Serotonrn-Dopamine Interaction and Its Relevance to Schizophrenia

Shitij Kapur, M.D., F.R.C.P.C., and Gary Remington, M.D., Ph.D., F.R.C.P.C.

Objective: The therapeutic success of clozapine and risperidone has focused attention on
the interaction between the serotonin and dopamine systems as an avenue for superior thera-
peutics in schizophrenia. The authors review the neurobiological basis for this interaction and
its clinical relevance. Method: The authors synthesized information from more than 1 00 pub-
lished articles obtained through electronic and bibliography-directed searches. Findings: The
serotonin system inhibits dopaminergic function at the level of the origin of the dopamine
system in the midbrain as well as at the terminal dopaminergic fields in the forebrain. Seroto-
nergic antagonists release the dopamine system from this inhibition. This disinhibition of the
dopamine system in the striatum may alleviate neuroleptic-induced extrapyramidal symptoms,
and a similar disinhibition in the prefrontal cortex may ameliorate negative symptoms. How-
ever, the benefits of combined serotonergic-dopaminergic blockade may be observed in only
a narrow dose range and may be lost with doses that produce suprathreshold dopaminergic
blockade. Conclusions: Serotonergic modulation of dopaminergic function provides a viable
mechanism for enhancing therapeutics in schizophrenia, but much remains unclear. Future
research will have to establish the existence of this interaction in humans in vivo, specify the
conditions under which it leads to optimal therapeutic benefits, and explore the possibility of
using specific serotonergic treatments as flexible adjuncts to typical neuroleptics, rather than
the present trend toward using single drugs with combined actions.
(Am J Psychiatry 1996; 153:466-476)

T he therapeutic
cently, risperidone
success of clozapine
has focused attention
and, more re-
on the Se-
reviews
and serotonin
the anatomy
systems
and physiology
and the neural
of the dopamine
bases for their
rotonin system and its interaction with the dopaminer- interaction. The second section examines the functional
gic system as an avenue for superior treatment of relevance of serotonin-dopamine interaction, as dem-
psychotic illnesses. Understanding the interaction be- onstrated in animal models and experimental human
tween serotonin and dopamine and its therapeutic im- studies. The third section evaluates the role of the sero-
plications is particularly timely because a number of tonin-dopamine interaction in the efficacy of the
new antipsychotic medications (e.g., olanzapine, sero- “atypical” neuroleptics like clozapine and risperidone.
quel, sertindole, ziprasidone) with serotonin-dopamine We conclude by highlighting the unanswered questions
interaction profiles are being tested in clinical trials (1). regarding the relevance of the serotonin-dopamine in-
In the light of this burgeoning scientific and clinical in- teraction and, in doing so, indicate directions for future
terest, we reviewed the neural basis and clinical rele- research.
vance of the serotonin-dopamine interaction. Evidence
for a primary role of serotonin in the etiology of schizo- NEUROBIOLOGICAl. BASIS OF THE SEROTONIN-
phrenia has been covered recently by others (2, 3) and
will not be a focus of this article. DOPAMINE INTERACTION
This review is divided into three sections. The first
The Dopamine and Serotonin Systems

Received Aug. 16, 1995; revision received Oct. 31, 1995; accepted
The dopaminergic system arises from groups of cells in
Nov. 17, 1995. From the Clarke Institute of Psychiatry. Address re-
print requests to Dr. Kapur, PET Centre, The Clarke Institute of Psy-
the midbrain. Neurons from the substantia nigra ascend
chiatry, 250 College St., Toronto, Ont., Canada MST 1R8. to the striatum, via the nigrostriatal pathway, and are
Supported in part by an award from the National Alliance for Re- primarily involved in the modulation of motor behavior,
search on Schizophrenia and Depression and by a Clinician Scientist whereas neurons from the ventral tegmental area pro-
Development Award from the Medical Research Council of Canada
ject to the limbic (mesolimbic projections) and cortical
(l)r. Kapur).
The authors thank Drs. Phil Seeman, Mary Seeman, and Robert (mesocortical projections) regions and are involved in cog-
Zipursky for their insightful comments. nition and modulation ofmotivation and reward (4). The

466 Am J Psychiatry I 53:4, April 1996

 SHITIJ KAPUR AND GARY REMINGTON

effects of dopamine released by FIGURE 1. Functional Interactions Between the Serotonin-Dopamine Systems and Their Role in
these projections are mediated Reducing Extrapyramidal Symptomsa
through a series of dopamine re-
ceptors (D1-D5) grouped into Striatitm
two families, the D1 family (D1
D2 blockade causes EPS.
and D5) and the D7 family (D2, Motor
Outputs from
D3, D4), on the basis of their ge- 5-HT antagonists release DA inhibition.

netic homology and common

Decrease EPS.
second messenger systems. The
a-_________#{149}
Raphe-striatal pathway
D1 receptors are prominent in
the cortical regions, D7 receptors
are prominent in the striatum,
and D3 and D4 receptors have a
higher distribution in the limbic
regions. Presynaptic dopamine
receptors may be localized on the
Raphe-nlgral pathway
cell bodies in the midbrain (so-
matodendritic autoreceptors),
where they modulate the firing 5-HT, antagonists release DA from inhibition.
Decreases EPS.
of dopamine neurons, or on the
axonal terminals of dopamine Substantla Nigra
neurons (terminal autorecep-
tors), where they modulate the re- aDAdopamine neurons, 5-HT=serotonin neurons, GABA=y-aminobutyric acid neurons,
lease ofdopamine (5, 6). Postsy- ACh=cholinergic interneurons, EPS=extrapyramidal symptoms. The D, dopamine receptors are
naptic dopamine receptors me- represented by an open cross, the 5-HT, receptors by a circle, and the 5-HTiA receptors by a triangle.
diate the effect of dopamine on This figure is a schematic representation of the mechanism and consequences of the interaction
between serotonin and dopamine at the level of the substantia nigra and the striatum. S-HT2 an-
the nondopaminergic postsy-
tagonists and the S-HTIA autoreceptor agonists inhibit the serotonin system and thus release the
naptic neurons. dopamine system from this inhibition (disinhibition of the dopamine system). The release of the
The serotonergic neurons also dopamine system from serotonergic inhibition ameliorates extrapyramidal symptoms.
arise from discrete midbrain
nuclei; the dorsal raphe nucleus
and the median raphe nucleus provide the most promi- the firing of the dopaminergic neurons (7, 13). Most of
nent projections. The dorsal raphe nucleus projects to these raphe-nigral neurons arise as collaterals of the ra-
the cortex and the striatal regions, and the median ra- phe-striatal neurons, thus providing a neural basis for
phe nucleus projects to the limbic regions (7). The sero- coordinated modulation of midbrain and terminal do-
tonin receptors are grouped on the basis of shared ge- paminergic function (14). The stimulation of dorsal ra-
netic sequences and second messenger systems into phe serotonergic fibers releases serotonin in the sub-
three classifications: 1 ) the 5-HT1 family (5-HTIA, 5- stantia nigra (13). This is associated with a decrease in
HTID, S-HTIE, and S-HTIF), which uses G-protein-me- the firing rate of the dopamine neurons and antagonizes
diated signal transduction; 2) the 5-HT family (5-HT2A, dopamine-mediated behaviors, suggesting an inhibi-
5-HT2, S-HT2, and S-HT4), which uses phosphoino- tory modulation of the dopamine neurons in the sub-
sitol-mediated signal transduction; and 3) the S-HT3 stantia nigra by serotonin (11, 12, 15-19). This inhibi-
receptor, which uses ion-gated channels for signal tory action seems to be modulated by S-HT2 receptors
transduction (8). The somatodendritic serotonergic located on the somatodendritic surface of the dopamine
autoreceptors, mainly 5-HT1A type, are found on the neurons (9, 12, 17, 20). As expected, anatomical or
serotonergic neurons in the raphe nuclei and modulate chemical lesions that disrupt the raphe-nigral projec-
the firing of the serotonergic neurons. The terminal tion (17, 18), 5-HT1A agonists that functionally inhibit
autoreceptors, probably S-HTID subtype, modulate the the raphe-nigral neurons (16, 21, 22), or 5-HT2 antago-
release of serotonin from the serotonergic neurons. On nists that antagonize the effect of the raphe-nigral sys-
the other hand, postsynaptic serotonin receptors medi- tem (20) all lead to a biochemical and functional disin-
ate the action of serotonin on the nonserotonergic neu- hibition of the dopamine system. Figure 1 illustrates the
rons, with the 5-HT1A receptors being prominent in the major elements of this interaction.
limbic regions and 5-HT2 receptors prominent in the
motor regions (7-10). Serotonergic Inhibition of Dopaminergic Function
in the Forebrain
Serotonergic Inhibition of Dopaminergic Function
in the Midbrain Tract tracing (23, 24) and immunohistochemical
studies (25-27) have shown that serotonergic neurons
Serotonergic projections from the dorsal raphe 1 1,( that arise in the dorsal raphe nucleus project uninter-
12) project directly to the substantia nigra and inhibit ruptedly via the medial forebrain bundle to the striatum

Am J Psychiatry I 53:4, April 1996 467

SEROTONIN-DOPAMINE INTERACTION AND SCHIZOPHRENIA

and cortex (7). Stimulation of these raphe-striatal neu- disinhibit the dopamine system and ameliorate cata-
rons, or the striatal administration of serotonergic lepsy. Conversely, enhancing serotonergic function
agonists, causes an inhibition of striatal neuronal firing, (with serotonin precursors, direct agonists, or SSRIs)
presumably by means of a decrease in synaptic dopa- would be expected to further inhibit the dopamine sys-
mine (24, 28-31 ). This effect seems to be mediated by tem and worsen catalepsy. We now examine evidence
the 5-HT2 receptors (30, 32-36) and may result from a in support of these paradigms.
decreased release (32, 33, 37, 38) or a decreased synthe- In one of the earliest studies of this phenomenon,
sis of dopamine in the terminals (18, 35, 39, 40), al- Kostowski et al. (37) showed that lesions of the raphe
though the decreased synthesis has not been consis- nuclei prevent and ameliorate neuroleptic-induced cata-
tently observed (41, 42). Nonetheless, the concept of lepsy in rodents, a finding subsequently confirmed for
serotonergic modulation of dopamine function receives anatomical and chemical raphe lesions (52, 53). Fur-
clear impetus from in vivo positron emission tomogra- thermore, there is a close relationship between the de-
phy (PET) studies in baboons showing that altanserin, gree of ablation of the raphe, the loss of serotonin in the
a S-HT2 antagonist, increases the release of endogenous striatum, and the degree to which the catalepsy is pre-
dopamine, while citalopram, a selective serotonin reup- vented (54).
take inhibitor (SSRI), decreases the release of endo- S-HT1A agonists, by means of their action on soma-
genous dopamine (43). todendritic autoreceptors, inhibit the firing of seroto-
Consistent with this inhibitory influence of serotonin nergic neurons. Several studies (55-58) reported a
on dopamine, lesioning the serotonergic projections beneficial effect of 5-HTIA agonists in reversing and
disinhibits the dopamine system and causes an increase preventing the development of catalepsy in rodents, and
in striatal dopamine levels (IS, 44). Similarly, 5-HT2 this effect has now been confirmed in primate models
antagonists block serotonin’s inhibitory action on of extrapyramidal symptoms (59, 60). It is specific for
striatal dopamine and result in increased dopamine 1ev- the S-HTIA subtype, is not observed with other S-HT1
els in the striatum (28, 31, 36, 43, 45). Similar evidence receptor subtypes (55), and is distinct from the S-HT2
exists for striatal control of limbic and cortical dopa- effect (56). These findings suggest that the combination
mine function (10, 46). It is to be noted, however, that of a S-HTIA agonist and a D,-antagonist may lead to
serotonin has a direct influence on the cholinergic and extrapyramidal symptom-free antipsychotic activity
‘y-aminobutyric acid (GABA) system, and some of sero- (58). However, to our knowledge, no such studies exist
tonin’s effects on the dopamine system may be medi- in humans.
ated, indirectly, through its modulation of the GABA With respect to 5-HT2 antagonism and its effect on
and cholinergic system (17, 18, 47-49). catalepsy in rodents, Maj et al. (61) reported that cy-
In summary, there is convincing evidence that the se- proheptadine, a 5-HT2 antagonist, prevents catalepsy,
rotonergic projections inhibit dopamine function at although this interpretation is confounded by the an-
two levels: at the level of the midbrain they inhibit the ticholinergic properties of cyproheptadine. Subsequent
firing of the dopamine cells projecting from the sub- reports using specific 5-HT2 antagonists have con-
stantia nigra, and in the striatum and cortex they inhibit firmed a role for 5-HT2 in alleviating catalepsy (53, 55,
the synaptic release of dopamine and probably the syn- 56, 62) and have also shown that 5-Hi’, antagonists
thesis of dopamine. As a result, serotonergic agonists, enhance dopamine-mediated motor behavior in models
serotonin precursors, and SSRIs enhance the inhibition other than catalepsy (63, 64). Other groups, however,
of the dopamine system. Conversely, lesions of the ra- failed to find this effect, even though they used drugs
phe nuclei, 5-HT1A agonists (through their action on with similar S-HT2 activity and similar animal models
autoreceptors), and 5-HT2 antagonists disinhibit the (58, 65). The results in primate models of extrapyrami-
dopamine system. dal symptoms also show variance: there have been re-
ports of a beneficial effect of 5-HT2 antagonists in the
Cercopethicus species (66) but no such effects in several
FUNCTIONAL RELEVANCE OF THE SEROTONIN- investigations of the Cebus species (59, 67, 68).
DOPAMINE INTERACTION This variance in the findings may reflect differences
in the relevance of the serotonin-dopamine interaction
Relevance of the Serotonin-Dopamine Interaction across different species or differences in the models used
in Animal Models of Extrapyramidal Symptoms to study extrapyramidal symptoms (68). The latter sug-
gestion is buttressed by the demonstration in physio-
Neuroleptic-induced extrapyramidal symptoms in logical experiments (38) that S-HT2 antagonism may
humans result from occupancy of D2 receptors in the ameliorate the functional effects of D7 antagonism
striatum (50). Neuroleptic-induced catalepsy in ani- when it is partial but may not be able to reverse the
mals, which represents a similar mechanism, provides a effects if D7 blockade is complete. In addition, a recent
valuable model to study extrapyramidal symptoms report (69) showed that ritanserin, a 5-HT2 antagonist,
(51). Since serotonin exerts an inhibitory influence on was able to antagonize haloperidol-induced catalepsy
the dopaminergic system, manipulations that inhibit se- when induced with low doses of haloperidol but was
rotonin function (raphe lesions, S-HTIA autoreceptor ineffective when suprathreshold doses of haloperidol
agonists, or 5T2 antagonists) would be expected to were used to induce catalepsy. Thus, 5-HT2 blockade

468 Am J Psychiatry 1 53:4, April 1996

 SHITIJ KAPUR AND GARY REMINGTON

may bestow only a limited protection from the effects out of 1,000 individuals treated with these drugs. This
of D, blockade, a concept that will be of particular rele- suggests that in some individuals who are either receiv-
vance in the discussion of the antagonism between 5- ing drugs inducing D2 antagonism or have asympto-
HT, and D7 in the clinical context. matic Parkinson’s disease the marginal increase in do-
In keeping with the overall argument, serotonergic pamine antagonism caused by the SSRI is enough to
agonists would be expected to further inhibit the dopa- push them over the threshold for extrapyramidal symp-
mine system and worsen extrapyramidal symptoms. In- toms (87). However, for the majority of individuals the
deed, it has been reported that S-hydroxytryptophan (a degree of D2 antagonism induced by SSRIs does not by
precursor of serotonin) and quipazine (a direct acting itself cross the extrapyramidal symptom threshold.
agonist) worsen haloperidol-induced catalepsy in rats
(53, 62). Similarly, SSRIs enhance serotonergic trans- The Serotonin-Dopamine Interaction
mission and worsen extrapyramidal symptoms in ro- and Negative Symptoms
dent and primate models, although the effect in pri-
mates may be species-dependent (62, 66, 67). Negative symptoms of schizophrenia involve a syn-
In summary, manipulations that inhibit the serotonin drome of flattened affect, alogia, and amotivation ac-
system (e.g., raphe lesions, 5-HTIA agonists, and S-Hi’, companied by emotional and social withdrawal. Typi-
antagonists) disinhibit the dopamine system and offer cal antipsychotics have limited efficacy against negative
an indirect avenue to alleviate neuroleptic-induced symptoms, and many patients freed from their delu-
extrapyramidal symptoms. The different interactions sions and hallucinations are still unable to resume pro-
and their functional effects on extrapyramidal symp- ductive lives due to enduring negative symptoms. De-
toms are illustrated in figure 1. spite their critical clinical importance, there are few, if
any, convincing animal models of negative symptoms
Relevance of the Serotonin-Dopamine Interaction (88). However, the neuropsychological similarity of pa-
in Alleviating Extrapyramidal Symptoms in Humans tients with prominent negative symptoms to patients
with frontal lesions and data from neuroimaging stud-
The earliest convincing evidence for serotonin-dopa- ies link negative symptoms to frontal dysfunction (89-
mine interaction in humans came from Ceulemans et al. 91 ). It has been suggested that this may reflect, at least
(70), who treated patients with schizophrenia with se- in part, hypodopaminergic function in the prefrontal
toperone, a S-HT, antagonist, in an open trial and dem- cortex (92-95). Such a model would predict that in-
onstrated a beneficial effect on extrapyramidal symp- creasing dopaminergic function in the prefrontal cortex
toms. It was unclear in this study, however, whether the may relieve negative symptoms, a view that led to the
benefit resulted from the discontinuation of the typical use of dopamine agonists with some success (96, 97).
neuroleptic or from the initiation of the setoperone. In Given the inhibitory effect of serotonin on dopami-
subsequent studies, Reyntjens et al. (71 ), Gelders (72), nergic transmission, it has been hypothesized that drugs
and Bersani et al. (73) used ritanserin, a more specific inhibiting serotonergic function may disinhibit dopami-
S-HT2 antagonist, in double-blind, placebo-controlled, nergic transmission in the prefrontal cortex and, as a
add-on trials and showed a significant improvement in result, may improve negative symptoms (97). This hy-
extrapyramidal symptoms. Beneficial effects of ritan- pothesis is supported by reports that clozapine, which
serin have now been reported in neuroleptic-induced is thought to improve negative symptoms, induces an
akathisia (74, 75) and in tremor arid akinesia observed increased turnover of dopamine in the prefrontal cortex
in Parkinson’s disease (76-78). Silver et al. (79) have of rodents, an effect not seen with typical antipsychotics
reported a beneficial trend for cyproheptadine in ame- (98, 99). More recent studies (100-102) suggest that
liorating extrapyramidal symptoms in patients receiv- this property of clozapine can be explained by its S-HT2
ing neuroleptics, although its anticholinergic properties antagonism. Thus, if current speculations regarding the
confound the role of its 5-HT2 blockade. In contrast, role of the prefrontal cortex in negative symptoms are
Korsgaard and Friis (80), using mianserin in a double- correct, 5-HT, antagonists could ameliorate negative
blind crossover trial in patients with neuroleptic-in- symptoms by means of their effects on the dopami-
duced parkinsonism, failed to find a beneficial effect of nergic system. It is worth noting that serotonergic pro-
5-HT2 antagonism. jections also have a direct inhibitory effect on the
SSRIs, the most commonly used serotonergic agon- prefrontal neurons, separate from their effect on the do-
ists, are known to induce an akathisia-like syndrome paminergic projections. Accordingly, some of the ef-
(81-83). More recent reports (77, 84, 85) also impli- fects of S-HT2 blockers on negative symptoms in ani-
cated SSRIs in a variety of extrapyramidal symptoms, mal models and humans may reflect a direct effect
ranging from tremor to dystonic reactions. Although rather than a dopamine-mediated effect on prefrontal
some of the subjects in these studies were receiving neurons (46, 103).
neuroleptics or had Parkinson’s disease (86), cases of de Ceulemans et al. (70) provided the first supporting
novo onset of characteristic parkinsonian symptoms clinical evidence by demonstrating that setoperone, a
have also been reported (85). Epidemiologic studies S-HT, antagonist, resulted in a significant improve-
(87) suggest that SSRI-induced extrapyramidal symp- ment in emotional withdrawal, autistic behavior, and
toms are definite, but rare, occurrences reported in one dysphoria in patients with schizophrenia. Reyntjens et

Am J Psychiatry 1 53:4, April 1996 469

SEROTONIN-DOPAMINE INTERACTION AND SCHIZOPHRENIA

al. (71) and Gelders (72), in an add-on, double-blind, that, in doses ranging from 4 to 8 mg/day, risperidone
placebo-controlled study of ritanserin, found a signifi- produces significantly fewer extrapyra midal symptoms
cant improvement in negative and affective symptoms than haloperidol (119-121), although the superiority
in the ritanserin-treated patients only. This finding has of risperidone in producing fewer extrapyramidal
now been replicated in another study (104), where symptoms is not as striking as that of clozapine. First,
maximum improvement was noted in affective flatten- the difference between risperidone and haloperidol in
ing and social relationships. Similar results have also terms of extrapyramidal symptoms became statistically
been reported in a study employing cyproheptadine in indistinguishable at doses beyond 6-8 mg (119, 120).
patients with predominantly negative symptoms (79), Second, no significant difference in producing extrapy-
although the 5-HT2 activity of cyproheptadine is con- ramidal symptoms was found when risperidone was
founded with its histaminergic and cholinergic effects. compared with perphenazine, a medium-potency agent
A little surprising, then, are the results of Silver and with a tendency to produce fewer extrapyramidal
Nassar (105), Spina et al. (106), and Goff et a!. (107), symptoms than haloperidol (122). Furthermore, recent
who found equally significant improvement in negative PET data suggest that risperidone and haloperidol are
symptoms with SSRI treatment. This presents an inter- almost equipotent at the dopamine D2 receptor (123,
esting puzzle-S-HT2 antagonists and SSRIs have op- 124); therefore, the comparative dose of haloperidol in
posing effects on the serotonergic system and, through these clinical trials (10-20 mg/day of haloperidol) may
the serotonin-dopamine interaction, on the dopaminer- have been too high (1, 125). Studies have shown that
gic system, so how do both of these drugs improve mean doses of 3.7 mg/day (126), 4 mg/day (127), or 3.3
negative symptoms? The answer lies, perhaps, in the mg/day (128) are as effective as 10-50 mg/day of halo-
possibility that what are currently recognized as nega- peridol and produce significantly fewer extrapyramidal
tive symptoms may in fact reflect separate pathophysi- symptoms. This raises the question of whether 4-8 mg
ological entities (90, 108, 109). Therefore, it is conceiv- day of risperidone would have shown the same supe-
able that both SSRIs and S-HT2 antagonists may riority in terms of extrapyramidal symptoms had it
improve manifest negative symptoms: the SSRIs may been compared with a lower dose of haloperidol. Al-
exert an effect on the depressive component of negative though clozapine causes virtually no extrapyramidal
symptoms, and the S-HT2 antagonists may exert an ef- symptoms, risperidone’s superiority is only relative to
fect on the extrapyramidal symptom component of high-potency neuroleptics and disappears with increas-
negative symptoms. ing dosage. This suggests that the mechanism for ris-
peridone’s superiority in terms of extrapyramidal
symptoms may be different from that of clozapine.
ROLE OF THE SEROTONIN-DOPAMINE INTER- The clue to risperidone’s having few extrapyramidal
ACTION IN THE EFFECTS OF CLOZAPINE symptoms at lower doses, as well as the diminution of
AND RISPERIDONE this benefit at high doses, may lie in the operation of the
mechanism of the serotonin-dopamine At a interaction.
Extrapyramidal Symptoms dose of 6 mg/day, risperidone 5-
demonstrates higher
HT2 than D2 occupancy (its 5-HT2 occupancy ranges
Numerous reports have established clozapine’s vir- from 80% to near saturation [129], and its D, occu-
tual freedom from extrapyramidal symptoms in usual pancy lies in the 74%-83% range, bordering on the
doses (1 10-1 13). Is this related to clozapine’s seroto- extrapyramidal symptom threshold 1123, 1291). At this
nin-dopamine interaction profile? It had been postu- dose, the presence of potent 5-HT2 antagonism may re-
lated that clozapine’s high ratio of S-HT2 to D2 affinity duce risperidone’s risk of extrapyramidal symptoms in
may account for its diminished extrapyramidal symp- comparison with a conventional neuroleptic. However,
toms (
1 14, 1 1 5). However, recent PET studies suggest as discussed earlier, the ability of S-HT2 antagonism to
otherwise. It has been shown that patients receiving counter the effects of D2 antagonism is limited. As the
conventional neuroleptics experience extrapyramidal dose of risperidone is increased beyond 6 mg/day, su-
symptoms only when D2 occupancy exceeds a thresh- prathreshold D2 blockade may result, and the seroto-
old, somewhere in the range of 75%-80% D2 occu- nin-dopamine interaction mechanism may no longer be
pancy (SO). Extrapyramidal symptoms are not ob- able to alleviate extrapyramidal symptoms (123).
served below these levels of D2 occupancy, even with It has been proposed that antipsychotics require a par-
the classical neuroleptics. Clozapine’s D2 occupancy ticular ratio of S-HT2 to D2 affinities (greater affinity for
varies from 20% to 67% (1 1 6, 1 1 7) and has never been 5-HT2 than D2) to obtain the beneficial effects of seroto-
shown to exceed the putative threshold for extrapy- nin-dopamine interaction with respect to extrapyramidal
ramidal symptoms. Thus, clozapine’s low extrapy- symptoms (1 14, 1 15). However, the S-F-IT2 to D2 affinity
ramidal symptom profile is explained more parsimoni- ratio of a drug is a fixed number, while the relative level
ously on the basis of its low D2 occupancy, and there of 5-HT2 and D2 blockade produced by a drug is a func-
appears to be no need to invoke the role of the seroto- tion of the dose. This is illustrated in figure 2. At low
nin-dopamine interaction to explain its superiority in doses, a drug with combined 5-HT2 and D, antagonist
alleviating extrapyramidal symptoms (118). activity shows marked preference for the S-HT2 receptors,
As for risperidone, a series of trials have confirmed whereas at the higher dose, both the D2 and the S-HT2

470 Am] Psychiatry 153:4, April 1996

 SHITIJ KAPUR AND GARY REMINGTON

receptors are almost completely blocked. FIGURE 2. Relationship Between Dose of Antipsychotic, 5HT2 and D2 Receptor Oc
Figure 2 demonstrates how the difference cupancy, and Extrapyramidal Symptomsa
between the 5-HT2 blockade and D2 block-
ade is notable when the level of D2 occu- D2strathreshold
pancy is just beyond the extrapyramidal t ‘
-

5-H; pnecIlon bat

symptom threshold, and this may prevent F -4------ D2ist threshokl
the clinical expression of extrapyramidal EPSonsetin , 5-H; protects against EPS
symptoms. However, at doses that result in a absence d5.HT

suprathreshold D2 occupancy, the prepon- 0

derance of S-HT2 blockade as well as the

benefits related to the serotonin-dopamine

I
‘I
interaction may be lost. This view is borne I
out by recent studies in animals (69), as well 5;HT2
as reports using PET imaging with risperi-
done in humans (123). Therefore, the thera-
peutic window observed in clinical trials
AB
U

with risperidone (1 1 9, 120) may not be pe-

culiar to risperidone but may simply reflect
Dose of a 5-H1 I D2 antipsychotic 0

limits of serotonergic protection in the face aThe figure demonstrates that levels of both 5-HT, (dashed curve) and D, receptor
of high D2 dopamine blockade. occupancy (solid curve) rise with increasing doses of an antipsychotic with S-HT, and
D, properties. At low doses, the 5-HT, occupancy is much higher than D, occupancy
Negative Symptoms (5-HT,>D,). However, at high doses the difference is negligible (S-HT,--D,). The ar-
row on the left represents the threshold for extrapyramidal symptoms in the absence
of S-HT, blockade. At dose A, the level of D2 blockade is just above the extrapyramidal
Prospective, controlled studies have
symptom threshold, but extrapyramidal symptoms are prevented because the S-HT,
demonstrated clozapine’s superiority to blockade is greater than the D2 blockade. However, at dose B, the D, blockade is
conventional neuroleptics in the treat- suprathreshold and the difference between S-HT, and D, blockade is minimal, con-
ment of negative symptoms (110, 130, ditions that result in the appearance ofextrapyramidal symptoms despite the presence
of 5-HT, blockade.
131). In the case of risperidone, the cvi-
dence is less clear. Of the published pro-
spective, double-blind trials, two (119, 120) reported renergic ai receptors (137, 138). In view ofthe putative
risperidone to be superior to haloperidol, but another roles of these other neurotransmitters in negative symp-
two studies (132, 133) failed to find such a difference. toms (79, 96, 139), it may be premature to assign the
In addition, these effects may be lost over time (121) superiority of clozapine and risperidone in the treat-
and may be evident only when low doses of risperidone ment of negative symptoms solely to their serotonin-do-
are compared with relatively higher doses of haloperi- pamine interaction properties.
dol (1 19, 120, 132). Moreover, few of these studies
have appropriately controlled for changes in factors
such as depression, extrapyramidal symptoms, and psy- FUTURE DIRECTIONS
chotic withdrawal, which could confound the improve-
ment in negative symptoms. When these confounding In summary, convincing evidence for the functional
factors are controlled statistically, some studies (134, relevance of the serotonin-dopamine interaction in alle-
135) found an effect of clozapine and risperidone on viating extrapyramidal symptoms in humans is avail-
primary negative symptoms, but others (136) failed to able from clinical trials in which specific 5-HT2 block-
distinguish these effects from changes in extrapy- ers have been added, and this is further buttressed by
ramidal symptoms and psychosis. the superior extrapyramidal symptom profile of risperi-
If we assume that these drugs have a primary effect done. The question still remains as to how S-HT2 an-
on negative symptoms, how do we explain this effect? tagonism prevents or alleviates extrapyramidal symp-
The preferential S-HT2 antagonism and resulting sero- toms in humans. Animal data permit us to postulate
tonin-dopamine interaction are promising candidates two plausible hypotheses, outlined in figure 3. Con-
for an explanation. This is supported by independent comitant 5-HT2 antagonism could release endogenous
clinical trials that have shown the superiority of selec- dopamine in the striatum, which in turn may displace
tive 5-HT2 antagonists in ameliorating negative symp- the neuroleptic from D2 sites in the striatum. Such a
toms and by the fact that the shared feature distinguish- hypothesis would predict that the addition of a S-HT2
ing clozapine and risperidone from conventional antagonist would shift the D2 occupancy curve to the
neuroleptics is their relatively higher S-HT2 than D2 an- right, thus increasing the dose at which the extrapy-
tagonism. However, these drugs are multifaceted, and ramidal symptom threshold is crossed (hypothesis I
clozapine demonstrates high affinities for the dopamine in figure 3). On the other hand, 5-HT2 blockade may
D4, serotonin 5-HTIC, adrenergic a, muscarinic, and elevate the threshold for extrapyramidal symptoms
histamine H1 receptors, while risperidone also exhibits through the modulating influences on cholinergic or
high affinity for dopamine D4, histamine H1, and ad- GABA-ergic mechanisms without a direct effect on

Am ] Psychiatry 1 53:4, April 1996 471

SEROTONIN-DOPAMINE INTERACTION AN1) SCHIZfI)PHRENIA

FIGURE 3. Two Hypotheses Regarding the Mechanisms Whereby 5-HI2 Antagonists Diminish tex are still in their infancy. There-
Extrapyramidal Symptomsa fore, investigating this aspect of se-
rotonin-dopamine interaction in hu-
mans may have to await the develop-
ment of valid in vivo measures of the
cortical dopamine system.
An assumption implicit in the
above explanations of the serotonin-
dopamine interaction is that the ef-
fect ofthe serotonin-dopamine inter-
action is different in different brain
regions. It is conventionally held that
23
antipsychotic action results from
EPS cns EPS
10
wlho5H1 wIt5HT inhibiting dopaminergic function
in the mesolimbic system and that
- Dose of a D2 antagonist-P - Dose a D2 antagorst + similar inhibition in the striatum
Hypothesis I Hypothesis II and the prefrontal cortex leads to the
5.HT, bbCk5d8 rise the EPS Ihreshoki
production or exacerbation of extra-
5-HT bbclieshitts Doccupancycttvetthe d1
pyramidal symptoms and negative
symptoms, respectively. We have ar-
‘EPS=extrapyramidal symptoms. Hypothesis I depicts how the addition of S-HT blockade
gued here that antipsychotics with a
releases endogenous dopamine and shifts the curve of D2 occupancy to the right (solid curve
serotonin-dopamine interaction pro-
depicts original ft occupancy curve, and the curve with dashes depicts the D, curve under the
influence of 5-HT, antagonists). The extrapyramidal symptom threshold remains the same, file may ameliorate extrapyramidal
hut the dose at which extrapyramidal symptoms manifests shifts because of a shift in the curve. symptoms and negative symptoms
In hypothesis II, the addition of the 5-HT, blockade raises the threshold of extrapyramidal by disinhihiting the dopamine system
symptoms, without a direct effect on D occupancy. This mechanism also increases the dose
in the striatum and the prefrontal
at which the extrapyramidal symptoms become clinically observable, hut there is no change
in the curve for 1) occupancy. Both mechanisms plausibly explain the observed finding that cortex. However, a similar func-
the addition of 5-HT) antagonism delays extrapyramidal symptoms. tional disinhibition in the mesolim-
bic regions would counteract the
primary antipsychotic action. There-
occupancy. In this case, one would expect no change in fore, our reasoning can he held together only if we can
the curve relating D, occupancy to dose, but one would demonstrate that serotonin’s influence on the dopamine
expect that the level of D, occupancy producing extra- system in the mesolimbic regions is either quantitatively
pyramidal symptoms would be higher, i.e., the extrapy- or qualitatively different from its effect in the striatum
ramidal symptom threshold would be raised (hypothe- and the prefrontal cortex.
515 II in figure 3). It is now possible to measure the Finally, we raise the issue of using two drugs, one
effects of 5-HT, antagonism on endogenous dopamine with specific 5-HT, and another with specific D2 an-
and D, blockade in humans, in vivo, and to relate these tagonism, to obtain the benefits of the serotonin-dopa-
findings to clinical outcomes. Therefore, these two hy- mine interaction. It is claimed ( 140) that newer antipsy-
potheses concerning the role of the serotonin-dopamine chotic agents like risperidone have an optimal balance
interaction in alleviating extrapyramidal symptoms are of S-HT, and D, affinities, which provides the benefits
eminently testable, and it is hoped that future research of the serotonin-dopamine interaction. However, the
will address them. crucial element is not the balance of 5-HT, and D, af-
The second major therapeutic role for the serotonin- finities of a givcn drug in a test tube, but the relative
dopamine interaction is in alleviating negative symptoms. levels of S-HT, and D, antagonism it produces in a
The clinical evidence available demonstrates improve- given patient. The limitation inherent in any drug that
ment in negative symptoms with S-HT2 antagonists but has both S-HT, and D, antagonism is that any effort to
does not unequivocally distinguish between primary and increase S-HT, blockade inexorably increases D2 an-
secondary improvements in negative symptoms. None- tagonism and vice versa (figure 2). Although recent
theless, how might the serotonin-dopamine interaction clinical trials have demonstrated the success of drugs
help in the amelioration of negative symptoms? It is pos- like risperidone, it is quite likely that independent con-
tulated that negative symptoms result from hypo- trol over the 5-HT, and D, system may provide for even
dopaminergic function in the prefrontal cortex. One could more effective treatment. Low-potency neuroleptics
hypothesize that 5-HT2 antagonism, by disinhibiting the that can be regarded as fixed combinations of anti-D2
dopaminergic system, would lead to enhanced dopami- and anticholinergic activity have been largely replaced
nergic transmission in the prefrontal cortex, which in turn by higher potency neuroleptics that provide relatively
could ameliorate negative symptoms. Although current selective D, blockade and that are electively and flex-
neuroimaging technologies permit the measurement of ibly combined with doses of anticholinergics. Thus,
dopamine receptors in the striatum, methods for evaluat- with better understanding of the role and implications
ing D2 receptors or dopamine levels in the prefrontal cor- of the serotonin-dopamine interaction, clinicians may

472 Am j Psvchiatr’v I 53:4, April 1 996

 SHITIJ KAPUR AND GARY REMINGTON

find that using two agents that permit independent con- 1 7. James TA, Starr MS: Rotational behaviour elicited by 5-HT in
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