Pindolol Augmentation
Selective Serotonin Reuptake Inhibitors

- a potential adverse reaction

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Negro, Brannan & Zuelzer

Thirty to forty per cent of patients will not respond to their initial antidepressant treatment. The augmentation of antidepressants is an important strategy for these treatment resistant patients (Thase & Rush, 1995). A new augmentation strategy, the use of pindolol, has been reported to potentiate the clinical effects of the selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors by enhancing serotonin function (Artigas et al, 1994, Blier & Bergeron, 1995). Pindolol, a known beta blocker, also blocks 5-HT1A receptors, thereby increasing the available amount of serotonin in the synaptic cleft (by preventing autoreceptor inhibitory regulation) (Hjorth & Auerbach, 1994).

There is also evidence of a role for serotonin in aggression (Mann, 1995). Perturbations in serotonergic system may exacerbate irritability and possibly trigger violent behavior. This could be a shortcoming of pindolol augmentation of SSRIs. We report a case of a patient who had an unexpected worsening of irritability after receiving pindolol to augment sertraline antidepressant action.


Case report

A 26-year-old male with a long history of dysthymic disorder presented for treatment after months of worsening of depressive symptoms (insomnia, anhedonia, irritability, poor concentration, low energy, and suicidal ideation), consistent with the diagnosis of major depression, -moderate. He also described episodes of physical aggression towards his spouse with increased irritability leading to violence. He was very regretful of his aggressive behavior, and reported a relation between irritability and proneness to violence. Despite the occurrence of violent behavior, the patient did not fill criteria for antisocial personality disorder. There was no evidence of alcohol or substance abuse during the treatment.

The patient was begun on sertraline 50mg/day and trazodone 50mg at bedtime with disappearance of irritability, partial improvement of insomnia and energy level, but persistence of sadness and anhedonia. A sertraline blood level was 17ng/ml (normal range 10-100ng/ml for our laboratory) after three weeks. His sertraline dose was increased to 150mg/day and trazodone was increased to 150mg/night in the following two weeks without improvement of sadness, anhedonia or residual insomnia. The patient developed anorgasmia. His sertraline dose was then decreased over one week to 50mg/day. There were no complaints of irritability, but patient still reported some anxiety and had transient withdrawal symptoms (mainly a flu-like syndrome for two days) during the one-week taper of sertraline from 150mg/day to 50mg/day.

At that point the patient was started on pindolol 5 mg twice a day (in addition to 50mg/day of sertraline). The patient reported an exacerbation of irritability and anxiety after two days, but no worsening of sadness, loss of concentration, decrease of energy, appetite or sleep. He missed work for the first time in two months and asked his spouse to leave him alone because he was afraid of becoming violent. Pindolol was discontinued at the end of the second day. Resolution of the irritability and anxiety occurred within 24 hours. On 50mg/day of sertraline there was no further irritability. The patient remained on 150mg/day of trazodone throughout these events.



Our patient’s irritability was stable for two months on sertraline prior to the addition of pindolol. As a result of the augmentation, there was an unexpected exacerbation of irritability and anxiety. Despite the good results of Artigas et al. and Blier & Bergeron, increasing irritability was one of the reported shortcomings of this treatment. In our patient increased irritability occurred soon after adding pindolol (to sertraline and trazodone) and rapidly dissipated after pindolol was discontinued. He did not report worsening of sadness or other depressive symptoms. This strongly implies that in this patient augmentation with pindolol was associated with increased irritability without affecting antidepressive activity. We hypothesize that pindolol’s role in changing the serotonergic system caused this occurrence.

The complexity of the serotonergic system precludes an easy explanation of these phenomena. In a recent review of the neurobiology of violence, Mann (1995) pointed at the inverse relation between CSF 5-HIAA and irritability and aggression. This implies decreases in serotonergic function may relate to irritability. This contradicts the association between irritability/aggressiveness and pindolol augmentation in our patient (which implies increased serotonergic function). We currently know of a multitude of serotonergic receptor subtypes. These subtypes likely correspond to different systems. Our patient was also receiving trazodone, which blocks 5-HT2 receptors. Trazodone inhibits serotonin reuptake and may have a serotonomimetic action through its major metabolite, m-chlorophenylpiperazine (m-CPP) and we could not rule out a putative fluctuation on anxiety and irritability due to the interaction of pindolol and trazodone (Hyman et al, 1996). Therefore, augmentation with pindolol altered the function of the serotonergic system in a complicated way and it is unlikely that simple increases or decreases of the serotonergic neurotransmitter system adequately explain these phenomena. We agree with Coplan et al. (1995) that dysfunction of interdependent 5-HT pathways, possibly secondary to pathological receptor sensitivities, might account for disparate aggressiveness, anxiety and mood effects of 5-HT related compounds.


Paulo Jácomo Negro, Jr., M.D.
Clinical Neuroendocrine Branch
National Institutes of Mental Health,
National Institutes of Health
10 Center Drive, Bldg.10, Rm 2D46
Bethesda, MD 20892

Stephen Brannan, M.D.

Department of Psychiatry
The University of Texas Health Science Center at San Antonio.

Mary Zuelzer, M.D.

Department of Psychiatry
The University of Texas Health Science Center at San Antonio.



Artigas F, Perez V, Alvarez E. (1994) Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry 248(51):248-51.

Blier P, Bergeron R. (1995) Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. Journal of Clinical Psychopharmacology 15(3):217-22.

Coplan JD, Wolk SI, Klein DF. (1995) Anxiety and serotonin 1A receptor. in Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York, NY, Raven Press, 1301-10.

Hjorth S, Auerbach S.B. (1994) Further evidence for the importance of 5-HT1A autoreceptors in the action of the selective serotonin reuptake receptors. European Journal of Pharmacology 1994;260:251-5.

Hyman SE, Arana GW, Rosenbaum JF.(1995) Handbook of Psychiatric Drug Therapy, 3rd. edition. Boston, Little, Brown and Company, 81.

Mann JJ. (1995) Violence and aggression. in: Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York, NY, Raven Press, 1919-28.

Thase ME, Rush AJ. (1995) Treatment-resistant depression. in Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York, NY, Raven Press, 1081-97.

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Version 1.0 First Published 6th June 1997

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