Buspirone and Gepirone

 

Buspirone and gepirone are interesting compounds.  As shown in the above 2D structures they are structurally similar -  with the main difference being a cyclopentane ring in the azapirone structure in buspirone and two methyl groups at the same atom in gepirone. That results in the molecular formulas of both compounds to be slightly different.   

Buspirone was initially proposed as an antipsychotic medication (2) but it showed no efficacy in clinical trials.  Buspirone was FDA approved for the treatment of anxiety on September 29, 1986.  Gepirone was approved for treatment of depression on September 28, 2023. The 37-year lag time for approving gepirone has always been a mystery to me, especially given the amount of buspirone I have prescribed over the years.  Buspirone came out during an era of benzodiazepine prescribing that at times was excessive.  Alprazolam or Xanax was heavily marketing just prior to the release of buspirone and it did not take long for some experts to recommend using higher doses than the package insert to treat anxiety and panic attacks. That led to complications including excessive use and in some cases withdrawal seizures.  When buspirone was marketed, there was emphasis placed on the fact that it did not lead to excessive use, it did not affect the GABA receptor like benzodiazepines, it did not have synergism with beverage alcohol, and it did not have any withdrawal liability.  As a result, many primary care physicians tried to use it as a substitute for patients taking benzodiazepines. It was ineffective when used in that manner because of the behavioral pharmacology.  A person taking buspirone did not notice any immediate effects, unlike benzodiazepines and it did not reinforce its own use.  It also did not start to work immediately and had an onset of action more like an antidepressant. These properties had the effect of creating the perception that it was an ineffective medication and that was reinforced by some experts – who claimed that only benzodiazepines were useful for anxiety. 

Historically the enthusiasm for benzodiazepines decreased over time with antidepressants (SSRIs, SNRIs, and TCAs) being recommended for anxiety and panic rather than benzodiazepines. Some psychiatrists (like myself) used buspirone for both primary anxiety without panic and antidepressant augmentation. I found that it was an effective medication for those indications but it required a detailed discussion with the patient, especially if they had previous benzodiazepine exposure. The very favorable side effect profile – including no intoxication or withdrawal effects were an important consideration.  Generally, people exposed to that discussion did well on buspirone and were able to avoid benzodiazepines.

The activity of both compounds is thought to be mediated by 5-HT1A agonism as noted in the table below.  Using the PDSP Ki database as the source, more detailed receptor information is available for buspirone than gepirone, probably because the latter approval date.  Partial data is also given for 2 metabolites of gepirone one of which is active at the 5-HT1A receptor.

 

 

Receptor	Buspirone	Gepirone	3’-OH-gepirone	1-PP-gepirone
5-HT1A	5 - 77	38	58
5-HT1B	>10,000	>10,000
5-HT1D	>10,000
5-HT2A	138	3,630
5-HT2B	213.8
5-HT2C	489	>10,000
5-HT3	>10,000
5-HT4	>10,000
5-HT6	398
5-HT7	375
DA D4.2	78-136	58
DA D2 like	1,210
α-2	>1,042	>1,042		42

 All receptor affinities are Ki as nM from PDSP Ki database. Affinities for human receptors included where available.

 

What is the evidence these medications are effective?  The real mystery for these medications is their efficacy and favorable side effect profile compared with clinical use. In terms of side effects – I don’t think it is an overstatement to say that they have the most favorable side effect profile of any psychiatric medications. In my experience, it was rare for anyone to get a side effect.  If it happened it was most likely dizziness.  In prescribing to hundreds of people – I can recall exactly one person who got sedated. When used for antidepressant augmentation I have observed two people become hypomanic and that resolved with discontinuation of the buspirone.

I have no real information to explain the partial and delayed approvals. Most of the clinical trials for both medications occurred in the late 1980s and early 1990s. At that time there was clear evidence that both were effective for anxiety and depression and yet only buspirone was approved at the time for an anxiety indication. Psychiatrists are more typically aware of the off-label use of buspirone as an antidepressant augmenting agent from the Star*D study protocols (3).  At the time buspirone was described as one of the three best studied augmentation strategies for treatment resistant depression with lithium and thyroid hormone being the other two.

Interestingly – I am not aware of any head-to-head comparisons of azapirones to typical antidepressants for the treatment of depression. There are currently 67 studies on ClinicalTrials.gov with buspirone listed as an intervention. Most of these studies investigate the use in novel clinical situations or mechanism of action.  There is one study about anxiety and quality of life when it is used to treat depression and that currently has no publications.  Another references the Star*D study from 20 years ago.

The best single source for the efficacy of azapirones in depression, anxiety, and some novel situations is a chapter by Ninan and Muntasser(4). Their general conclusions are that buspirone is effective in treating generalized anxiety disorder (GAD), GAD with depression, and is more effective in treating the depression associated with anxiety than benzodiazepines. In studies with a crossover design and initial benzodiazepine exposure – response to buspirone was reduced but not eliminated. In a head-to-head comparison of buspirone 30 mg and venlafaxine ER (75 or 150 mg) for GAD both were superior to placebo but venlafaxine was superior to buspirone.  Buspirone has demonstrated efficacy in studies of both non-melancholic and melancholic depression.

Gepirone ER was studies in 3 RCTs for major depression and was effective in all three. One of those studies was a dose ranging study and only the higher dose was noted to be effective.  Gepirone was also studied in GAD with diazepam as a comparator.  Both medications were efficacious, but diazepam had a more rapid onset and consistent effects.  The anxiolytic effects of gepirone occurred at 6 weeks. When both medications were discontinued rebound anxiety occurred with diazepam but not gepirone.  There is some evidence from the buspirone trials that the anxiolytic effect of these medications improves over time.

The current azapirones are interesting and neglected compounds in clinical psychiatry.  They have not been vigorously studied for their primary indications of GAD and major depression.  Most of the interest in this class of medications was generated in studies that look at antidepressant augmentation. Although there is always a lack of pharmacosurveillance data in the US, my speculation is that second and third generation antipsychotics (aripiprazole, brexpiprazole) are much more likely to be prescribed as augmenting agents – despite the risk of tardive dyskinesia and metabolic effects (the azapirones have neither). In my experience with buspirone, I found it to be effective for GAD and antidepressant augmentations.  Despite the theoretical risk of serotonin syndrome – I never saw any symptoms of serotonin toxicity.  If gradually titrated - side effects were rare.  In any detailed informed consent discussion, the azapirones come across as having distinct advantages over other medication classes - primarily from the side effect perspective. With all medication there is a question of efficacy – but in relatively non-urgent situations most people prefer to try the medication with the lowest risk of adverse events – first.

 

George Dawson, MD, DFAPA

 

References:

(1) Piercey MF, Smith MW, Lum-Ragan JT. Excitation of noradrenergic cell firing by 5-hydroxytryptamine1A agonists correlates with dopamine antagonist properties. Journal of Pharmacology and Experimental Therapeutics. 1994 Mar 1;268(3):1297-303.

(2) Le Foll B, Payer D, Di Ciano P, Guranda M, Nakajima S, Tong J, Mansouri E, Wilson AA, Houle S, Meyer JH, Graff-Guerrero A. Occupancy of dopamine D3 and D2 receptors by buspirone: A [11C]-(+)-PHNO PET study in humans. Neuropsychopharmacology. 2016 Jan;41(2):529-37.

Modest occupancy of D2/D3 receptors cannot R/O MOA of this plus 5-HT1A as MOA.

(3)  Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, Quitkin FM, Wisniewski S, Lavori PW, Rosenbaum JF, Kupfer DJ. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR∗ D) study. Psychiatric Clinics. 2003 Jun 1;26(2):457-94.

(4)  Ninan PT, Muntasser S.  Buspirone and gepirone. In: Schatzberg AF, Nemeroff CB.  The American Psychiatric Publishing Textbook of Psychopharmacology.  3^rd ed. Washington DC, American Psychiatric Publishing, 2004: 391-404.

(5)  Robinson DS, Rickels K. Buspirone.  In:  Schatzberg AF, Nemeroff CB.  The American Psychiatric Publishing Textbook of Psychopharmacology.  5th ed. Washington DC, American Psychiatric Publishing, 2017: 585-600.

“We speculate that had buspirone’s sponsor persuaded a depression rather than a GAD indication, buspirone might have well become the first 5-HT1A partial agonist developed as an antidepressant. At present, however, buspirone exists in the shadow of numerous approved antidepressant drugs with high clinical exposure and promotion”. (p. 591-592)