Anxiety and the Serotonin1A Receptor

Jeremy D. Coplan, Susan I. Wolk, and Donald F. Klein

The serotonin (5-HT) receptor was first described in 1957 (25). Since then, there has been an explosion of knowledge regarding this ubiquitous neurotransmitter system. Despite extensive documentation of a role for the central 5-HT system in regulation of mood, anxiety, feeding, sleep, sexual activity, body temperature, and nociception (for review, see ref. 5), the mechanisms by which disorders of these functions are mediated remain unclear. At least eight receptor subtypes with specific neuroanatomical location and multiple intracellular effects following receptor activation have been identified (for review, see ref. 30 and Anatomy, Cell Biology, and Maturation of the Serotoerginic System: Neurotropic Implications for the Actions of Psychotropic Drugs). Such diversification of function implies an exceedingly complex system. Rheostat models of neural dysfunction propose that reductions or increases of a single neurotransmitter system are responsible for clinical psychopathology and are inadequate in understanding 5-HT receptor-related abnormalities. These authors (16, 37) have previously proposed a cybernetic model describing the inability of the system to maintain or regain homeostatic control of its neurotransmitters to facilitate understanding of 5-HT–related abnormalities in panic–anxiety. The neural substrate for cybernetic dysfunction is unclear, although the observation that certain psychotherapeutic drugs may act, in part, through regulatory 5-HT1A autoreceptors is of interest.

The 5-HT1A receptor was first described in 1981 (49), and is probably the best characterized of the 5-HT receptors. The recognition of anxiolytic effects of nonbenzodiazepine azapirones agents, which act as 5-HT1A partial agonists, such as buspirone, gepirone, and ipsapirone and their therapeutic role in clinical anxiety and mood disorders has further focused attention on the 5-HT1A receptor. Although the azapirones interact with other neurotransmitter systems, such as the dopaminergic (56) and noradrenergic (60), the azapirones display nanomolar affinity for 5-HT1A receptor sites (66). Interestingly, the anxiolytic effects of azapirones follow a time course observed with antidepressants where therapeutic effects are delayed for 3 to 4 weeks, which is unlike the rapid effects observed with benzodiazepine anxiolytics. The putative mechanism of therapeutic effects of these piperazine derivatives are complex and involve both pre- and postsynaptic receptor sites of action. We first review the preclinical studies followed by the available clinical data (see Serotonin Receptor Subtypes and Liagands).

Basic science and animal studies have facilitated identification of the 5-HT1A partial agonists, as well as delineated a role of the 5-HT1A receptor in the regulation of animal models of anxiety. From a preclinical perspective, the 5-HT1A receptor is discussed regarding its neuroanatomical location, its pharmacological properties, molecular biological structure, and intracellular signal transduction. The effects of the azapirones on behavioral responses reflective of anxiety in rodents are divided according to Lucki and Wieland (42) into three categories: (a) unconditioned behaviors elicited by 5-HT1A agonists (b) drug discrimination studies, and (c) conditioned behaviors. Studies suggesting an effect of 5-HT1A ligands on rodent distress vocalizations elicited by mother–infant separation are reviewed. Despite the recent extensive elaboration of the 5-HT system in preclinical studies, the emerging complexity of its function has only complicated clarification of its role in clinical anxiety.

Serotonergic pathways may be divided into ascending and descending pathways that project to the spinal cord and brainstem and to cortical and subcortical structures, respectively. There is good evidence that 5-HT modulates both motor and sensory processing at the level of the brainstem and spinal cord. Certain serotonergic nuclei are closely associated and modulate other brainstem structures implicated in anxiety, such as the nucleus locus coeruleus (47) and the nucleus paragigantocellularis (4). Serotonin-related dysfunction of sensory and motor modulatory processes may have consequences for nociceptive and cardiorespiratory psychophysiology.

Dense ascending serotonergic pathways project to the monkey amygdala, the parlimbic entorhinal and dentate gyrus, the rectus gyrus of the frontal lobe, and the inferior and superior gyri of the temporal lobe. The lowest levels in primates are seen in the occipital lobe and the precentral motor cortex of the frontal lobe (for review, see ref. 5). In man, rat, and guinea pig, 5-HT1A receptors are found in high concentration in the dorsal raphe nuclei, the hippocampal pyramidal cell layer, the lateral septum, the frontal cortex, and the dorsal horn of the spinal cord (19, 72). Neurotoxicity studies using 5,7-DHT (dihydroxytryptamine) indicate that the 5-HT1A receptors of the dorsal raphe are generally presynaptic, whereas hippocampal 5-HT1A receptors are largely postsynaptic (72).

Specific ligand studies with high affinity for the 5-HT1A receptor have facilitated characterization of the functional consequences of receptor activation. 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)-tetralin] possesses an almost 1000-fold selectivity for the 5-HT1A binding site (45). Many other ligands have been developed (30), although 8-OH-DPAT possesses the greatest specificity and has been most studied. In contrast to 5-HT1A agonists, ligands that are not strong 5-HT1A agonists (e.g., 1-3-fluoromethyl)phenyl]-piperazine (TFMPP) which is predominantly a 5-HT1B agonist) (65) and 1-(3-chlorophenyl)piperazine (mCPP, a functional 5-HT2 and 5-HT1C agonist) (29) are weak dorsal raphe autoreceptor agonists (1). b-Adrenoceptor antagonists including (-)-propranolol, spiperone, and pindolol may possess 5-HT1A antagonistic properties (1), but also show affinity for 5-HT1C receptors. Intracellular recordings from hippocampal pyramidal cells (CA1) in rat-brain slices have shown that direct application of 5-HT produces a membrane hyperpolarization and reduction in the input resistance from an opening of potassium channels (3). Buspirone and ipsapirone, which displace 5-HT binding in hippocampal preparations (26), produce only small hyperpolarizations, which is in accordance with their partial agonistic action at postsynaptic sites (2) but also reduces in a dose-dependent fashion certain firing patterns of the pyramidal cell layer (CA1) of the hippocampus (7). Low-dose microiontophoretic applications of ipsapirone, which do not affect spontaneous firing rates, attenuate excitation of pyramidal cells induced by the excitatory amino acid, glutamate (1).

The 5-HT1A receptor has been cloned and sequenced (see ref. 30, for review). The receptor structure is similar to that of the G-protein–coupled superfamily of neurotransmitter receptors. In the presence of guanosine triphosphate (GTP), the receptor complex dissociates into two components. The smaller 60-kd component is the actual receptor, whereas the larger 90-kd component is the associated G protein.

The human receptor is approximately 420 amino acids long and has seven putative transmembrane regions with four intervening peptide sequences facing the extracellular space, whereas four others face the cytoplasm. Like other receptors that inhibit adenylate cyclase, the 5-HT1A receptor has a relatively long third cytoplasmic peptide loop (C3), portions of which have been used to generate antibodies. In transmembrane regions 3, 6, and 7, the 5-HT1A receptor shares significant levels of amino acid sequences with the a2-, b1- and b2-adrenergic receptors. Interestingly, single-point mutations in the seventh transmembrane loop of the 5-HT1A receptor reduces receptor affinity by 100-fold for the b-antagonist, pindolol, but not for 5-HT and 8-OH-DPAT (see ref. 30, for review). Such data suggest that point mutations of receptor peptide sequences may have profound consequences for 5-HT receptor sensitivity.

The second messenger effects of the 5-HT1A receptor are diverse. Activation of the 5-HT1A receptor in rat hippocampal membranes was noted to inhibit forskolin-induced increases in adenylate cyclase. This 5-HT1A-mediated effect was abolished by pertussis toxin, suggesting involvement of the pertussis-sensitive Gi-protein. The Gi protein is negatively coupled to adenylate cyclase and thereby reduces cyclic adenosine monophosphate (cAMP) dependent protein kinase activity. Cloning studies using human 5-HT1A receptors transfected in cell cultures support the view that 5-HT1A receptor activation mediates inhibition of adenylate cyclase via the pertussis-sensitive Gi protein and also stimulates phosphoinositide turnover. The clinical relevance of abnormal intracellular signal transduction following 5-HT receptor activation is relatively unexplored (for review, see ref. 30).

Based on in vivo electrophysiological experiments, Blier et al. (8) have postulated that 5HT1A partial agonists mediate antidepressant effects through a net increase in serotonergic neurotransmission following adaptive receptor changes. The firing activity of 5-HT neurons of the dorsal raphe nucleus during the course of gepirone administration was studied. The responsiveness of 5-HT neurons to autoreceptor stimulation by lysergic acid diethylamide (LSD) given intravenously and microiontophoretic dorsal raphe applications of 5-HT, LSD, 8-OH-DPAT, and gepirone was decreased after 14 days of gepirone treatment. Gepirone applied microiontophoretically to postsynaptic sites of the hippocampal pyramidal neurons decreased firing rates, as does 5-HT application, although the responsiveness of hippocampal neurons did not diminish after 14 days of gepirone administration. Thus, gepirone activates postsynaptic 5-HT receptors without inducing a desensitization upon long-term administration. The recovery of presynaptic release of 5-HT in combination with pharmacological activation of unaltered postsynaptic 5-HT receptors putatively results in an enhancement of 5-HT neurotransmission. The usefulness of the Blier et al. (8) model is limited by the extent to which single dorsal raphe neuron studies are representative of 5-HT neurons in general. In addition, the postsynaptic effects described are localized and may not generalize to other projection sites. For instance, in radioligand studies, chronic antidepressants downregulate 5-HT2 binding in the rat cortex, which would tend to reduce 5-HT neurotransmission (51).

Schreiber and DeVry (62) hypothesized that the anxiolytic effects of 5-HT1A partial agonists result predominantly from an interaction with presynaptic 5-HT1A receptors, resulting in a decrease of hyperactive serotonergic neurotransmission. The same authors report that reduction of serotonergic function by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) and depletion of 5-HT by the non-competitive antagonist, parachlorphenylalanine (PCPA), diminishes conditioned inhibition in rat studies. The observation that PCPA and 5,7-DHT also induce muricidal behavior in rodents calls into question the specificity of conditioned inhibition as a model of anxiety. Rats in an elevated maze (an anxiety paradigm) have increased 5-HT levels in the ventral hippocampus (74). Nevertheless, the lack of anxiolytic (or anxiogenic) effect in panic disorder patients following depletion of central 5-HT using a tryptophan-free amino acid preparation (27) contradicts the view that anxiety is consistently due to an increase of 5-HT neurotransmission. Moreover, based on the Blier et al. studies (8), 5-HT1A partial agonists would be predicted to exert immediate clinical anxiolytic effects that would dissipate following desensitization of raphe autoreceptors. The limitations of extrapolating animal models directly to clinical psychopathology are evident.

The antidepressant effects of the 5-HT1A partial agonists are postulated to result from an enhancement of serotonergic neurotransmission through their interaction with postsynaptic 5-HT1A sites (62). However, evidence for low 5-HT function in clinical depression is conflicting. Although cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) is found to be reduced in depressed subjects, its strong association with impulsive–aggressive behaviors implies a secondary rather than central role in depression (12). Supporting the view of hypoactive 5-HT neurotransmission in depression is that the prolactin response to intravenous tryptophan is reduced in patients with the disorder (31), although similar reduced prolactin responses in response to fenfluramine have been reported in impulsive-aggressives (12). Augmentation of prolactin response to intravenous tryptophan by a range of antidepressant medications occurs irrespective of clinical response (54), suggesting that simple augmentation of 5-HT activity is desirable but not always sufficient for therapeutic response. Further casting doubt on the rheostat model of the association of low 5-HT with depression is the finding by Delgado et al. (20) that rapid 5-HT depletion using an oral tryptophan-free amino-acid preparation causes relapse in 73% of selective serotonin reuptake inhibitor (SSRI)-treated subjects, but only 15% of desipramine (DMI) treated subjects, and does not acutely worsen depression in untreated subjects. These conflicting data suggest a complex interaction between 5-HT and other unknown target systems, which produces manifestations of clinical anxiety and mood disorders and their therapeutic response.

With respect to receptor function, Schreiber and DeVry (62) have postulated a preliminary distinction between receptors that mediate anxiolytic and antidepressants effects and those that produce opposing effects. For instance, in vivo rat studies demonstrate that acute administration of 5-HT1A agonists lead to hyperpolarization of the neuron (8) whereas down-regulation of 5-HT2 receptors by many antidepressant treatments may contribute to reductions of anxiety, although it should be noted that many antidepressants also down-regulate 5-HT1A receptors (50).

The 5-HT syndrome is most studied in rats and can be produced by administering a direct or indirect 5-HT agonist (70). In addition to the standard features of the rodent serotonin syndrome, other behaviors include low outstretched posture, hyperreactivity, hyperactivity, intense salivation, backward walking, and piloerection. Serotonin agonists that do not have high affinity for the 5-HT1A receptor do not produce the syndrome as strongly. In contrast to b-receptor antagonists with high 5-HT1A affinity, 5-HT2 antagonists do not block the syndrome. Acute depletion of 5-HT does not affect the syndrome, suggesting postsynaptic mediation. Destruction of 5-HT neurons may in fact enhance susceptibility to the 5-HT syndrome by the 5-HT1A agonist 8-OH-DPAT (70). Recent data suggest that the 5-HT syndrome may be mediated by descending pathways of the nucleus raphe obscurus. Such 5-HT1A partial agonists as buspirone induce the syndrome weakly and antagonize the effects of more potent 5-HT1A agonists, such as 8-OH-DPAT (for review, see ref. 42).

In humans, excessive increase of synaptic 5-HT may lead to a clinical 5-HT syndrome, which may respond to nonspecific 5-HT antagonists, such as cyproheptadine (see ref. 16, for review). A more frequently encountered observation (34) regarding the use of SSRIs and the 5-HT precursor, 5-hydroxytryptophan in panic disorder patients was that there appeared to be a biphasic treatment response. Patients initially experienced a worsening of generalized anxiety accompanied by a cluster of stimulation symptoms, including jitteriness, insomnia, diarrhea, and a sensation of jumping out one's skin. Of note, panic frequency appeared unchanged despite an overall increase in anxiety symptoms. If patients were able to tolerate these symptoms for several weeks, an ensuing reduction in panic attacks and anxiety was evident. Such stimulation reactions have also been noted with imipramine and desipramine (75) suggesting that they are not specific to the SSRIs or 5-HT. However, the syndrome itself is most frequently encountered in patients with panic attacks in contrast to subjects with other SSRI, clomipramine (CMI), and/or tricyclic-antidepressant (TCA) responsive psychiatric disorders (16). Of note, partial 5-HT1A agonists do not, to our knowledge, consistently produce the jitteriness syndrome, suggesting a necessity for full 5-HT agonism at postsynaptic sites. The relationship of the jitteriness syndrome to the rodent 5-HT syndrome remains unclarified. Reports of subsensitivity of the 5-HT1A receptor in panic disorder as reflected by hypothermic and corticoid response (41) suggests that 5-HT1A receptors are not likely to be associated with the jitteriness syndrome. Nevertheless, a parallel pattern is shown with the rodent 5-HT syndrome—induction by full but not partial agonism (42!popup(ch123)—suggesting some similarity to the human jitteriness syndrome.

Rats trained to discriminate the stimulus properties of 8-OH-DPAT generalized this stimulus to the 5-HT1A partial agonists. Benzodiazepines, on the other hand, do not generalize to the stimulus properties of the 5-HT1A partial agonists, suggesting that the stimulus properties of these two classes of anxiolytics are mediated by distinct mechanisms. Interestingly, fenfluramine, which acts as a nonspecific 5-HT agonist through enhancement of presynaptic release and reuptake blockade and sertraline, a 5-HT reuptake inhibitor, fail to substitute for the 5-HT1A agonist 8-OH-DPAT, but do generalize to non-5-HT1A agonists such as TFMPP (largely a 5-HT1B agonist) and [+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 agonist. These data suggest preferential stimulation of non-5-HT1A receptors (particularly 5-HT1B and 5-HT2) by nonspecific indirect agonists, whereas the stimulus properties of 8-OH-DPAT are probably mediated by the inhibition of 5-HT release by 5-HT1A autoreceptor activation. This view is supported by the observation that PCPA-induced 5-HT depletion generalizes to 8-OH-DPAT but not TFMPP (for review, see ref. 42).

Drugs with therapeutic effects in humans exert effects on various animal models of anxiety. These models facilitate the prediction of the effects of novel compounds. The 5-HT1A agonist (8-OH-DPAT) and 5-HT1A partial agonists increase punished responding in rats (18), similar to the effects of the benzodiazepines (71). However, it should be noted that the magnitude of buspirone's effects on punished responding is weak relative to the benzodiazepine anxiolytics. In addition, benzodiazepines enhance punished responding in certain paradigms where azapirones fail to exert such effects. Further evidence for the distinction between benzodiazepine versus azapirone effects on punished responding is the observation that flumazenil antagonizes benzodiazepine-induced suppression of scheduled behavior but has no effect on azapirone-induced effects (6). Again, the enhanced punished responding effects of the 5-HT1A partial agonists appear to be mediated by presynaptic receptors as PCPA-induced depletion, neurotoxic destruction of 5-HT neurons, and direct raphe injection of 5-HT1A agonists antagonize the effects of the azapirones. In accordance with their clinical effects, the azapirones, in contrast to benzodiazepines, exert behavioral effects in rodent task tests that are analogous to antidepressant drugs, but these effects appear to be postsynaptically mediated (for review, see ref. 42). These rodent studies suggest that benzodiazepines may exert a more generalized anxiolytic effect than the azapirones, but the latter class of drugs possess the advantage of antidepressant properties.

A modulatory role for 5-HT has been described for the development and expression of the ultrasonic call of infant rat pups during brief maternal separations. Serotonin reuptake inhibitors reduce the rate of calling following acute administration to 9- to 11-day-old pups, and a 5-HT neurotoxin [3,4-methylenedioxymethamphetamine (MDMA)] systematically disrupted the development of ultrasonic vocalizations but not other measures of motor development (73). Consistent with their clinical effects, acute administration of the 5-HT1A agonists buspirone and 8-OH-DPAT (73) and ipsapirone (62) reduces the rate of calling at doses that did not affect motor activity or core body temperature. In the same study, administration of the purported 5-HT1B receptor agonist, CGS12066B {7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrro lo[1,2-a] quinoxaline} and the 5-HT1B agonist TFMPP increased the rate of calling. D,L-Propranolol, a 5-HT1 receptor antagonist, blocked the effects of both 8-OH-DPAT and TFMPP. Calling was decreased by both m-CPP (an agonist at 5-HT1C and 5-HT2 receptor sites) and DOI (a drug with putative agonistic action at 5-HT2 sites). Ritanserin, a 5-HT2 and 5-HT1C antagonist, produced a dose-related increase in call rate. These data suggest that in certain models of anxiety, 5-HT2 receptor activation may exert an anxiolytic and not anxiogenic effect. The possibility is raised that ontogenetic or species factors may influence the function of specific 5-HT receptor subtypes.

Bearing the preclinical correlates in mind, we review below the therapeutic effects of the 5-HT1A partial agonists in the DSM-IIIR anxiety disorder categories.

The azapirones, such as buspirone, are the first modern pharmacotherapeutic alternative to benzodiazepines for the treatment of generalized anxiety disorder (GAD). The 3- to 4-week delay in onset of anxiolytic effects of the azapirones closely resembles that of imipramine treatment of GAD (33), but benzodiazepine effects are more rapid. Several well-controlled studies have shown that buspirone is superior to placebo and are equivalent to a range of benzodiazepines in the treatment of GAD. Goldberg and Finnerty (28) first reported anxiolytic properties of buspirone. Rickels et al. (57) subsequently reported in a placebo-controlled study that buspirone (20 to 25 mg/day) was as effective as diazepam (20 to 25 mg/day) over a 4-week period in the treatment of 212 anxious outpatients, although diazepam appeared slightly better than buspirone for somatic anxiety symptoms, whereas the opposite was observed for interpersonal difficulties. Subsequent controlled studies indicate similar efficacy for buspirone as compared to diazepam (22) and clorazepate (13), lorazepam, and alprazolam (14). Subsequent studies by Petracca et al. indicate similar efficacy for buspirone and lorazepam, although abrupt termination of treatment at 8 weeks resulted in discontinuation symptoms only in the lorazepam group (52). Strand et al. (67) have reported on the similar efficacy of buspirone and oxazepam treatment of GAD in a primary care setting, where anxiety disorders are the most frequently encountered psychiatric disorders. Rickels (58) has suggested that buspirone, the only azapirone approved by the U.S. Food and Drug Administration, may be particularly appropriate in those with chronic variants of GAD, the anxious elderly, and possibly those with mixed anxiety and depression. Buspirone, according to the authors, appears most helpful in GAD patients who do not insist on the immediate relief provided by the benzodiazepines. If GAD patients are able to wait for a more gradual onset of anxiolytic effects, they avoid the dependency-producing effects of benzodiazepines.

Anxious patients frequently present with complicating depressive symptomatology. Early clinical observation of buspirone-treated patients suggested antidepressant properties in addition to anxiolytic effects. Robinson and colleagues (59) report on five placebo-controlled studies involving 382 patients with DSM-III major depression and significant associated anxiety symptoms (i.e., Hamilton Anxiety Rating Scales (HARS) greater than or equal to 18). Buspirone, initiated at 15 mg/day, and increased to a maximal dose of 90 mg/day was effective for both depressive and anxiety symptoms. In general patients with higher HARS and HDRS scores responded better to buspirone than did less severely ill patients. A limitation of this analysis was the absence of separate evaluation of depressive symptoms, raising the possibility that improvement of HDRS scores were primarily related to improvement of overlapping anxiety-related items. Other depression studies using azapirones are remarkable for their high drop-out rates. Fabre (23) reports a 64% drop-out rate from a buspirone-treated group for various reasons. Jenkins et al. (32) reports a 71% drop-out rate from a group treated with high doses of gepirone, whereas a 57% drop-out rate was observed for the low-dose group. Other controlled studies have confirmed gepirone's antidepressant properties (55). The high drop-out rates observed with azapirone treatment combined with the lack of confirmatory data supporting primary antidepressant efficacy suggests a limited role where a range of other effective antidepressant treatments are available.

Tollefson treated recently detoxified patients who met criteria for DSM-III-R GAD criteria (69). In a placebo-controlled double-blind trial involving 51 dually diagnosed subjects, buspirone was superior to placebo in reducing measures of anxiety and number of days craving alcohol with increases in clinical global improvement scores observed. At the final study dose, blood levels of the buspirone metabolite 1-pyrimidinyl-piperazine (1-PP) were correlated to improvement in anxiety, global depressive symptoms, and number of days not using alcohol. Because this was not a fixed-dose study, this result is ambiguous. Also, the lack of a significant relationship between the parent compound and metabolite concentrations needs explanation. Nevertheless, buspirone may be a useful anxiolytic agent in alcoholic patients when the use of conventional anxiolytics such as the benzodiazepines are to be avoided. However, the specificity of these therapeutic effects to the 5-HT1A receptor is unclear, as the 1-PP derivative lacks 5-HT1A affinity and may function as an a2 antagonist (24).

Buspirone does not appear to be effective in panic disorder in several controlled studies. The role of other 5-HT1A partial agonists such as gepirone and ipsapirone in panic disorder have not, to our knowledge, been formally studied.

Sheehan et al. (64) compared the relative efficacy of buspirone, imipramine, and placebo in a double-blind controlled study of 52 randomly assigned patients with panic disorder. Imipramine was superior to placebo on many outcome measures. Although sample differences favored buspirone, these differences were not statistically significant. Of note, buspirone, like its 1-PP metabolite, may increases locus coeruleus firing modestly (60). That patients did not worsen on buspirone is therefore of interest, since an increase of noradrenergic locus coeruleus activity has been associated with worsening anxiety (10).

Pohl and associates (53) tested the efficacy of buspirone in 60 panic disorder patients in a placebo-controlled imipramine comparison design. There were no significant differences between treatments on outcome measures, although 25% of the buspirone patients were panic free as compared to 7% on imipramine and 14% on placebo. At the end of the study, mean doses of imipramine were 140 mg/day and of buspirone 29.5 mg/day. The authors attribute the lack of a treatment effect to the relatively small number of patients in each group and the robust placebo response observed in the study sample. The lack of imipramine–placebo difference raises questions about the nature of this sample and the measures used. Since a type II error is likely, one cannot evaluate buspirone effects. Further confirmation of the lack of buspirone efficacy in panic disorder is reported in a small controlled study by Schweizer and Rickels (57).

Investigators have speculated that activation of 5-HT1A and 5-HT2 receptors may produce opposing effects (62). Such 5-HT2 antagonists as ritanserin may therefore facilitate preferential 5-HT1A receptor activation with putative anxiolytic effects. Den Boer and Westenberg (21) administered ritanserin and the SSRI, fluvoxamine in a double-blind placebo-controlled design. Fluvoxamine treatment significantly reduced panic attacks, whereas ritanserin was indistinguishable from placebo. Ritanserin has been reported as effective as lorazepam in the treatment of GAD (9). The study suggests that the previously proposed relationship (62) between 5-HT1A (anxiolytic) and 5-HT2 (anxiogenic) receptors does not apply to therapeutic effects in panic disorder but may be of relevance in GAD.

To explore the sensitivity of the 5-HT1A receptor in panic disorder, Lesch and colleagues (38, 41) investigated the hypothermic, neuroendocrine, and behavioral responses in 14 patients and matched controls to a single oral dose of 0.3 mg/kg of ipsapirone and placebo. Ipsapirone produced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior. The panic disorder patients showed reduced hypothermic and corticoid responses to ipsapirone when compared to controls. Hypothermia is postulated to reflect presynaptic 5-HT1A receptor activation, whereas corticoid responses reflect activation of postsynaptic 5-HT1A receptors. Although the prototype 5-HT1A agonist, 8-OH-DPAT, produces hypothermic and corticoid responses in rodents and these responses are blocked by selective 5-HT1A antagonists (spiperone and (-)-pindolol) (46), evidence for this functional distinction is lacking in humans. Nevertheless, these data are of interest as Targum (68) reports greater corticoid responses in panic-disorder patients to oral fenfluramine (a nonspecific indirect 5-HT agonist) challenge than in healthy controls. Although fenfluramine induces anxiety, it is described by the authors as not resembling panic but rather waves of generalized anxiety. In rodent studies, mCPP does not functionally interact with 5-HT1A receptor sites but acts as a 5-HT1C and 5-HT2 agonist (73). Also, mCPP produces enhanced anxiety responses and exaggerated corticoid responses when administered orally in panic-disorder subjects (34) but produces equivalent anxiety and corticoid responses when administered intravenously (11). As dyspnea is not evident during mCPP-induced anxiety, a question is posed as to its validity in producing panic attacks. Taken together, these data raise the possibility of normosensitive, supersensitive, and subsensitive 5-HT receptors in panic disorder, suggesting a mosaic of receptor abnormalities. The effects of treatment on challenge response to the various 5-HT ligands may further facilitate characterization of 5-HT receptor abnormality in panic disorder.

In an open trial, Markovitz et al. (43) reported modest benefits in 9 out of 11 patients with obsessive– compulsive disorder (OCD) when buspirone was added to fluoxetine treatment, suggesting a potential ancillary role for 5-HT1A partial agonists in OCD. McDougle et al. (44) subsequently performed a placebo-controlled double-blind study to test the augmenting efficacy of buspirone in OCD patients treated with standard medications for OCD. Buspirone was not different from placebo as an augmenting agent. The role of buspirone in OCD, therefore, appears limited, particularly since 5-HT reuptake blockers and clomipramine are generally effective in this population. Its role as an augmenting agent in specific refractory cases is of interest.

Challenge studies using the 5-HT1A partial agonist, buspirone, in ten OCD patients and ten controls did not show differences in prolactin responses. Lesch and colleagues (39) examined hypothermic, neuroendocrine, and behavioral responses to the selective 5-HT1A receptor ligand ipsapirone in patients with OCD and healthy controls. A single dose of ipsapirone (0.3 mg/kg) or placebo was administered to 12 patients and 22 controls under double-blind, random-assignment conditions. Ipsapirone induced hypothermia (presynaptic effect) and release of corticotropin and cortisol (postsynaptic effect) but had no effect on behavior, including obsessive or compulsive symptoms. Thermoregulatory and neuroendocrine responses to ipsapirone were not consistently different between healthy controls and patients with OCD. In a double-blind random-assignment study of 10 OCD patients, Lesch and colleagues (40) challenged subjects with ipsapirone and placebo before and during open fluoxetine treatment. The authors report ipsapirone-induced hypothermia and ACTH/cortisol release was significantly attenuated following chronic fluoxetine when compared to the pretreatment ipsapirone challenge. Although fluoxetine was effective in reducing the severity of obsessive–compulsive symptoms, no significant correlation between attenuation of ipsapirone-induced responses and fluoxetine improvement in OCD symptoms was detected. Thus, it remains unclear whether the ability of fluoxetine to down-regulate pre- and/or postsynaptic 5-HT1A receptors is specific to its antiobsessional effects. Moreover, the absence of repeat ipsapirone challenges in a healthy control group limits evaluation of the possibility of a nonspecific reduction in ipsapirone response.

Of an original 21 social phobia patients, Schneier et al. (61) reported modest improvement in 8 of 17 (47%) patients who tolerated at least 2 weeks in an open 12-week trial of buspirone. Of the 12 patients who were able to tolerate a dose of 45 mg/day or greater, 9 (67%) were at least much improved on the clinical global improvement scale. Of note, one patient was unable to tolerate the drug because of panic-like side effects. Other side effects included gastrointestinal upset, dizziness, and increased anxiety. The authors noted that response status related to the ability to tolerate high doses of the drug. Similar results have been reported by Munjack et al. (48) in open buspirone treatment of SP. The drug may provide a non-monoamine-oxidase-inhibitor alternative to the treatment of social phobia with a substance abuse history, although systematic controlled studies are required.

To our knowledge, 5-HT1A partial agonists have not been systematically studied for the treatment of posttraumatic stress disorder or simple phobia.

That the azapirones are effective in GAD but not in panic-anxiety supports the tenet of pharmacological dissection proposed by Klein. Moreover, azapirones appear effective as antidepressants and therefore are included in the group of antidepressants that do not block panic attacks—bupropion, trazodone, deprenyl, and maprotiline (see ref. 16 for review). The differing therapeutic responses to the azapirones support the nosological distinction between GAD and panic disorder. Specific potential for the azapirones in the treatment of GAD patients with comorbid alcoholism requires replication. Use of the azapirones in social phobia requires systematic study, whereas the initial open observations in OCD have not been replicated under double-blind placebo controlled conditions. Considered in the context of the advent of the 5-HT reuptake inhibitors, effective agents in non-GAD anxiety disorders with a favorable side effects profile, the therapeutic role of the azapirones is greatly restricted. Moreover, the high doses of azapirone that are often required for adequate therapeutic effects are often associated with significant side effects, such as gastrointestinal upset, dizziness, and anxiety. Of note, SSRIs have not been systematically studied in GAD. The development of compounds with selective 5-HT receptor binding profiles is nevertheless an important psychopharmacological advance and expands the clinician's armamentarium, particularly for atypical cases.

Dysfunction of putatively reciprocal and interdependent 5-HT pathways, possibly as a result of pathological receptor sensitivities may account for disparate clinical disorders and effects of 5-HT related compounds. We have previously proposed homeostatic failure along cybernetic lines, that is, an inability of the neural system to buffer pertubations in either direction. We hypothesize a neural substrate for 5-HT dysfunction in anxiety disorders whereby a distinction is made between raphe pathways that mediate inhibitory effects, particularly to brainstem and limbic sites, and raphe projections that mediate stimulatory effects, such as hypothalamic activation and the elicitation of a corticoid response. Loss of 5-HT tone in the inhibitory systems is hypothesized to be associated with depression and panic. Panic-anxiety may preferentially involve descending inhibitory pathways to medullary respiratory centers, and disruption of such activity may contribute to the misevaluation of the threat for suffocation. The available data suggest that either partial 5-HT1A agonism is not sufficient to suppress ventilatory overdrive or other inhibitory 5-HT receptors are involved. In panic disorder, an exaggerated reciprocal relationship between inhibitory and stimulatory 5-HT pathways may exist. Recent data by our group (15) suggest that 5-HT–modulated functions, such as ventilation (pCO2) and corticoid response are negatively correlated during the prelactate period in patients who panic when challenged with lactate. Depressive symptoms may relate to a loss of 5-HT tone in the ascending projections to limbic (and cortical) structures which may be corrected by an enhancement of serotonergic neurotransmission produced by most antidepressants (8).

Overactivity of stimulatory pathways is hypothesized to generate generalized or anticipatory anxiety. In this instance, azapirones may act as antagonists, attenuating raphe hyperactivity. Of note, SSRIs and 5-hydroxytryptophan transiently worsen generalized anxiety, conceivably due to increased synaptic cleft 5-HT, until adaptive receptor changes have taken place. OCD is characterized by overactivity of stimulatory projections to the caudate nuclei and orbitofrontal cortex and blunted corticoid responses to 5-HT agonists (see Table 1).

In conclusion, despite an unprecedented increase in knowledge of the 5-HT receptors and their role in anxiety, the study of the relationship between serotonin and clinical pathophysiology is in its infancy. Future studies are required to delineate functional and neuroanatomical correlations and receptor sensitivity profile status of the multiple raphe nuclei and their projections.

This work has been supported in part by a National Institute of Mental Health Scientist Development Award for Clinicians (1-K20-MH01039-01A1 to JDC and a Mental Health Clinical Research grant (NIMH P50-MH-30906.

published 2000