24-HOUR MH HOTLINE
FOR EMERGENCIES ONLY
Off-label use of ‘dopamine stabilizer’ requires caution.
Mahendra T. Bhati, MD
Neuropsychiatry fellow, Department of psychiatry, University of Pennsylvania, Philadelphia, PA
Aripiprazole, the first FDA-approved partial dopamine agonist, causes few side effects when used to treat schizophrenia or acute bipolar mania. This relatively safe profile in approved uses has led clinicians to try aripiprazole for off-label uses as well, though evidence of the drug’s efficacy and safety in other psychiatric conditions is limited (Box 1).1-7 Because this practice may involve unknown risks, this article:
Off-label aripiprazole: The unknowns
Dopamine neurons arise from two major nuclei in the mesencephalon (midbrain): the substantia nigra and ventral tegmental area (VTA). Neurons from the substantia nigra extend to the basal ganglia via the mesostriatal (nigrostriatal) pathway, which influences extrapyramidal motor function. The VTA sends dopaminergic neurons through mesolimbic and mesocortical pathways.
The basic limbic system includes the cingulate and orbitofrontal gyri, hippocampus, hypothalamus, thalamus, amygdala, medial temporal cortex, and the periaqueductal gray. This system controls emotion, episodic memory, pain, and primitive behaviors such as eating, fighting, sexual desire, and grooming.8 The limbic system is surrounded by cortex, where higher-order sensory, cognitive, and motor processes occur. The VTA links limbic and cortical functions via dopamine.
The tuberoinfundibular pathway, another clinically important dopaminergic route, projects from the hypothalamus to the anterior pituitary gland and regulates prolactin secretion.
Functional dopamine neurotransmission abnormalities in schizophrenia are generally characterized by region, with:
• excessive mesolimbic pathway activity resulting in positive symptoms such as delusions and hallucinations
• mesocortical projection deficits resulting in cognitive and negative symptoms such as impaired memory and attention, emotional blunting, alogia, avolition, and anhedonia.
Dopamine function abnormalities in schizophrenia occur in:
• projections from the substantia nigra to the caudate and putamen in the basal ganglia
• mesolimbic connections to the anterior cingulate, hippocampus, and parahippocampus
• mesocortical projections to the prefrontal cortex.
These dysfunctions contribute to abnormal motor function, perception, attention, memory, volition, emotion, and executive function.9
Differences in regional dopamine function and observations of dopamine agonists’ therapeutic effects in schizophrenia10 led to development of partial dopamine agonists such as aripiprazole (Box 2).11,12
Aripiprazole and the investigational agent bifeprunox have complex pharmacologic actions involving numerous neurotransmitters—dopamine, serotonin, and histamine—but are believed to be principally partial agonists at pre- and postsynaptic dopamine receptors. Specifically, aripiprazole decreases hyperdopaminergic states while preserving dopamine function by partial agonism and decreased stimulation of presynaptic regulatory autoreceptors.5
The FDA approved aripiprazole for treating schizophrenia in 2002 and acute bipolar mania in 2004. A dihydroquinolone unrelated to other antipsychotics, it has an active partial agonist metabolite (dehydro-aripiprazole), high affinity for D2 receptors (Figure 1), and partial agonism at dopamine and serotonin receptors.13
Phase III trials are in progress for bifeprunox, a partial dopamine agonist/antagonist and serotonin receptor agonist being investigated for schizophrenia. An FDA decision on its approvability is expected in 2007.
Aripiprazole has approximately 30% intrinsic dopaminergic activity, estimated from studies showing a low incidence of extrapyramidal symptoms (EPS) with dosages up to 30 mg and PET studies showing a therapeutic range of postsynaptic D2 receptor occupancy of 80% to 95%.14 This small intrinsic activity limits excessive stimulation and dopamine receptor blockade.11 It also limits down-regulation of regulatory dopamine autoreceptors and preserves dopaminergic function in pre- and postsynaptic neurons.
The therapeutic window for dopamine receptor agonists (DA) and serotonin-dopamine receptor agonists (SDA) used in schizophrenia is 60% to 80% D2 receptor occupancy in mesostriatal neurons. D2 receptor occupancy and antagonism >80% significantly increases risk of EPS.15 Excessive dosing of high-potency antipsychotics with strong postsynaptic dopamine receptor affinity carries the highest risk of hypodopaminergic side effects, such as cognitive impairment, worsening of negative symptoms, akathisia, Parkinsonism, and hyperprolactinemia.
Aripiprazole’s intrinsic activity allows for higher D2 receptor occupancy with fewer side effects associated with full dopamine receptor antagonism. Clinical implications of this profile are unknown. Dopamine’s role in schizophrenia’s pathophysiology is inferred from knowledge that all effective antipsychotics offer some postsynaptic D2 receptor blockade.
What makes partial dopamine agonists ‘different’ antipsychotics
Figure - Download
Antipsychotics’ D2 receptor binding affinities
Evidence shows fewer side effects with aripiprazole when used to treat schizophrenia and schizoaffective disorder compared with DAs such as haloperidol and SDAs such as risperidone.1,2,4
Dosage-dependent somnolence occurs with aripiprazole; the most common side effects include headache, agitation, anxiety, and insomnia (24.5%, 34.6%, 24%, and 18.6%, respectively).2 continued on page 60 A 10-week, placebo-controlled study using aripiprazole, 2 to 15 mg/d, to treat psychosis in Alzheimer’s dementia showed significantly increased risk of somnolence, accidental injury, and bronchitis (likely caused by aspiration).16
In placebo-controlled trials, aripiprazole, 2 to 30 mg/d, did not increase risk of cardiac, lipid, or prolactin-related side effects2 but showed increased risk of:
• tremor when used at 15 mg/d for up to 26 weeks in chronic schizophrenia, (9% incidence vs 1% with placebo)17
• akathisia when used at mean dosages of 27.9 mg/d to treat acute bipolar mania (11% incidence vs 2%with placebo).3 Aripiprazole also increased akathisia incidence in normal subjects.18
Risk of tardive dyskinesia or hyperglycemia-related adverse events with aripiprazole are unknown. Studies report weight gain of 19
Determining neuroleptic malignant syndrome risk with aripiprazole is difficult; two cases were reported in the premarketing sample.16 One animal study showed diminished catalepsy with chronic aripiprazole use, in contrast to persistent catalepsy with haloperidol.20
A Medline search for aripiprazole in February 2005 found several reports of treatment-emergent side effects, including:
• 3 reports of worsening agitation or psychosis21-23
• 2 reports of EPS24,25
• 1 report of excessive somnolence in a child.26
Adverse effects are probably underrepresented. Clinical deterioration and adverse effects were reported after starting, switching to, or combining aripiprazole with other antipsychotics or serotonergic agents (trazodone, sertraline, or venlafaxine).27,28
Promising New Investigator: Mahendra T. Bhati, MD
Lieberman, J. Aripiprazole. In: Schatzberg, A, Nemeroff, C (eds.) Textbook of Psychopharmacology. Washington DC: American Psychiatric Publishing, 2004:487-494.
FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/foi/nda/2002/21-436_Abilify.htm
Medline Plus Drug Information. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a603012.html
Clozapine • Clozaril
Haloperidol • Haldol
Risperidone • Risperdal
Trazodone • Desyrel
Sertraline • Zoloft
Venlafaxine • Effexor
This author is supported by grant 2R25MH060490-06 from the National Institute of Mental Health.