Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue8.2000:

Pindolol Augmentation of Antidepressant Treatment:
Recent Contributions from Brain Imaging Studies
Diana Martinez, Allegra Broft, and Marc Laruelle
Preclinical studies suggest that augmentation of selective
serotonin (5-HT) reuptake inhibitors by the 5-HT1A receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response, an effect
largely mediated by blockade of 5-HT1A autoreceptors in
the dorsal raphe nuclei. Although some controlled clinical
trials suggest that pindolol might reduce latency to selective serotonin reuptake inhibitor response in acute depressive episodes, the effect is moderate and highly variable.
Recent positron emission tomography studies investigating the occupancy of 5-HT1A receptors in humans by
pindolol have shown that at the dose used most often in
clinical trials the occupancy is low and variable, which
might explain the inconsistent clinical results. Positron
emission tomography studies also suggest that pindolol
might be more potent at blocking 5-HT1A autoreceptors
than at blocking postsynaptic receptors, a property that
may be useful in this pharmacologic strategy. Thus, the
positron emission tomography data support the potential
of pindolol to augment the antidepressant response of
selective serotonin reuptake inhibitors, but also imply that
this potential has not been fully evaluated. Here we review
the clinical trials, the positron emission tomography

studies, and the possible mechanisms of pindolol augmentation. It is also suggested that positron emission tomography may be used to define therapeutic dosing early on in
the process of clinical evaluation of new treatment
strategies. Biol Psychiatry 2000;48:844 – 853 © 2000
Society of Biological Psychiatry
Key Words: Serotonin, pindolol, major depression, PET,
[11C]WAY 100635

Introduction

T

he antidepressant effect of the selective serotonin
reuptake inhibitors (SSRIs) is thought to be mediated
by enhanced serotonin (5-HT) transmission; however,
initial exposure to SSRIs is associated with no change or
even a decrease in extracellular 5-HT levels in the terminal

From the Department of Psychiatry and Radiology, Columbia University College of
Physicians and Surgeons, New York State Psychiatric Institute, New York.
Address reprint requests to Diana Martinez, New York State Psychiatric Institute,

1051 Riverside Drive, Box #42, New York NY 10032.
Received May 2, 2000; revised July 11, 2000; accepted July 19, 2000.

© 2000 Society of Biological Psychiatry

fields of the forebrain (Chaput et al 1986; Gartside et al
1999; Invernizzi et al 1992; Romero et al 1996), due to
stimulation of somatodendritic 5-HT1A autoreceptors in
the dorsal raphe nuclei (DRN), the major source of
serotonin projection fibers to the corticolimbic brain regions (for a review, see Artigas et al 1996). Electrophysiologic rodent studies have demonstrated that sustained
administration of SSRIs or 5-HT1A agonists is associated
with desensitization of 5-HT1A autoreceptors (Blier and
De Montigny 1983; Blier and de Montigny 1985, 1987;
Chaput et al 1986; Godbout et al 1991; Jolas et al 1994;
Schechter et al 1990). Desensitization of 5-HT1A autoreceptors has been shown to preferentially affect the somatodendritic autoreceptor over the postsynaptic receptor
(Blier and de Montigny 1987; Chaput et al 1986; Godbout
et al 1991; Jolas et al 1994). Although desensitization has
been demonstrated as early as 3 days following treatment
(Le Poul et al 1995), the percentage of desensitized
neurons reaches 60 – 80% at around 21 days, a time frame

that approximates the time of onset of the antidepressant
effect (for reviews, see Artigas et al 1996; Blier and de
Montigny 1994).
The above observations led to the hypothesis that
blockade of the somatodendritic 5-HT1A autoreceptor
might decrease the latency to improvement (Artigas et
al 1996; Blier and de Montigny 1990). Pindolol, a
b-blocker with activity at the 5-HT1A receptor (Hoyer
and Schoeffter 1991), was therefore proposed as an
augmentation strategy in SSRI treatment, to accelerate
the clinical response. This strategy has been evaluated
in several clinical trials, with inconsistent results. It is
noteworthy that the dose of pindolol used in these
clinical trials (7.5 mg/day) was selected based on the
expectation that this dose would be too low to induce
significant cardiovascular side effects. Yet, the extent to
which 5-HT1A receptors are blocked in humans following this dose of pindolol has only recently been characterized, using positron emission tomography (PET)
and the selective 5-HT1A receptor radiotracer
[11C]WAY 100635 (Andree et al 1999; Martinez et al,
in press; Rabiner et al 2000). These studies indicate that

the occupancy of 5-HT1A receptors achieved in clinical
trials has been low and variable, and that the strategy of
0006-3223/00/$20.00
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Pindolol Augmentation of SSRI Treatment

blocking 5-HT1A autoreceptors as an adjunctive treatment of depression has not yet been fully tested.
In this review, we will briefly discuss the preclinical
evidence supporting the potential usefulness of pindolol in
augmenting 5-HT system response to SSRIs. Results of
clinical trials are reviewed next, followed by a summary of
the recent PET studies evaluating pindolol occupancy of
5-HT1A receptors in humans. The implications of the brain
imaging studies for further development and validation of
this augmentation strategy are then discussed.

Preclinical Evidence Supporting the
Rationale for Pindolol Augmentation
The pindolol augmentation strategy stems from the rationale that pindolol should potentiate the increase in 5-HT

transmission induced by SSRIs in cortical and limbic
areas. To produce this effect, pindolol should preferentially block the 5-HT1A autoreceptors in the DRN relative
to the postsynaptic 5-HT1A receptors in corticolimbic
areas. Although the augmentation of the SSRI effect on
5-HT levels by pindolol is well supported by preclinical
studies, the potential selectivity of pindolol for DRN
autoreceptors remains controversial.
The coadministration of pindolol with an SSRI has been
shown to either prevent the immediate reduction in 5-HT
transmission or augment 5-HT levels in the terminal fields
of the brain, including the dorsal striatum (Romero et al
1996), hippocampus (Hjorth 1996; Hjorth and Auerbach
1994, 1996), and hypothalamus (Dreshfield et al 1996). In
the prefrontal cortex, pindolol was shown to enhance 5-HT
transmission in conjunction with fluoxetine, duloxetine,
and imipramine (Dawson and Nguyen 2000; Gobert and
Millan 1999; Maione et al 1997), although this was not
seen in a study with paroxetine (Gartside et al 1999).
Pindolol has also been shown to attenuate the SSRIinduced reduction in the firing rate of the 5-HT neurons in
some studies (Artigas et al 1996; Romero et al 1996) but

not in others (Fornal et al 1999b). Pindolol also attenuates
the decrease in 5-HT release induced by 5-HT1A agonists
(Bosker et al 1994; Gobert and Millan 1999; Sharp et al
1989, 1993; Sharp and Hjorth, 1990).
For pindolol to be maximally effective, it would be
important for pindolol to have, relative to the postsynaptic
receptor, a preferential effect at the presynaptic receptor.
In these conditions, selective blockade of the presynaptic
5-HT1A receptor would result in maximized 5-HT release
in the terminal fields, without interfering with 5-HT
transmission at the postsynaptic 5-HT1A receptor, as these
receptors may also be involved in the antidepressant effect
of increased 5-HT transmission (Lopez et al 1998; Martin
et al 1990). Some preclinical studies have demonstrated a
greater effect of pindolol at the 5-HT1A autoreceptor

BIOL PSYCHIATRY
2000;48:844 – 853

845

relative to the postsynaptic receptor. Romero et al (1996)
found that pindolol failed to prevent 5-HT1A agonist–
induced inhibition in the hippocampus, and Tada et al
(1999) demonstrated that pindolol itself did not affect
neuronal activity of hippocampal cells, nor did it attenuate
the inhibition of neuronal activity induced by the agonist
buspirone. Other studies, however, have demonstrated that
pindolol does have a pharmacologic effect at the postsynaptic receptor (Hadrava et al 1995; Millan et al 1993), and
Corradetti et al (1998) demonstrated that pindolol antagonizes the effects of a 5-HT1A receptor agonist equally in
both the DRN and the hippocampus.
In vivo binding studies in rodents have also reported
contradictory data. Hirani et al (2000) reported preferential
inhibition of binding of the selective 5-HT1A receptor
antagonist [11C]WAY 100635 by various doses of (2)pindolol (ranging from 0.001 to 3 mg kg21 intravenously) in
the DRN in rats studied with a small animal PET scanner.
The median effective dose (ED50) of (2)pindolol was
significantly lower in the DRN (ED50 5 0.26 6 0.05 mg
kg21) than in the hippocampus (0.48 6 0.12 mg kg21) and
the frontal cortex (0.44 6 0.13 mg kg21); however,

Corradetti et al (1998) reported blocking studies of
[3H]WAY 100635 binding by (2)pindolol (15 mg kg21
intraoperitoneally [IP]) and showed an almost complete
and equivalent binding inhibition in DRN (276%), CA1
(269%), CA3 (279%), and the parietal cortex (282%).
Finally, data from human postmortem autoradiographic
binding studies are also contradictory. One study showed
similar potencies of (2)pindolol to displace [3H]WAY
100635 in DRN and the hippocampus [Ki (2)pindolol was
17.0 6 5.9 nmol/L in the DRN and 17.3 6 3.7 nmol/L in
the hippocampus; Raurich et al 1999]; however, Castro et
al (1999) reported a significantly higher affinity of pindolol for the 5-HT1A receptors in the DRN (Ki 5 8.9 6 2.2
nmol/L) than for the receptors in the hippocampus (Ki 5
14.4 6 2.9 nmol/L in CA1, p , .05), using the same
ligand ([3H]WAY 100635) and same number of human
subjects (n 5 4). Thus, some, but not all, preclinical
pharmacologic and human postmortem data support the
hypothesis that pindolol might act preferentially at the
autoreceptor.

Clinical Trials
Open Clinical Trials
The initial open-label clinical study by Artigas et al (1994)
reported that the coadministration of pindolol with the
SSRI paroxetine resulted in a decreased latency to improvement and augmentation of the antidepressant effect
in refractory depression. Following this report, subsequent
open-label studies continued to report both a decreased
latency and augmentation in treatment-refractory patients

846

D. Martinez et al

BIOL PSYCHIATRY
2000;48:844 – 853

Table 1. Double-Blind Placebo-Controlled Clinical Trials of Pindolol Augmentation of Antidepressant Treatment

Reference
Moreno et al 1997

Maes et al 1999
Berman et al 1999a
Perez et al, in pressb
Tome et al 1997
Zanardi et al 1997
Bordet et al 1998
Zanardi et al 1998
Perez et al 1999

SSRI

SSRI dose

Fluoxetine
Fluoxetine
Fluoxetine
Fluoxetine
Paroxetine
Paroxetine
Paroxetine

Fluvoxamine
Fluoxetine
Paroxetine
Fluvoxamine
Clomipramine

20 – 40 mg/day
20 mg/day
20 mg/day
20 mg/day
20 mg/day
20 mg/day
20 mg/day
300 mg/day
40 mg/day
40 mg/day
200 mg/day
150 mg/day

Pindolol
dose

Duration
(weeks)

7.5 mg/day
7.5 mg/day
7.5 mg/day
7.5 mg/day
7.5 mg/day
7.5 mg/day
15.0 mg/day
7.5 mg/day
7.5 mg/day

2
5
6
6
6
4
4
6
1.5

Total

n

Chronic/
treatment
resistant

Other
axis 1
excluded

Increased
efficacy

Decreased
latency

8
21
86
111
80
63
100
72
80

100%
70%
50%
—
—
—
—
—
100%

No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes

2
1
2
1
2
1
2
2
2

2
2
2
1
1
1
1
1
2

31/62

51/42

621

SSRI, selective serotonin reuptake inhibitor.
a
Preliminary analysis published in Berman et al (1997).
b
Efficacy results published in Perez et al (1997).

(Blier and Bergeron 1995; Blier et al 1997; Vinar et al
1996). Pindolol was also shown to function as an augmentation strategy with buspirone (Blier et al 1997) and
nefazodone (Bakish et al 1997). On the other hand, the
combination of pindolol with tricyclic antidepressant
drugs devoid of effect on the 5-HT reuptake process
(desipramine or trimipramine) did not appear to have an
effect (Blier et al 1997). Of the open-label studies, only
one reported no improvement in treatment-refractory patients (Dinan and Scott 1996).

Double-Blind Controlled Trials
While initial open-label clinical trials suggested that this
regimen of pindolol might accelerate and/or enhance
clinical response, subsequent double-blind placebo-controlled studies provided mixed results. Table 1 lists published double-blind placebo-controlled studies of pindolol
augmentation of antidepressant treatment with SSRIs.
When results from the same data sets were included in
more than one article, only the latest article with the
largest number of subjects is listed. Studies are sorted by
type of SSRI and publication year; published studies
include studies of pindolol versus placebo augmentation of
fluoxetine (n 5 4, Berman et al 1999; Maes et al 1999;
Moreno et al 1997; Perez et al, in press), paroxetine (n 5
3, Bordet et al 1998; Tome et al 1997; Zanardi et al 1997),
fluvoxamine (n 5 1, Zanardi et al 1998), and various
antidepressant drugs (Perez et al 1999). The pindolol
regimen was typically 7.5 mg/day, with one study using
higher doses (15 mg/day, Bordet et al 1998). Duration of
the trials varied from 10 days to 6 weeks. The number of
subjects per study varied from 8 to 111; a total of 621
subjects were included in these studies. All studies in-

cluded patients who met criteria for a major depressive
episode, and inclusion criteria generally included a score
greater than 18 on the Hamilton Depression Scale
(HAM-D; Hamilton 1960). Other than these criteria, a
considerable heterogeneity in clinical presentation is
noted. Some studies excluded comorbid axis I diagnoses,
whereas others did not. The degree to which each study
included patients whose current episode showed resistance
to previous treatment also varied (two studies were specifically targeted at treatment-resistant patients: Moreno et
al 1997; Perez et al 1999).
Two types of clinical outcomes were evaluated. First,
increased efficacy of pindolol versus placebo augmentation was tested by comparing the reduction in HAM-D or
the response rate at the end point. Increased efficacy was
demonstrated in three studies and was not demonstrated in
six studies. Second, decreased latency was evaluated as a
difference in the time to reach clinical response between
groups. Decreased latency was demonstrated in five studies but not in four studies. Studies that reported decreased
latency mostly included patients with recent onset of the
current episode (Bordet et al 1998; Perez et al, in press;
Tome et al 1997; Zanardi et al 1997, 1998). The two
studies restricted to treatment-resistant patients (Moreno et
al 1997; Perez et al 1999) failed to report superiority of
pindolol augmentation versus placebo augmentation.
Finally, a common finding in these clinical studies is a
high degree of variability in response. For example, even
in the largest of the positive studies with fluoxetine the
proportion of patients demonstrating a sustained response
(greater than 19 days) was 38/55 in the pindolol group and
27/56 in the placebo group (Perez et al, in press). It is of
note that the one study conducted with 15 mg/day of

Pindolol Augmentation of SSRI Treatment

847

BIOL PSYCHIATRY
2000;48:844 – 853

Table 2. Occupancy of Corticolimbic and DRN 5-HT1A Receptors by Pindolol in Humans: PET Studies

Reference
Andree et al 1999
Rabiner et al 2000

Martinez et al, in press

Pindolol
regimen

Scan timing
relative to
dose

10 mg pindolol p.o. single dose
5 mg pindolol p.o. single dose
10 mg pindolol p.o. single dose
20 mg pindolol p.o. single dose
7.5 mg pindolol CR QD for 7 days
7.5 mg pindolol CR QD for 7 days
30 mg pindolol CR single dose

2 hours
2 hours
2 hours
2 hours
4 hours
10 hours
4 hours

n

Pindolol
plasma level at
scan time
(ng mL21)

Corticolimbic
regions

DRN

DRN vs.
cortical regions

3
3
4
3
8
8
8

32 6 5
10 6 5
15 6 3
55 6 17
18 6 8
763
58 6 24

24% 6 5%
9% 6 5%
13% 6 8%
46% 6 10%
18% 6 5%
12% 6 3%
42% 6 4%

16% 6 9%
10% 6 20%
37% 6 9%
39% 6 3%
40% 6 29%
38% 6 26%
64% 6 15%

ns
ns
,.001
ns
,.001
,.001
,.001

Occupancy

DRN, dorsal raphe nuclei; 5-HT, serotonin; PET, positron emission tomography; p.o., per os; CR, controlled release; QD, quaque die.

pindolol showed both increased SSRI efficacy and decreased latency period (Bordet et al 1998). With two
exceptions (Perez et al 1997, in press), studies did not
report pindolol plasma levels.

PET Studies
WAY-100635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide] is a
potent and selective 5-HT1A antagonist (Kd 5 0.1– 0.4
nmol/L) (Fletcher et al 1993; Forster et al 1995; Gozlan et
al 1995). Labeled with carbon 11 in the carbonyl position,
this ligand allows reliable quantification of 5-HT1A receptor availability in the human brain using PET (Farde et al
1998; Gunn et al 1998; Parsey et al, in press; Pike et al
1995). Three studies have measured the occupancy of the
5-HT1A receptor achieved in humans by pindolol (Andree
et al 1999; Martinez et al, in press; Rabiner et al 2000).
Findings from these PET studies are summarized in Table
2.
Andree et al (1999) studied inhibition of [11C]WAY
100635 binding in three male volunteers, 2 hours following the oral administration of 10 mg of pindolol. Pindolol
occupancy of 5-HT1A receptors in the DRN (16% 6 9%)
was not significantly different from the occupancy in
temporal and frontal cortices (24% 6 5%), at a mean
plasma pindolol level of 32 ng mL21.
Rabiner et al (in press) reported occupancy of 5-HT1A
receptors by pindolol following oral administration of
three different doses of pindolol (5 mg, 10 mg, and 20
mg), given as a single dose 2 hours before scanning. At the
5-mg dose (plasma level 10 6 5 ng mL21), no significant
occupancy was detected in either the DRN or temporal
regions, whereas occupancy was seen in all regions
examined (DRN, insula, and medial temporal lobe) at
10-mg and 20-mg doses. Following the 10-mg dose
(plasma level 15 6 3 ng mL21), a significantly larger
occupancy was measured in the DRN (37% 6 9%) than in
the cortical regions (13% 6 8%, p , .001). Following

the 20-mg dose (plasma level 55.1 6 16.8 ng mL21), the
DRN occupancy (39% 6 3%) was similar to the cortical
occupancy (46% 6 10%, p 5 .24). Rabiner et al (2000)
also evaluated the 5-HT1A receptor occupancy of two
other beta blockers, penbutolol and tertatolol, which have
also been shown to exhibit 5-HT1A activity and to enhance
the effect of paroxetine on 5-HT in the frontal cortex
(Gartside et al 1999). Penbutolol achieved significant
occupancy of 5-HT1A receptors at both doses tested (40
mg and 80 mg), with no differences between DRN and
corticolimbic 5-HT1A receptors. Tertatolol did not significantly affect [11C]WAY 100635 binding at the doses
tested (5 mg and 10 mg).
Martinez et al (in press) studied eight male subjects
under four conditions: at baseline (scan 1), then following
5 days of 7.5-mg controlled release pindolol (scan 2 at 4
hours after dose and scan 3 at 10 hours after dose), and 4
hours following an increase of the oral dose to 30 mg (scan
4). Pindolol occupancy of all brain regions examined
(dorsolateral, medial, orbitofrontal, and subgenual prefrontal cortices; anterior cingulate; parietal, occipital, insular, and medial temporal cortices; and DRN) was significant (20% 6 8% at scan 2, 14% 6 8% at scan 3, and
44% 6 8% at scan 4 at plasma pindolol concentrations of
18 6 8 ng mL21, 7 6 3 ng mL21, and 58 6 24 ng mL21,
respectively). Occupancy in the DRN was significantly
higher than occupancy in all other regions at each dose.
Dorsal raphe nuclei occupancy was 40% 6 29% on scan
2, 38% 6 26% on scan 3, and 64% 6 15% on scan 4
compared to an average occupancy in all other regions of
18% 6 5% on scan 2, 12% 6 3% on scan 3, and 42% 6
4% on scan 4. Analysis of the relationship between
pindolol plasma level and 5-HT1A occupancy in scans 2
and 4 revealed maximal effect values (6 SE) of 95% 6
23% in the DRN and 53% 6 17% in postsynaptic regions
and concentration at the half maximal response values of
24 6 15 ng mL21 for the DRN and 21 6 18 ng mL21 in
postsynaptic regions. This result suggests that the sites that
display high affinity for pindolol corresponded to the

848

BIOL PSYCHIATRY
2000;48:844 – 853

whole population of 5-HT1A receptors in the DRN and
only about half of the 5-HT1A receptors in the postsynaptic
areas.
In summary, PET studies demonstrate a significant
occupancy of 5-HT1A receptors in humans by pindolol but
also suggest that the occupancy resulting from the regimens used in clinical trials (2.5 mg thrice daily) is low and
highly variable between subjects. Higher occupancy and
lower variability are observed at large doses.
Differences in DRN versus corticolimbic occupancy
have not been consistently reported by PET studies (Table
2). These differences might be related to differences in
experimental design and imaging protocol. Martinez et al
(in press) measured occupancy following sustained administration of a controlled release formulation of pindolol,
rather than following a single dose of pindolol (Andree et
al 1999; Rabiner et al 2000). The duration of the scans
varied and data were analyzed using different methods;
however, none of these differences are suspected a priori
to bias the comparison of the DRN versus cortical occupancy. More likely, the failure to observe DRN selectivity
in the study of Andree et al (1999) and in the high dose
used by Rabiner et al (2000) might be due to the noise
associated with the measurement of DRN [11C]WAY
100635 binding potential (BP) and the small number of
subjects (three to four) included in these two studies.
Lastly, it is important to note that the partial volume
effect will influence [11C]WAY 100635 BP measurements
more in the DRN than in corticolimbic regions, given the
difference in the respective sizes of these regions. Yet, the
magnitude of the partial volume effect is dependent only
on the volume of the structure and not on the level of
activity (Kessler et al 1984). Therefore, the partial volume
effect would be expected to affect both the baseline and
pindolol occupancy scans equally, and would not explain
the greater pindolol-induced decrease in DRN binding
relative to corticolimbic regions.

Potential Mechanisms Underlying Pindolol
DRN Selectivity
The apparent relative selectivity of pindolol for DRN
5-HT1A autoreceptors might result from the fact that
pindolol is a weak agonist rather than a pure antagonist.
Pindolol was initially characterized as an antagonist at the
5-HT1A receptor, given that it was shown to have no effect
on 5-HT levels (Hjorth and Sharp 1990, 1993; Romero et
al 1996; Sharp et al 1989) or was reported to increase
extracellular 5-HT in the prefrontal cortex (Maione et al
1997), hippocampus (Assie and Koek 1996; Bosker et al
1994; Gur et al 1997; Matos et al 1996), and caudate
(Fornal et al 1999a), as well as the DRN itself (Maione et
al 1997; Matos et al 1996), via blockade of the 5-HT1A

D. Martinez et al

autoreceptor. More recent studies, however, have indicated that pindolol acts as a partial agonist at the 5-HT1A
autoreceptor. Pindolol alone has been shown to inhibit the
cells of the DRN (Clifford et al 1998; Fornal et al 1999c,c;
Haddjeri et al 1999), decrease 5-HT in the frontal cortex
(Gobert and Millan 1999), and decrease 5-HT synthesis
and metabolism (Hjorth and Carlsson 1986). NewmanTancredi et al (1998) demonstrated that pindolol produces
an increase in guanosine-59-O-(3-[35S]thio)-triphosphate
binding in cells transfected with the human 5-HT1A
receptor, but that the increase is only 20% that of induced
by 5-HT, consistent with weak partial agonist activity.
Taking all of these findings together, it appears that the
effect of pindolol as an antagonist or weak partial agonist
at the 5-HT1A receptor may ultimately depend upon the
local concentration of endogenous 5-HT (Gobert and
Millan 1999).
The agonist nature of pindolol at the 5-HT1A receptor
might account for the regional differences in binding
observed in the PET studies. The binding of agonists to the
5-HT1A receptor is modulated by G protein coupling
(Harrington and Peroutka 1990); the addition of GTP or its
analogue guanylyl imidodiphosphate results in a significant reduction in the percentage of 5-HT1A receptors
configured in a state of high affinity for agonists (Mongeau et al 1992; Nenonene et al 1994). Thus, addition of
GTP results in reduced binding of 5-HT1A agonists
(Emerit et al 1990; Hall et al 1986; Mongeau et al 1992),
whereas the binding of pure antagonists such as [3H]WAY
100635 is unaffected (Emerit et al 1990; Gozlan et al
1995; Khawaja et al 1995). As a partial agonist, the
binding of pindolol is expected to be affected by G protein
coupling and affinity state. Therefore, the preferential
occupancy by pindolol of the DRN 5-HT1A receptors
relative to corticolimbic 5-HT1A receptors might stem
from the presence of a larger proportion of DRN 5-HT1A
receptors being configured in the high-affinity state. This
hypothesis is supported by preclinical data. The number of
receptor sites labeled by [3H]WAY 100635 in corticolimbic areas is 36 – 60% higher than those labeled with
agonist [3H]8-OH-DPAT (Fletcher et al 1993; Gozlan et al
1995; Khawaja 1995; Khawaja et al 1995), suggesting that
only a subset of 5-HT1A receptors is in the high-affinity
state in these regions. In contrast, Khawaja et al (1995)
reported similar Bmax for [3H]WAY 100635 and [3H]8OH-DPAT in the DRN, suggesting that most of the DRN
5-HT1A receptors are configured in the high agonist
affinity state.
Although differences in G protein coupling may contribute to the regional differences in occupancy, there is
also evidence to support a role for cellular processes
further downstream. A study by Radja et al (1992)
demonstrated that receptor/G protein coupling was similar

Pindolol Augmentation of SSRI Treatment

in the hippocampus and DRN, a finding also reported in a
more recent study by Meller et al (2000). Although both
receptors have been shown to be linked to pertussis
toxin–sensitive Gi/Go regulatory proteins, activation of the
somatodendritic autoreceptor results in membrane hyperpolarization secondary to G protein– coupled K1 conductance, which inhibits firing and results in a reduction of
5-HT synthesis and release in the forebrain (Blier et al
1993; Hjorth and Magnusson 1988; Meller et al 2000);
however, unlike the postsynaptic receptor, the presynaptic
receptor does not appear to affect adenylyl cyclase activity
(Clarke et al 1996; Johnson et al 1997). Furthermore, the
postsynaptic receptor appears to have two populations of
receptors, one that produces hyperpolarization via increased K1 conductance and another that inhibits forskolin-mediated stimulation of adenylyl cyclase activity
(Meller et al 2000). The relevance of these differences
between pre- and postsynaptic 5-HT1A for the binding of
pindolol remains to be elucidated.

Clinical Implications of PET Data
Estimation of Occupancy Achieved in
Clinical Trials
To our knowledge, only two clinical studies reported
plasma levels of pindolol. Perez et al (1999) measured
pindolol plasma levels of 9.9 6 5.1 (SD) ng mL21 in a
sample of 40 subjects treated with a combination of
pindolol (2.5 mg thrice daily) and SSRIs (fluoxetine,
paroxetine, fluvoxamine, or clomipramine). Slightly lower
pindolol plasma values (6 –7 ng mL21) were reported in a
group of 55 patients under a pindolol–fluoxetine combination (Perez et al, in press). These data indicate that the
pindolol plasma levels reached in clinical studies are in the
6 –10 ng mL21 range. Using pharmacokinetic parameters
derived from Martinez et al (in press), a plasma level of 10
ng mL21 is predicted to be associated with low 5-HT1A
occupancy (28% and 17% in the DRN and corticolimbic
regions, respectively). Plasma levels of 6 ng mL21 are
predicted to be associated with only 19% and 12%
occupancy in the DRN and corticolimbic regions, respectively. The average DRN 5-HT1A receptor occupancy is
thus in the 25% range in these clinical studies.
It is unclear if 25% occupancy of DRN 5-HT1A receptors is enough to achieve the desired clinical effect. The
minimal occupancy of DRN 5-HT1A receptors needed to
achieve blockade of the SSRI-induced activation of these
receptors has not been well documented. In the classic
study of Romero et al (1996), a (2)pindolol dose of at
least 10 mg/kg IP was required to significantly block the
decrease in striatal 5-HT induced by direct application of
citalopram (50 mM) in the DRN. To our knowledge, the
occupancy of DRN 5-HT1A receptors achieved by 10

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2000;48:844 – 853

849

mg/kg IP pindolol in the rat has not been reported. Yet, a
dose of 15 mg/kg IP (2)pindolol has been reported to
occupy 76% of DRN 5-HT1A receptors (Corradetti et al
1998), and it is likely that the occupancy following 10
mg/kg IP is in the range of 50% (i.e., higher than the 25%
achieved in clinical studies). Studies combining occupancy and electrophysiologic or microdialysis measurements are needed to clarify this question.

Between-Subject Variability
The second practical implication of the PET studies is the
large between-subject variability in both pindolol plasma
levels and occupancy, particularly at the lower dose. For
example, the occupancy of DRN 5-HT1A receptors following 1 week of pindolol 7.5 mg/day varied from no
detectable occupancy to 48% occupancy in the group
studied by Martinez et al (in press). Rabiner et al (2000)
also reported a greater degree of variability between
subjects at the lower dose. This variability might account
for some of the variability in response observed in the
clinical studies. In the study by Martinez et al (in press) the
variability in DRN occupancy was partially accounted for
by between-subject differences in pindolol plasma levels,
indicating that plasma level monitoring would be useful in
clinical studies to adjust the dose to a level compatible
with appropriate occupancy.

Therapeutic Window
The selective DRN occupancy of pindolol observed in
PET studies implies the existence of a therapeutic window
of pindolol plasma concentrations. The therapeutic window includes the range of pindolol concentrations at
which a marked difference is reached between DRN
occupancy (which should be high to potentiate SSRI
effects on 5-HT transmission) and cortical occupancy
(which should be low to maintain activation of postsynaptic 5-HT1A receptors). Positron emission tomography
studies predict that a pindolol regimen of 6.25 mg thrice
daily (18.75 mg/day) would be necessary to achieve 50%
occupancy of DRN 5-HT1A receptors. At this dose, occupancy in corticolimbic regions would be only 32%, and the
difference in occupancy between the two regions would be
18%. The difference in occupancy achieved at this dose is
close to the maximal difference in occupancy, which is
predicted to occur at a plasma pindolol level of 63 ng/mL
(DRN occupancy of 73% and corticolimbic occupancy of
52%, difference of 21%).

Profile of the Ideal Compound for Augmentation of
SSRI Antidepressant Effects
Assuming that selective blockade of 5-HT1A autoreceptors is useful for hastening the clinical response to

850

D. Martinez et al

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2000;48:844 – 853

SSRI, the PET data presented here provide some clues
about the desired properties of compounds selected for
this application. The data suggest that pindolol might
not be the ideal compound, since the side effects
associated with its b-adrenergic blocking properties
might preclude its use in routine clinical practice at
doses (15–25 mg/day) required to block 50% of the
DRN 5-HT1A receptors. It is currently assumed that
silent 5-HT1A antagonists would be the optimal pharmacologic agents for this application: WAY 100635 or
other silent antagonists provide superior potentiation of
SSRIs’ acute effects on 5-HT transmission compared
with pindolol, a difference attributed to the fact that
pindolol is a partial agonist (Clifford et al 1998;
Gartside et al 1999; Sharp et al 1993); however, if DRN
selectivity is a unique feature of partial agonists and if
it is important to minimize blockade of postsynaptic
5-HT1A receptors, a weak and DRN-selective partial
agonist might still be the drug of choice for this
application. Positron emission tomography studies of
other 5-HT1A partial agonists and silent antagonists are
warranted to evaluate the relationship between pharmacologic profile and DRN selectivity. The higher the
DRN selectivity of the candidate drug, the larger the
therapeutic window within which DRN autoreceptors
would be inhibited without interfering with 5-HT transmission at the postsynaptic receptors. Finally, given that
the goal of this pharmacologic strategy is to hasten
therapeutic response, appropriate plasma levels of the
candidate drug should be reached rapidly, maybe using
an initial loading dose. Again, PET imaging provides a
unique tool to define the relationship between pharmacokinetic and therapeutic windows.

Conclusion
Recent PET imaging studies revealed that the occupancy
of DRN 5-HT1A receptors achieved during clinical trials
aimed at hastening or augmenting the antidepressant
effects of SSRIs might have been suboptimal for achieving
the desired potentiation of 5-HT transmission. This factor,
as well as the important between-subject variability in
occupancy, might account for the mixed results reported in
double-blind, placebo-controlled studies. On the other
hand, pindolol appeared to be associated with significant
in vivo selectivity for DRN 5-HT1A autoreceptors, relative
to corticolimbic postsynaptic receptors. This DRN selectivity is presumably desirable for potentiation of 5-HT
transmission and represents an important proof of concept
for the development of new 5-HT1A agents for this
application. Early evaluation of new drugs with PET
imaging will enable rapid screening of compounds based

on DRN selectivity, and more rigorous determination of
doses to be tested in clinical trials.

This work was supported by the U.S. Public Health Service (National
Institute of Mental Health Grants Nos. K02 MH01603-0 and T32-MH
18870).

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