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Letter to the Editor   |    
Letters to the Editor
Am J Psychiatry 1997;154:1790-1794.

TO THE EDITOR: In an important contribution, Robert M. Berman, M.D., and colleagues (1) concluded that the combination of the selective serotonin reuptake inhibitor (SSRI) fluoxetine with pindolol, a serotonin (5-HT) blocker at 5-HT1A receptors, conveyed no advantage over treatment with fluoxetine alone in either response time or efficacy. The authors' experience differs from earlier open-label studies of the combination (2, 3), which were themselves based on promising studies in rats (4). We have recently completed a randomized, placebo-controlled, double-blind trial in which pindolol was combined with paroxetine in the treatment of major depression (5). The combination demonstrated both a reduction in latency of the antidepressant action and a possible superior efficacy that was sustained for up to 6 months after the trial's completion.

We were struck by some apparent differences between the two studies in the patient groups that were used. For example, we found that the pindolol-paroxetine combination worked less well for men over 35 years of age and for male and female subjects with a chronic history of dysthymia or depression or who were more severely depressed. We specifically excluded subjects who misused substances. It may be relevant that our patients were reviewed twice weekly during the first 2 weeks of the study and weekly thereafter to permit ascertainment of an early medication response.

These methodological issues apart, other possibilities may explain why Berman et al.'s patients did not show positive results. It is becoming clearer that the 5-HT1A receptor is subject to genetic polymorphism (6), and such differences may be highlighted by use of a 5-HT1A receptor blocker. Moreover, the isomer and the mixed enantiomer compositions of pindolol appear to act differently (in rats at any rate [7]) in their activity as partial agonists of 5-HT1A receptors. Thus, it could be that the isomeric composition differed between the two studies. Finally, although we agree with Berman et al. that there are no a priori reasons to suggest that the absence of an effect is due to the choice of fluoxetine, rather than paroxetine or citalopram, perhaps this requires more examination as well.

Studies have suggested that patients with treatment-resistant schizophrenia who require long-term hospitalization profit most from treatment programs that emphasize highly structured behavioral techniques, including a token economy, point systems, and skills training that can improve patients' functioningParadoxically, despite its demonstrated efficacy, the token economy is not often used in clinical settings..Obstacles to its implementation include resistance by staff who hold tightly to traditional custodial methods, increased costs (for the reinforcers backing up the tokens), lack of support from administrators, and inadequate training of clinical staff."

Berman RM, Darnell AM, Miller HL, Anand A, Charney DS: Effect of pindolol in hastening response to fluoxetine in the treatment of major depression: a double-blind, placebo-controlled trial. Am J Psychiatry  1997; 154:37–43
[PubMed]
 
Artigas F, Perez V, Alvarez E: Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors (letter). Arch Gen Psychiatry  1994; 51:248–251
[PubMed]
 
Blier P, Bergeron R: Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J Clin Psychopharmacol  1995; 15:217–222
[PubMed]
[CrossRef]
 
Hjorth S, Auerbach SB: Further evidence for the importance of 5-HT1A autoreceptors in the action of selective serotonin reuptake inhibitors. Eur J Pharmacol  1994; 260:251–255
[PubMed]
[CrossRef]
 
Tomé MB, Isaac MT, Harte R, Holland C: Paroxetine and pindolol: a randomised trial of serotonergic autoreceptor blockade in the reduction of antidepressant latency. Int J Clin Psychopharmacol (in press)
 
Bergen A, Wang CY, Nakhai B, Goldman D: Mass allele detection (MAD) of rare 5-HT1A structural variants with allele-specific amplification and electrochemiluminescent detection. Hum Mutat  1996; 7:135–143
[PubMed]
[CrossRef]
 
Hjorth S, Carlsson A: Is pindolol a mixed agonist-antagonist at central serotonin (5-HT) receptors? Eur J Pharmacol  1986; 129:131–138
 
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References

Berman RM, Darnell AM, Miller HL, Anand A, Charney DS: Effect of pindolol in hastening response to fluoxetine in the treatment of major depression: a double-blind, placebo-controlled trial. Am J Psychiatry  1997; 154:37–43
[PubMed]
 
Artigas F, Perez V, Alvarez E: Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors (letter). Arch Gen Psychiatry  1994; 51:248–251
[PubMed]
 
Blier P, Bergeron R: Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J Clin Psychopharmacol  1995; 15:217–222
[PubMed]
[CrossRef]
 
Hjorth S, Auerbach SB: Further evidence for the importance of 5-HT1A autoreceptors in the action of selective serotonin reuptake inhibitors. Eur J Pharmacol  1994; 260:251–255
[PubMed]
[CrossRef]
 
Tomé MB, Isaac MT, Harte R, Holland C: Paroxetine and pindolol: a randomised trial of serotonergic autoreceptor blockade in the reduction of antidepressant latency. Int J Clin Psychopharmacol (in press)
 
Bergen A, Wang CY, Nakhai B, Goldman D: Mass allele detection (MAD) of rare 5-HT1A structural variants with allele-specific amplification and electrochemiluminescent detection. Hum Mutat  1996; 7:135–143
[PubMed]
[CrossRef]
 
Hjorth S, Carlsson A: Is pindolol a mixed agonist-antagonist at central serotonin (5-HT) receptors? Eur J Pharmacol  1986; 129:131–138
 
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