Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.
Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, CeNeRx, Epix, Genaissance, Medicinova, Ono Pharmaceuticals, Predix, and Somerset.
Buspirone was the first of a series of central nervous system (CNS) drugs exhibiting selective effects on a single subtype of serotonin (5-HT) receptor. Buspirone binds selectively with high affinity to 5-HT1A receptors and unlike most psychiatric drugs, which are mainly receptor antagonists, functions as a partial agonist at this CNS receptor.1 The pharmacologic attribute of receptor partial agonism confers on buspirone therapeutic efficacy in serotonin-deficient states and minimizes receptor overstimulation in the presence of an excess of neurotransmitter. CNS drugs acting as partial agonists represent an attractive strategy for discovery of new psychopharmacologic agents with therapeutic advantages because they offer clinical efficacy with a diminished liability for producing side effects or toxicity. This emerging class of partial agonist drugs may function by inducing signal attenuation at a single or multiple receptors.
The second-generation antipsychotic (SGA) aripiprazole is a novel CNS drug with partial agonist properties. With demonstrated efficacy and excellent tolerability for treatment of schizophrenia, aripiprazole has a favorable side-effect profile compared with other antipsychotics, due in part to its pharmacologic mechanism of action as a partial agonist at dopamine (D)2/3 receptors. The pharmaceutical industry is devoting considerable drug discovery effort toward identifying innovative CNS drugs that serve as partial agonists.
Discovered in 1968 and approved as an anxiolytic in the 1980s, buspirone is now available by generic prescription. Because buspirone was active in conditioned avoidance paradigms in animal tests, it was initially investigated as a putative antipsychotic devoid of the typical side effects of that drug class. When it lacked therapeutic utility in schizophrenia, further study showed that buspirone in single dose had a marked taming effect on aggressive monkeys and with chronic administration reversed stress-induced behavior in several animal models of anxiety.2
Serotonin 5-HT1A Receptors
Fourteen different 5-HT receptor subtypes have been unequivocally identified, divided into distinct groups depending on function. When a specific binding ligand for the 5-HT1A receptor became available, this receptor subtype was the first of the serotonin family of receptors to be characterized. 5-HT1A receptors are highly expressed in the dorsal raphe, hippocampus, and frontal cortex. Immunochemistry studies show that 5-HT1A receptors are located on neuronal cell bodies and dendrites in the dorsal raphe3 where they act as autoreceptors and inhibit serotonergic neurotransmission. In limbic brain regions receiving input from serotonin-containing neurons, particularly the hippocampus and frontal cortex, 5-HT1A receptors are predominantly postsynaptic and facilitate serotonergic neurotransmission. This regional distribution of 5-HT1A receptors in midbrain and the limbic system is consistent with the notion that serotonin neurotransmission modulates mood and anxiety. Postmortem studies find an increase in 5-HT1A autoreceptors in the midbrain of suicide victims with major depressive disorder (MDD), suggesting diminished activity of serotonin neurons.4 Blunted 5-HT1A receptor-mediated response of corticosteroids has been reported in patients with MDD, suggesting a desensitization of these receptors in patients with anxiety and depression.5
Selective partial agonists of 5-HT1A receptors have been investigated clinically for treatment of generalized anxiety disorder (GAD) and MDD. As yet, only buspirone has successfully gained approval as an anxiolytic by the Food and Drug Administration. Gepirone, a partial but more complete agonist than buspirone at 5-HT1A postsynaptic receptors, currently has a new drug application pending at the FDA as an extended release (ER) formulation for treatment of MDD. As a drug class, buspirone and other 5-HT1A partial agonists have proven to be extremely safe compounds with good tolerability, attributable to highly selective partial agonism properties at a single 5-HT receptor subtype.
In positive, placebo-controlled efficacy trials conducted in the early 1980s in patients with anxiety neurosis,6 buspirone was noted to have a gradual onset of therapeutic benefit compared with a benzodiazepine. This was attributed to the early relief of somatic anxiety symptoms by the benzodiazepine comparator drug while there were no differences between the two anxiolytics in ameliorating symptoms of psychic anxiety. Experience suggests that acute treatment of anxious patients may warrant benzodiazepine therapy initially, but long-term use promotes physical dependence and chronicity of anxiety symptoms. Buspirone, which is non-sedating, non-addicting, and spares memory and cognitive functions, is preferred for long-term therapy of anxious patients and for older patients with anxiety symptoms, because it is safe, well tolerated, and does not interfere with new coping skills.7,8
Mixed Anxiety-Depression and Major Depressive Disorder
In clinical trials, anxious patients with subsyndromal depression exhibited significant improvement in depressive symptoms with buspirone therapy. Because of high comorbidity of GAD and MDD with evidence of shared genetic vulnerability of the two disorders,9-11 drugs with dual therapeutic efficacy for treating anxiety and depression have attracted interest. Placebo-controlled trials show buspirone to be effective in MDD patients who have significant anxiety, generally at doses averaging >50 mg/day.12,13 Augmentation of selective serotonin reuptake inhibitor (SSRI) treatment with buspirone also is advocated in partial responders.14-17 In the evidence-based Sequenced Treatment Alternatives to Relieve Depression study, patients failing an initial adequate trial with an SSRI and augmented with either buspirone or bupropion experienced comparable therapeutic responses.18
Aripiprazole, an effective SGA for the treatment of schizophrenia, has a unique pharmacologic profile in that it functions through partial agonism at D2/3 receptors.1 Aripiprazole does not induce extrapyramidal symptoms, an increase in prolactin, weight gain, type II diabetes, or sedation. Instead of blocking D2/3 receptors as is the case with other antipsychotics, aripiprazole acts as a partial agonist at dopamine receptors. In vitro assay shows aripiprazole to be less potent as a receptor agonist than dopamine (range 30% to 80%). In behavioral tests, aripiprazole blocks apomorphine-induced climbing behavior (mediated by dopamine receptors) at low dose without inducing catalepsy, unlike typical antipsychotics which do produce catalepsy. This suggests that aripiprazole’s primary mechanism of action of partial agonism at D2/3 receptors has successfully differentiated antipsychotic efficacy and the adverse effects associated with typical antipsychotics.
Aripiprazole is a partial agonist of 5-HT1A receptors at therapeutic concentrations as well. Clozapine and the SGAs ziprasidone and quetiapine also exhibit 5-HT1A partial agonism at clinically effective doses. This distinguishes aripiprazole and these other atypical antipsychotics from first-generation antipsychotics, and suggests they may have particular utility in ameliorating the affective components of psychosis, such as anxiety and negative symptoms of schizophrenia. It appears that the distinctive therapeutic profiles of SGAs are related to partial agonism at dopamine and serotonin receptors.
Partial agonist drugs show therapeutic promise for treatment of substance abuse disorders.1 Buprenorphine, a partial agonist at μ-opiate receptors, is effective in combination with the narcotic antagonist naloxone for treatment of heroin addiction. Because D2 and D3 receptors mediate reward components of addictive drugs, partial agonists of dopamine receptors such as aripiprazole and related agents represent a logical therapeutic strategy which could prove useful as second-line treatment for opioid addiction and as first-line therapy to reduce the craving and self-administration of stimulant drugs without incurring liability for producing drug dependence. Agents acting as partial agonists at dopamine and nicotinic receptors are being extensively investigated in animal models to assess potential utility in inhibiting drug-seeking behavior and addiction.
Drugs acting as partial agonists at CNS receptors have become an attractive target for discovery of novel agents. Buspirone, the first of an emerging line of drugs with partial agonist properties, has proven to be a safe anxiolytic without abuse liability showing efficacy in mixed anxiety-depression. The SGA aripiprazole functions as a partial agonist at D2/3 receptors, which may account for its unique side-effect profile. Aripiprazole is also a partial agonist at 5-HT1A receptors, as are ziprasidone, quetiapine, and clozapine, suggesting these drugs may have therapeutic utility for treating affective components of psychotic disorders. CNS agents that function as receptor partial agonists show promise for treating substance abuse and addictive behaviors. Partial agonists of CNS receptors represent an attractive approach to the discovery of new psychotropic agents. PP
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