16 studies included aripiprazole. Aripiprazole and risperidone are different in their pharmacology and clinical profiles. Risperidone and certain other atypical drugs are more akin to first-generation antipsychotic drugs in some respects and are more prone to adverse motor effects. Nine of the 12 long-term studies in this review included risperidone; one of the four cross-sectional studies involved risperidone alone. These findings are therefore weighted heavily toward risperidone, and they do not representationally characterize the relative incidence or prevalence of TD and other motor side effects of individual second-generation antipsychotic drugs, especially aripiprazole. Attributing adverse effects to a particular drug solely by that drug’s classification within a larger group of multiple drugs is an example of guilt by association (Howland, 2014). The patient populations of these 16 studies are also diverse with respect to age, diagnosis, and other clinical characteristics relevant to a risk of TD.
Friedman and Tarsy (2010) conclude: “Aripiprazole may produce TD, which may be permanent. It should therefore be used only when necessary” (para. 5). How does one define “necessary”? Several of the alternatives specifically suggested by the authors for refractory depression (i.e., tricyclic antidepressant drugs, combining drugs of different chemical families, lithium, and thyroid) carry their own inherent risks. Are the inherent risks of these alternative therapies necessarily better or less serious than a 3.9% risk of TD, assuming, without evidence, that aripiprazole carries this 3.9% risk? I do not doubt that aripiprazole, such as any other drug that affects the basal ganglia, may cause TD, but the risk associated with aripiprazole is not similar to the risk posed by other first- and second-generation anti-psychotic drugs.
Friedman and Tarsy (2010) specifically express concern about the potential medicolegal issues associated with the use of aripiprazole and the risk of TD. However, many drugs, not just antipsychotic agents, have been associated with TD, and lawyers are aware of these associations. Conducting an Internet search using the phrase “50 drugs that can cause tardive dyskinesia” will illustrate my point. When evaluating patients for pharmacotherapy, a risk of TD should be considered in the context of any and all risks associated with all potential drug therapies for a particular patient.
For any drug prescribed for any reason, documenting a discussion about common and potentially serious adverse effects, as well as documentation of clinical monitoring, should be performed by prescribers, including nurses who prescribe or monitor pharmacotherapy. Records may include documentation that (a) patients were given product package insert information or a medication guide and (b) questions raised by patients regarding potential side effects were answered. Alternative treatments and their inherent risks, along with the risks of not taking medication for a particular condition, should also be discussed with patients and documented.
- Correll, C.U. & Schenk, E.M. (2008). Tardive dyskinesia and new antipsychotics. Current Opinion in Psychiatry, 21, 151–156. doi:10.1097/YCO.0b013e3282f53132 [CrossRef]
- Friedman, J.H. (2010). Tardive dystonia due to aripiprazole use in a neuroleptic-naïve patient. Journal of Clinical Psychiatry, 71, 652–653. doi:10.4088/JCP.09l05836gre [CrossRef]
- Friedman, J.H. & Tarsy, D. (2010). Aripiprazole for depression: A warning [Letter to the Editor]. Primary Psychiatry, 17(9). Retrieved from http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=2844
- Gerber, P.E. & Lynd, L.D. (1998). Selective serotonin-reuptake inhibitor-induced movement disorders. Annals of Pharmacotherapy, 32, 692–698. doi:10.1345/aph.17302 [CrossRef]
- Howland, R.H. (2014). Mortality risk of mirtazapine: Guilt by association?JAMA Psychiatry, 71, 585–586. doi:10.1001/jamapsychiatry.2013.4582 [CrossRef]
- Lee, Y., Lin, P.Y., Chang, Y.Y., Chong, M.Y. & Cheng, A.T. (2013). Antidepressant-induced tardive syndrome: A retrospective epidemiological study. Pharmacopsychiatry, 46, 281–285. doi:10.1055/s-0033-1354407 [CrossRef]
- Lungu, C., Aia, P.G., Shih, L.C., Esper, C.D., Factor, S.A. & Tarsy, D. (2009). Tardive dyskinesia due to aripiprazole: Report of 2 cases. Journal of Clinical Psychopharmacology, 29, 185–186. doi:10.1097/JCP.0b013e31819a4bd5 [CrossRef]
- Pae, C.U., Forbes, A. & Patkar, A.A. (2011). Aripiprazole as adjunctive therapy for patients with major depressive disorder: Overview and implications of clinical trial data. CNS Drugs, 25, 109–127. doi:10.2165/11538980-000000000-00000 [CrossRef]
- Schillevoort, I., van Puijenbroek, E.P., de Boer, A., Roos, R.A., Jansen, P.A. & Leufkens, H.G. (2002). Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors: A case-control study using spontaneous reports. International Clinical Psychopharmacology, 17, 75–79. doi:10.1097/00004850-200203000-00006 [CrossRef]
- Shapiro, D.A., Renock, S., Arrington, E., Chiodo, L.A., Liu, L.X., Sibley, D.R. & Mailman, R. (2003). Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology, 28, 1400–1411. doi:10.1038/sj.npp.1300203 [CrossRef]
- Torrey, E.F. (2002). Studies of individuals with schizophrenia never treated with antipsychotic medications: A review.Schizophrenia Research, 58, 101–115. doi:10.1016/S0920-9964(02)00381-X [CrossRef]