The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial

Berman, R.; Anand, Amit; Cappiello, Angela; Miller, Helen; Hu, Xin; Oren, Dan A.; Charney, Dennis S.

doi:10.1016/s0006-3223(98)00383-7

Cited by 70 publications

(49 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This rapid restoration of the sensitivity to electrical stimulation (i.e., relative increase in reward) may be attributable to increased serotonin function in forebrain structures, such as the frontal cortex, the hippocampus and the striatum (e.g., Bel and Artigas 1993;Dreshfield et al 1996Dreshfield et al , 1997Invernizzi et al 1994;Gobert and Millan 1999;Rutter et al 1994). The present data are consistent with the hypothesis that the rapid onset of clinical antidepressant action of SSRIs when combined with pindolol (Bordet et al 1998;Tome et al 1997aTome et al , 1997bZanardi et al 1997Zanardi et al , 1998; however, see Berman et al 1997Berman et al , 1999) is partly attributable to pindolol's 5-HT 1A antagonist properties. Nevertheless, other receptors, such as the 5-HT 1B and ␣-adrenergic receptors, for which pindolol has antagonist and/or partial agonist properties, and other neuromechanisms may also contribute to pindolol's augmentation of SSRI antidepressant effects.…”

Section: Discussionsupporting

confidence: 91%

Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats

Harrison

Liem

Markou

2001

Neuropsychopharmacology

158

126

View full text Add to dashboard Cite

Cessation of chronic nicotine or amphetamine administration precipitates withdrawal syndromes characterized by affective symptoms, including "diminished interest or pleasure" in rewarding stimuli (i.e., anhedonia) (American Psychiatric Association 1994;Covey et al. 1998;Glassman 1993;Hughes 1992). Interestingly, the symptom of "diminished interest or pleasure" is not only a symptom of drug withdrawal, but also a core symptom of depression and a negative symptom of schizophrenia (American Psychiatric Association 1994;Markou et al. 1998). Brain reward threshold elevation is an operational measure of this symptom because it reflects diminished sensitivity to rewarding electrical stimuli. In rats, withdrawal from drugs of abuse belonging to diverse pharmacological classes, such as nicotine (Epping-Jordan et al. 1998 Watkins et al. 2000b), amphetamine Zacharko 1980a, 1980b;Kokkinidis et al. 1980Kokkinidis et al. , 1986 Barrett 1976, 1980;Lin et al. 1999Lin et al. , 2000Paterson et al. 2000;Wise and Munn 1995), cocaine (Baldo et al. 1999;Kokkinidis and McCarter 1990; Koob 1991, 1992a;Markou et al. 1992) morphine (Schulteis et al. 1994) and ethanol (Schulteis et al. 1995) elevated brain stimulation reward thresholds.In addition to the affective aspects of drug withdrawal reflected in threshold elevations, nicotine, opiate, or ethanol withdrawal also lead to alterations in a set of behaviors termed somatic signs. In the case of nicotine, these somatic signs are primarily gasps, writhes, eye blinks, and ptosis (Epping-Jordan et al. 1998;Hildebrand et al. 1997Hildebrand et al. , 1999Malin et al. 1992). It is unlikely that these somatic signs in the rat reflect the affective component of drug withdrawal. Nevertheless, the study of both threshold elevations and somatic signs permits the investigation of the effects of manipulations on the various aspects of withdrawal.Based on evidence demonstrating the efficacy of serotonergic antidepressant treatments, reduced cerebrospinal fluid levels of serotonin metabolites, endocrine measures reflecting reduced serotonergic neurotransmission and the exacerbation of depressive symptomatology seen after serotonin (5-HT) depletion in depressed individuals, it is hypothesized that reduced serotonergic neurotransmission underlies at least some aspects or some subtypes of non-drug-induced depressions (for reviews, see Caldecott-Hazard et al. 1991; CaldecottHazard and Schneider 1992;Heninger et al. 1996;Markou et al. 1998;Meltzer and Lowy 1988;Willner 1985). The purpose of the present study was to test the hypothesis that reduced serotonergic neurotransmission mediates some of the affective aspects, not only of non-drug-induced depressions, but also of druginduced depressions. Thus, the present study tested the hypothesis that enhancement of serotonergic neurotransmission through acute administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Wong et al. 1995) in combination with a relatively selective 5-HT 1A receptor antagonist would alleviate the symptom of "dimin...

show abstract

Section: Discussionsupporting

confidence: 91%

Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats

Harrison

Liem

Markou

2001

Neuropsychopharmacology

158

126

View full text Add to dashboard Cite

show abstract

“…Thus, NK1R antagonists may exert their anxiolytic effect by modulating the activity of noradrenergic neurons, which in turn modulate serotonergic function. In this regard, we have shown that NK1R antagonism attenuates ␣-2 adrenoreceptor responsiveness in the LC (39). However, it remains to be investigated whether ␣-2 desensitization results in an increased LC firing rate in our mice.…”

Section: Resultsmentioning

confidence: 71%

Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function

Santarelli¹

2001

Proceedings of the National Academy of Sciences

120

View full text Add to dashboard Cite

Alterations in serotonin (5-hydroxytriptamine, 5-HT), norepinephrine, and ␥-aminobutyric acid have been linked to the pathophysiology of anxiety and depression, and medications that modulate these neurotransmitters are widely used to treat mood disorders. Recently, the neuropeptide substance P (SP) and its receptor, the neurokinin 1 receptor (NK1R), have been proposed as possible targets for new antidepressant and anxiolytic therapies. However, animal and human studies have so far failed to provide a clear consensus on the role of SP in the modulation of emotional states. Here we show that both genetic disruption and acute pharmacological blockade of the NK1R in mice result in a marked reduction of anxiety and stress-related responses. These behavioral changes are paralleled by an increase in the firing rate of 5-HT neurons in the dorsal raphe nucleus, a major source of serotonergic input to the forebrain. NK1R disruption also results in a selective desensitization of 5-HT1A inhibitory autoreceptors, which resembles the effect of sustained antidepressant treatment. Together these results indicate that the SP system powerfully modulates anxiety and suggest that this effect is at least in part mediated by changes in the 5-HT system. S ubstance P (SP) and its receptor, the neurokinin 1 receptor (NK1R), participate in the neural processing of a range of noxious and stressful stimuli. In the spinal cord, SP contributes to nociception, and disruption of the NK1R decreases or ablates the late-phase response to peripheral injury (1-3). In the brainstem, SP modulates emesis, which can be decreased in animals and humans by NK1R antagonists (4). Peripheral inflammation in a variety of structures including gut, joints, and cutaneous tissue also partly depends on SP release and NK1R activation (5).Recently, SP also has been implicated in the modulation of stress responses, mood, and anxiety, but its exact role remains unclear. Localized administration of SP in the central nervous system may produce anxiogenic or anxiolytic responses, depending on the animal species and location of injection (6-8). Conflicting results also have been obtained from the use of NK1R antagonists, and issues of drug access and species specificity have further clouded the roles of SP in stress-related behaviors (9). Interestingly, in humans, an NK1R antagonist has been reported to be an effective antidepressant and anxiolytic, although this result has not been replicated (10). It has been proposed that the antidepressant activity of NK1R antagonism may be independent of serotonergic and noradrenergic pathways and thus may represent an alternative therapeutic strategy for the treatment of mood disorders (10).In the present study we used genetic disruption and pharmacological blockade of the NK1R to examine the roles of SP in the generation of anxiety-related behaviors in mice. Genetic disruption of NK1R function markedly reduced anxiety-related behaviors in the elevated plus maze (EPM), novelty suppressed feeding (NSF), and maternal separation paradi...

show abstract

“…Artigas and colleagues (1994) reported that coadministration of paroxetine and the 5-HT 1A receptor partial agonist and b-adrenergic receptor antagonist, (7) pindolol decreased the time to onset of antidepressant action compared to the SSRI alone from 2-3 weeks to 3-7 days. These findings have been confirmed by numerous groups (Blier and Bergeron, 1995;Zanardi et al, 1997;Bordet et al, 1998;McAskill et al, 1998;Maes et al, 1999) and in a meta-analysis by Ballesteros and Callado (2004), but have been refuted by others (Berman et al, 1997(Berman et al, , 1999. It is likely that the recent controversy surrounding the optimal dose of pindolol used in the augmentation of SSRI (Segrave and Nathan, 2005;Rabiner et al, 2001) may explain these inconsistencies.…”

Section: Introductionmentioning

confidence: 80%

“…Hence, it has been hypothesized that concomitant therapy with an SSRI increasing 5-HT in the forebrain and a 5-HT 1A receptor antagonist preventing feedback via blockade of the autoreceptors may result in a reduction of the time to onset of efficacy in the clinic. In support of this hypothesis, clinical data have indicated that the coadministration of an SSRI with the mixed b-adrenergic and 5-HT 1A receptor antagonist (7) pindolol can hasten the commencement of antidepressant efficacy from several weeks to between 3 and 7 days (Artigas et al, 1994;Blier and Bergeron, 1995), although there has been evidence to the contrary in depression (Berman et al, 1997(Berman et al, , 1999 and anxiety (Stein et al, 2001). There are also a substantial number of preclinical rodent neurochemistry studies that support the proposal that the increase in forebrain 5-HT seen with SSRIs after chronic administration can been seen acutely with concurrent blockade of the 5-HT 1A autoreceptors (Dawson and Nguyen, 1998;Gartside et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Starr

Price

Watson

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (7) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT 1A/B receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED 50 of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [ 3 H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (po0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.

show abstract

The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial

Cited by 70 publications

References 22 publications

Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats

Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats

Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Contact Info

Product

Resources

About