Exploring psychotherapeutic issues and agents in clinical practice
“WHAT'S PAST IS PROLOGUE" wrote William Shakespeare in The Tempest (Act 2, Scene 1, 245–254), and so it is with the drug buspirone. The azapirones are a class of structurally unique molecules developed and investigated as possible anxiolytic and anti-psychotic drugs, and buspirone is the prototypical drug in this class (Eison, 1990). Although it was first synthesized in 1968, buspirone was not approved by the U.S. Food and Drug Administration (FDA) until 1986, when it was granted marketing approval under the brand name Buspar® for the treatment of generalized anxiety disorder (Fulton & Brogden, 1997). In this month's column, I will review the use of buspirone, as this agent exemplifies how the use of an old drug evolves and expands over time.
Pharmacology of Buspirone
Buspirone is a partial agonist at post-synaptic serotonin-1A–type receptors; an antagonist at pre-synaptic dopamine D2, D3, and D4 receptors; and a partial agonist at alpha-1 adrenergic receptors (Riblet, Taylor, Eison, & Stanton, 1982). It is not chemically related to benzodiazepine drugs, does not bind to benzodiazepine receptors, does not influence activity of the inhibitory amino acid gamma-aminobutyric acid, and lacks anticholinergic and antihistamine effects.
Buspirone is extensively metabolized by the hepatic enzyme cytochrome P450-3A4 and has one active metabolite. The parent drug and metabolites are mainly cleared through the kidneys. Use of compounds that inhibit 3A4, such as nefazodone (Serzone®) or grapefruit juice, will increase buspirone concentrations. Carbamazepine (Tegretol®) and other 3A4 enzyme inducers will lead to reduced concentrations. Buspirone has a short half-life (<12 hours), so it is often dosed two to three times per day. Severe impairment of hepatic or renal function results in a longer half-life and reduced clearance of buspirone. Buspirone does not affect the metabolism of other drugs. The maximum FDA recommended dose is 60 mg per day, but higher doses can be used and are well tolerated, and it is considered safe in an overdose (Fulton & Brogden, 1997).
Efficacy of Buspirone for Anxiety
In animal studies conducted during the 1970s, the tranquilizing activity of buspirone was characterized by its ability to tame aggressive rhesus monkeys, block conditioned avoidance responding in rats, inhibit shock-induced fighting in mice, and attenuate shock-induced suppression of drinking in rats (Riblet et al., 1982). These properties in animals originally suggested potential therapeutic use in schizophrenia, but clinical trials with buspirone in schizophrenia produced inconsistent findings (Ghaleiha, Noorbala, Farnaghi, Hajiazim, & Akhondzadeh, 2010). Although buspirone may provide some benefit when combined with an antipsychotic drug in schizophrenia (Ghaleiha et al., 2010), the drug was not further developed for this indication. Based on its pharmacology and tranquilizing properties in animals, subsequent clinical studies were conducted for generalized anxiety, resulting in its FDA approval (Fulton & Brogden, 1997).
Despite the efficacy of buspirone for generalized anxiety, it appears to have relatively weak effects for the treatment of panic disorder and obsessive compulsive disorder (Fulton & Brogden, 1997). This limited effect should be contrasted with the established therapeutic effectiveness and FDA approval of many antidepressant drugs for various anxiety disorders.
Efficacy of Buspirone for Depression
The pharmacological profile of buspirone suggests potential antidepressant effects, which have been demonstrated in animal studies (Eison, 1990). In humans, buspirone monotherapy has significant antidepressant efficacy at higher doses (e.g., up to 90 mg per day) in placebo-controlled studies (Fulton & Brogden, 1997).
Buspirone is often combined with antidepressant drugs to treat adverse sexual effects (Landen, Eriksson, Agren, & Fahlen, 1999) or to augment their antidepressant effects. Several placebo-controlled studies have found buspirone augmentation to be effective in treatment-resistant depression (Appelberg et al., 2001; Trivedi et al., 2006). In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (Trivedi et al., 2006), the efficacy and tolerability of various antidepressant therapies were evaluated through four sequential treatment levels. During the first level of STAR*D, all patients were treated with the antidepressant drug citalopram (Celexa®). In the augmentation arm of the second level of STAR*D, non-remitters to citalopram were randomized to receive augmentation with bupropion (Wellbutrin®) or buspirone (Trivedi et al., 2006). The bupropion and buspirone groups had similar rates of remission and response, but bupropion was associated with a significantly greater reduction in depression scores (from baseline to the end of Level 2) than buspirone. Bupropion was also associated with a significantly lower dropout rate due to intolerance than buspirone.
More recently, Fava et al. (2012) and Targum, Wedel, and Fava (2015) investigated the antidepressant and cognitive effects of the combination of low doses of buspirone (15 mg per day) and melatonin (3 mg per day). The use of this combination was based on the preclinical finding that it facilitated neurogenesis. Adult neurogenesis is the process of generating functional neurons from neural stem cells in the adult brain. Neurogenesis has been documented within the hippocampus in animal studies and in some human studies. Disturbed adult neurogenesis is associated with depression-like behavior and cognitive deficits in animal studies. Antidepressant therapies enhance hippocampal neurogenesis in animals. Disturbed neurogenesis affecting the hippocampus may contribute to the cognitive deficits and reduced hippocampal volumes seen in patients with depression. The exploratory studies by Fava et al. (2012) and Targum et al. (2015) demonstrated a significant benefit on mood and cognition for the combination versus buspirone alone or placebo.
Buspirone for Irritability, Agitation, and Aggression
Buspirone has been demonstrated to reduce abnormal aggressiveness in laboratory studies of animals (Haller, Horvath, & Bakos, 2007; Ratey, Sovner, Parks, & Rogentine, 1991; Riblet et al., 1982). Open-label studies demonstrated benefit with the use of buspirone for agitation and aggression associated with dementia and mental retardation (Herrmann & Eryavec, 1993; Ratey et al., 1991). A randomized, double-blind trial for agitation in a nursing home population with dementia found comparable benefits for buspirone 15 mg per day and haloperidol (Haldol®) 1.5 mg per day, but tension and anxiety decreased to a greater extent with buspirone (Cantillon, Brunswick, Molina, & Bahro, 1996). More recently, Ghanizadeh and Ayoobzadehshirazi (2015) conducted a randomized trial and found that risperidone plus low-dose buspirone was more effective than risperidone plus placebo for treating irritability in children and adolescents with autism.
Other studies have not demonstrated significant benefit for buspirone compared to atomoxetine (Strattera®) or methylphenidate (Ritalin®) among children or adults with attention-deficit/hyperactivity disorder (Mohammadi, Hafezi, Galeiha, Hajiaghaee, & Akhondzadeh, 2012; Sutherland, Adler, Chen, Smith, & Feltner, 2012).
Buspirone and Substance Use Disorders
Preclinical studies suggested buspirone might be an effective pharmacological therapy for various substance use disorders, but controlled clinical trials have demonstrated little to no benefit for smoking (Schneider et al., 1996), alcohol (Malec, Malec, & Dongier, 1996), cocaine (Winhusen et al., 2014), or cannabis (McRae-Clark et al., 2015). Buspirone is effective for treating anxiety in individuals with alcohol dependence (Malec et al., 1996), but not in those with opioid dependence (McRae, Sonne, Brady, Durkalski, & Palesch, 2004). Curiously, a placebo-controlled study found that buspirone 30 to 45 mg per day was as effective as a methadone taper in alleviating withdrawal symptoms of heroin (Buydens-Branchey, Branchey, & Reel-Brander, 2005).
Buspirone is a pharmacologically unique agent among currently available psychotropic drugs, with a good safety profile and several potential therapeutic uses. Its effectiveness has been most clearly demonstrated for generalized anxiety, but not for other anxiety disorders. Buspirone is also efficacious for depression, either alone or with an antidepressant drug, and for treating antidepressant-associated adverse sexual effects. Studies of buspirone for substance use disorders have had disappointing outcomes, although it may be useful for treating anxiety among individuals who are alcohol dependent and one controlled study suggested it is effective for heroin detoxification. Contemporary safety concerns have been raised, not only for the use of antipsychotic drugs in older adult patients with dementia, but also for their use in children and adolescents. For this reason, buspirone should be considered a reasonable treatment option for managing irritability, agitation, and aggression in these patient populations, although additional efficacy and safety studies are warranted. The potential synergism of buspirone combined with melatonin, promoting neurogenesis and treating depression and cognitive impairment, is intriguing. For an old drug, buspirone may have an interesting future.
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- Ghaleiha, A., Noorbala, A.A., Farnaghi, F., Hajiazim, M. & Akhondzadeh, S. (2010). A double-blind, randomized, and placebo-controlled trial of buspirone added to risperidone in patients with chronic schizophrenia. Journal of Clinical Psychopharmacology, 30, 678–682. doi:10.1097/JCP.0b013e3181fa8720 [CrossRef]
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- Mohammadi, M.R., Hafezi, P., Galeiha, A., Hajiaghaee, R. & Akhondzadeh, S. (2012). Buspirone versus methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder: Randomized double-blind study. Acta Medica Iranica, 50, 723–728.
- Ratey, J., Sovner, R., Parks, A. & Rogentine, K. (1991). Buspirone treatment of aggression and anxiety in mentally retarded patients: A multiple-baseline, placebo lead-in study. Journal of Clinical Psychiatry, 52, 159–162.
- Riblet, L.A., Taylor, D.P., Eison, M.S. & Stanton, H.C. (1982). Pharmacology and neurochemistry of buspirone. Journal of Clinical Psychiatry, 43, 11–18.
- Schneider, N.G., Olmstead, R.E., Steinberg, C., Sloan, K., Daims, R.M. & Brown, H.V. (1996). Efficacy of buspirone in smoking cessation: A placebo-controlled trial. Clinical Pharmacology and Therapeutics, 60, 568–575. doi:10.1016/S0009-9236(96)90153-8 [CrossRef]
- Sutherland, S.M., Adler, L.A., Chen, C., Smith, M.D. & Feltner, D.E. (2012). An 8-week, randomized controlled trial of atomoxetine, atomoxetine plus buspirone, or placebo in adults with ADHD. Journal of Clinical Psychiatry, 73, 445–450. doi:10.4088/JCP.10m06788 [CrossRef]
- Targum, S.D., Wedel, P.C. & Fava, M. (2015). Changes in cognitive symptoms after a buspirone-melatonin combination treatment for major depressive disorder. Journal of Psychiatric Research, 68, 392–396. doi:10.1016/j.jpsychires.2015.04.024 [CrossRef]
- Trivedi, M.H., Fava, M., Wisniewski, S.R., Thase, M.E., Quitkin, F., Warden, D. & Rush, A.J. (2006). Medication augmentation after the failure of SSRIs for depression. New England Journal of Medicine, 354, 1243–1252. doi:10.1056/NEJMoa052964 [CrossRef]
- Winhusen, T.M., Kropp, F., Lindblad, R., Douaihy, A., Haynes, L., Hodgkins, C. & Brigham, G.S. (2014). Multisite, randomized, double-blind, placebo-controlled pilot clinical trial to evaluate the efficacy of buspirone as a relapse-prevention treatment for cocaine dependence. Journal of Clinical Psychiatry, 75, 757–764. doi:10.4088/JCP.13m08862 [CrossRef]