Recently, the addition of drugs with prominent 5-HT2 receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive–compulsive disorder (OCD). These 5-HT2 antagonists may also be effective in ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At the doses used, these drugs would be expected to saturate 5-HT2A receptors. These findings suggest that the simultaneous blockade of 5-HT2A receptors and activation of an unknown constellation of other 5-HT receptors indirectly as a result of 5-HT uptake inhibition might have greater therapeutic efficacy than either action alone. Animal studies have suggested that activation of 5-HT1A and 5-HT2C receptors may counteract the effects of activating 5-HT2A receptors. Additional 5-HT receptors, such as the 5-HT1B/1D/5/7 receptors, may similarly counteract the effects of 5-HT2A receptor activation. These clinical and preclinical observations suggest that the combination of highly selective 5-HT2A antagonists and SSRIs, as well as strategies to combine high-potency 5-HT2A receptor and 5-HT transporter blockade in a single compound, offer the potential for therapeutic advances in a number of neuropsychiatric disorders.
Blockade of the serotonin (5-hydroxytryptamine; 5-HT) transporter is the common pharmacological action shared by selective serotonin reuptake inhibitors (SSRIs; eg fluoxetine, sertraline, fluvoxamine, paroxetine, citalopram). Enhancement of the synaptic availability of 5-HT appears to be a critical component of the mechanism underlying the action of SSRIs in the treatment of depression, as demonstrated by the tryptophan depletion paradigm (Delgado et al, 1990,1999). While long-term adaptations to blockade of monoamine reuptake must be present to explain the delay in antidepressant efficacy (Duman et al, 1997), the relatively rapid (<7 h) return of depressive symptoms in recently remitted patients during the monoamine depletion studies suggests that the long-term adaptations, like enhanced synaptic availability of monoamines, are necessary, but not sufficient, for a therapeutic response. Both enhanced synaptic availability of monoamines and long-term adaptations appear to be necessary for the therapeutic effect in most depressed patients during the initial month(s) of treatment. However, there are little clinical data regarding which of the known 15 5-HT receptors are involved in mediating the actions of SSRIs in the diverse range of neuro-qpsychiatric syndromes in which they have shown efficacy (eg major depression, obsessive–compulsive disorder (OCD), pervasive developmental disorders (PDDs) such as autism, panic disorder, and post-traumatic stress disorder (PTSD)).
Recently, addition of the 5-HT2A/dopamine D2 receptor antagonist risperidone at low doses to ongoing SSRI treatment has been shown in an open-label study to enhance therapeutic responses in patients with major depression (Ostroff and Nelson, 1999). Patients with treatment-refractory OCD have been shown to benefit from a similar strategy in a double-blind placebo-controlled study (McDougle et al, 2000)). It is not known whether monotherapy with low-dose risperidone might also possess therapeutic effects in these disorders. Like the SSRIs, risperidone has demonstrated some efficacy as a monotherapy in the treatment of PDDs (McDougle et al, 1998; Research Units on Pediatric Psychopharmacology Autism Network, 2002).
The only receptor subtype that risperidone is likely or known to saturate at these lower doses (0.5–1 mg/day) is the 5-HT2A receptor (Schotte et al, 1996; Nyberg et al, 1999; Talvik-Lofti et al, 2000). Such findings suggest the hypothesis discussed in detail below, that activation of 5-HT2A receptors secondary to the blockade of 5-HT transporters by SSRIs functionally opposes the therapeutic effects that are achieved by the activation of non-5-HT2A receptors. This review will discuss preclinical evidence for opposing effects of 5-HT2A and non-5-HT2A receptors that may contribute to a synergistic clinical action between blockade of 5-HT2A receptors and activation of non-5-HT2A receptors. Then, evidence for the clinical efficacy of 5-HT2A antagonists, both in monotherapy and in combination therapy with SSRIs, will be examined.
INTERACTIONS BETWEEN 5-HT2A AND 5-HT1A RECEPTORS
At a cellular level, activation of 5-HT2A and 5-HT1A receptors exerts depolarizing and hyperpolarizing effects, respectively, on cortical pyramidal cells (Araneda and Andrade, 1991; Tanaka and North, 1993; Ashby et al, 1994; Aghajanian and Marek, 1997). These interactions have been observed both under in vitro conditions and during in vivo recordings from the rodent medial prefrontal cortex. Similar interactions have also been observed at a behavioral level. For example, stimulation of 5-HT1A receptors suppresses head shakes in rats induced by hallucinogenic drugs, which activate 5-HT2A receptors (Arnt and Hyttel, 1989; Schreiber et al, 1995). Previous studies have demonstrated that systemic administration of 5-HT1A agonists can block head shakes induced by direct infusion of the hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) into the medial prefrontal cortex (Granhoff et al, 1992; Willins and Meltzer, 1997).
Evidence for opposing effects of activation of 5-HT2A and 5-HT1A receptors has also been obtained from a behavioral screen for antidepressant drugs, rats performing on a differential reinforcement of low rate 72-s (DRL 72-s) schedule (Marek et al, 1989a,1989b; Marek and Seiden, 1994; Jolly et al, 1999). This behavioral screen measures a cardinal feature of prefrontal cortical ‘executive function,’ that is, withholding inappropriate responses (Fuster, 1997). At an operational level, water-deprived animals in this paradigm must wait at least 72 s following the previous response in order to receive a reinforcer (water) for making a response. The efficacy of 5-HT antagonists in exerting an antidepressant-like response on this screen (increased reinforcement rate, decreased response rate, and a cohesive rightward shift in the inter-response time (IRT) histogram) is related to the selectivity of the antagonists for 5-HT2A relative to 5-HT1A receptors (Marek et al, 1989a; Marek and Seiden, 1994).
Interactions have also been observed between 5-HT2A and 5-HT2C receptors at a behavioral level. Opposing effects exist for 5-HT2A and 5-HT2C receptors in modulating hyperlocomotion induced in mice by noncompetitive N-methyl-D-aspartate (NMDA) antagonists (Martin et al, 1997). A recent study has found clear evidence supporting opposing effects of 5-HT2A and 5-HT2C receptors in modulating head shakes in rats (Vickers et al, 2001). Activation of 5-HT2A and 5-HT2C receptors also leads to opposing effects on sexual function in rodents (Berendsen et al, 1990), in a manner suggesting that activation of 5-HT2A receptors could be responsible for the sexual side effects of SSRIs. DRL 72-s behavior also appears to involve reciprocal interactions between 5-HT2A and 5-HT2C receptors, since 5-HT2C agonists, similar to 5-HT2A antagonists, exert antidepressant-like actions in rats performing under this operant paradigm (Marek and Seiden, 1988; Martin et al, 1998; Marek et al, 2001a). In a similar vein, blockade of 5-HT2C receptors may attenuate the antidepressant-like effects observed on the DRL 72-s schedule following administration of drugs that block 5-HT2A receptors (Marek and Seiden, 1994).
Opposing interactions may also occur between other 5-HT receptors and the 5-HT2A receptor. One prominent effect of activating the 5-HT2A receptor in the cortex appears to be the induction of glutamate release from thalamocortical afferents (Marek et al, 2001b). This anatomical substrate may be of interest with respect to major neuropsychiatric disorders because the likely source of these thalamocortical afferents for the prefrontal cortex, the intralaminar and midline thalamic nuclei project to other important limbic-related forebrain regions such as the ventral striatum (nucleus accumbens) and the amygdala, as well as the prefrontal cortex (Berendse and Groenewegen, 1990,1991; Su and Bentivoglio, 1990). 5-HT itself is able to suppress late excitatory postsynaptic potentials (EPSPs) induced by the combination of the 5-HT2 agonist DOI and electrical stimulation of the white matter (Aghajanian and Marek, 1999). Preliminary experiments have suggested that activation of 5-HT1-like, 5-HT5, or 5-HT7 receptors may mediate this effect, which opposes 5-HT2A receptor activation (G Marek, unpublished observations).
RISPERIDONE: PHARMACOLOGICAL PROFILE
The actions of risperidone are considered before those of other 5-HT2 antagonists because this drug is the most potent and selective (with respect to other 5-HT receptors) 5-HT2A antagonist available to clinicians. Blockade of 5-HT2A receptors is the most potent action of risperidone as assessed by in vitro receptor-binding studies (Schotte et al, 1996; Richelson and Souder, 2000). This is hardly surprising given that risperidone was developed using blockade of the behavioral effects of hallucinogenic drugs and potency in binding to 5-HT2A receptors as two of the principal drug targets. Risperidone is approximately 20 to 50-fold more potent at binding to the 5-HT2A receptor than to the α1-adrenergic, dopamine D2, histamine H1, and α2-adrenergic receptors ( Table 1). It is one of the most selective compounds clinically available with respect to selectivity at the 5-HT2A vs the 5-HT2C receptor. The 1000-fold selectivity of risperidone for the 5-HT2A vs the 5-HT1A receptor may also be relevant to the drug's therapeutic actions in mood disorders, OCD, and PDDs.
The dose of risperidone reported to be effective for depression (0.5–1 mg/day) is in contrast to the doses of 3–6 mg/day used in schizophrenia. Risperidone at 4 mg is thought to produce 70–80% occupancy of striatal dopamine D2 receptors (Nyberg et al, 1999). Higher doses increase the likelihood of extrapyramidal side effects. In contrast, the 0.5–1 mg dose of risperidone probably saturates the 5-HT2A receptors. The previous lower estimates for cortical 5-HT2A receptor occupancy using N-methyl-spiperone as the radiotracer are now thought to be an underestimate of the true occupancy (Talvik-Lofti et al, 2000). Animal studies using ex vivo autoradiographic techniques have supported the increased potency of risperidone for displacement of binding to 5-HT2A receptors relative to histamine H1, dopamine D2, α1-adrenergic, and α2-adrenergic receptors (Schotte et al, 1996). Extrapolation of these results to humans would suggest that only the 5-HT2A receptor would show appreciable occupation at risperidone doses of 0.5–1 mg.
RISPERIDONE: CLINICAL ACTIVITY IN MAJOR DEPRESSION, OCD, AND PDD
Several open-label reports with a total of 12 patients have suggested that addition of low-dose risperidone (0.5–1 mg/day) to ongoing treatment with SSRIs may have clinically significant antidepressant action in patients with major depression (O'Connor and Silver, 1998; Ostroff and Nelson, 1999). The report by Ostroff and Nelson is notable for the rapid (1–2 days) antidepressant effect of risperidone addition in the majority of patients. Another open series of five patients suggested that addition of risperidone (0.5–1.5 mg/day) to the monoamine oxidase inhibitor (MAOI) tranylcypromine resulted in a rapid antidepressant effect in patients lacking a satisfactory response to the MAOI alone (Stoll and Haura, 2000). Our own experience with depressed patients has been that the addition of risperidone to ongoing treatment with SSRIs does rapidly induce a therapeutic response, but that this response is not generally sustained (LL Carpenter, LH Price, unpublished observations). These open-label reports will require confirmation from double-blind placebo-controlled studies with respect to response efficacy, speed of response onset, and maintenance of therapeutic efficacy.
As in the depression literature, a number of open-label case series have suggested that addition of risperidone results in a therapeutic response in patients with OCD who have failed to obtain a satisfactory response to monotherapy with SSRIs after an appropriate duration of treatment (Jacobsen, 1995; McDougle et al, 1995b; Ravizza et al, 1996; Saxena et al, 1996; Stein et al, 1997). Recently, these earlier reports have been confirmed by a double-blind placebo-controlled study in which the addition of risperidone in a mean dose of 2.2 mg/day to ongoing SSRI treatment resulted in clinically significant improvement in refractory OCD patients (McDougle et al, 2000). The beneficial effects of risperidone did not appear to be limited to patients with chronic motor tics or schizotypal personality disorder, which had appeared to be the case with typical neuroleptic drugs (McDougle et al, 1994). Analyses of drug levels in a subset of patients did not reveal any evidence that risperidone might be enhancing the effects of the SSRIs via a pharmacokinetic, rather than pharmacodynamic, interaction.
In all, 14 anecdotal reports and open-label studies of risperidone in children, adolescents, and adults through 1998 have suggested that this atypical neuroleptic is effective in ameliorating repetitive behavior and aggression towards oneself, others, and property in patients with autism and other PDDs (McDougle et al, 1998). A double-blind placebo-controlled study in adults with autism and other PDDs has confirmed these earlier reports (McDougle et al, 1998). Monotherapy with risperidone in a mean dose of 2.9 mg/day decreased aggression, anxiety, depression, irritability, and repetitive behaviors, although core symptoms involving aberrant social behavior and language were not affected. While this dose of risperidone approaches doses currently recommended for the treatment of schizophrenia and would result in a significant occupation of dopamine D2 receptors, it is notable that acute dietary tryptophan depletion (McDougle et al, 1996) worsened symptoms in adult patients with autistic disorder. Specifically, an increase in repetitive behavior, depression, and anxiety was observed, without any change in social behavior or language. This and other evidence of the involvement of 5-HT in the pathophysiology of PDDs increases the likelihood that the therapeutic action of risperidone in these disorders might also involve 5-HT. In a recently completed multisite controlled trial, risperidone was significantly better than placebo for reducing self-injury, aggression, and agitation in autistic children and adolescents (Research Units on Pediatric Psychopharmacology Autism Network, 2002). The effect size for risperidone in this study was greater than what has been reported with the D2 antagonist haloperidol in this patient group.
OLANZAPINE: PHARMACOLOGICAL PROFILE
Olanzapine has a more complicated profile of G-protein-coupled receptor targets than risperidone. In essence, the ‘dirty’ pharmacological profile of clozapine served as a template for designing an effective atypical neuroleptic medication free of major adverse effects, such as agranulocytosis and seizures. Olanzapine potently blocks 5-HT2A, 5-HT2C, and histamine H1receptors with a low nanomolar affinity ( Table 1). Olanzapine is four-to-ten-fold less potent at dopamine D2, α1-adrenergic, and muscarinic receptors than at the 5-HT2A receptor (Bymaster et al, 1996; Schotte et al, 1996). This mild selectivity for 5-HT2A receptors compared to dopamine D2 receptors is observed in human positron emission tomography (PET) neuroimaging studies at low olanzapine doses (eg 5 mg), but is lost at higher doses (20 mg) (Kapur et al, 1999). Unlike mirtazapine and mianserin (see below, Table 1), olanzapine is approximately 189-fold less potent at displacing binding to α2-adrenergic receptors than to 5-HT2A receptors. Olanzapine, similar to the other 5-HT2 antagonists used to augment SSRIs, is also about 412-fold less potent at displacing binding to 5-HT1A vs 5-HT2A receptors.
OLANZAPINE: CLINICAL ACTIVITY IN MAJOR DEPRESSION, OCD, AND PDD
The atypical neuroleptic olanzapine has been found to augment the effects of the SSRI fluoxetine in depressed patients who were refractory to SSRI monotherapy (Shelton et al, 2001). The most striking finding from this double-blind, placebo-controlled study was that the greatest degree of improvement in the olanzapine+fluoxetine group occurred within the first week of treatment, while patients were receiving only 5 mg/day of olanzapine. This suggests an acceleration in the onset of action in addition to enhancement of efficacy. Notably, this dose of olanzapine would be expected to saturate about 98% of 5-HT2A receptors while saturating only about 55% of dopamine D2 receptors (Kapur et al, 1999).
Several open-label studies have also found that a relatively low dose of olanzapine (5 mg) improves the symptoms of patients with OCD who were refractory to SSRIs (Weiss et al, 1999; Bogetto et al, 2000). However, all of the patients from Bogetto et al and 5/8 positive responders from Weiss et al were treated with fluvoxamine, which could have elevated olanzapine levels by interactions with cytochrome P450 microsomal isoenzymes. Thus, pharmacokinetic data and experience with different SSRIs will be necessary to conclude that this effect reflects a pharmacodynamic interaction. Furthermore, the utility of olanzapine as an augmenting strategy in OCD may be compromised by sedation in this patient group (Weiss et al, 1999). In contrast to studies of olanzapine in the treatment of depression and OCD, there are no published double-blind studies concerning this drug's efficacy in the treatment of autism and other PDDs. However, an open-label case series described positive responses to olanzapine (7.8 mg/day) in patients with autistic disorder and other PDDs (Potenza et al, 1999). In a more recently published study employing a parallel-groups design, 12 children with autistic disorder were randomized to 6 weeks of open-label olanzapine or haloperidol (Malone et al, 2001). Mean final dosages were 7.9 mg/day for olanzapine and 1.4 mg/day for haloperidol. Five of six subjects in the olanzapine group and three of six in the haloperidol group were responders.
MIRTAZAPINE AND MIANSERIN: PHARMACOLOGICAL PROFILE
Unlike risperidone, the most potent pharmacological action of mirtazapine and mianserin is blockade of histamine H1 receptors, which is thought to play a role in the sedative side effects of these drugs (Table 1). Their second most potent pharmacological action is blockade of the 5-HT2 family of receptors. Mirtazapine and mianserin appear to block the 5-HT2A, 5-HT2C, and α2-adrenergic receptors with approximately equal affinity. Both drugs are potent antagonists, although at slightly lower affinities, of 5-HT3 receptors. Like risperidone, mirtazapine and mianserin are at least 300-fold more selective for blocking 5-HT2A vs 5-HT1A receptors. Both agents lack appreciable affinity for dopamine D2 receptors. Blockade of α2-adrenergic receptors by mirtazapine has attracted significant interest as a potentially important mechanism of therapeutic action by increasing synaptic concentrations of 5-HT in the hippocampus (De Boer, 1996; Haddjeri et al, 1997). Specifically, blockade of α2-adrenergic heteroceptors on serotonergic terminals in the prefrontal cortex is thought to play a role in alterations of hippocampal 5-HT. However, it should be noted that mirtazapine does not increase extracellular 5-HT levels in the prefrontal cortex, whereas norepinephrine and dopamine levels are increased (Millan et al, 2000). Furthermore, mianserin does not appear to possess appreciable affinity for the same adrenergic autoreceptor as does mirtazapine (De Boer et al, 1996). Hjorth and colleagues (Bengtsson et al, 2000) failed to observe increased extracellular 5-HT levels in the prefrontal cortex, the ventral hippocampus, or the dorsal hippocampus in response to either mirtazapine or idazoxan, at doses that did clearly block α2-adrenergic responses. Finally, there are no double-blind placebo-controlled studies demonstrating clinical antidepressant action for an α2-adrenergic antagonist lacking biologically significant 5-HT2A receptor affinity. Evidence reported thus far for the selective α2-adrenergic antagonist idazoxan suggests that the suspected beneficial effects of this drug for mood disorders may be mostly restricted to bipolar depression (Osman et al, 1989; Potter et al, 1994; Grossman et al, 1999). Taken together, it is far from clear that the beneficial effects from combining mirtazapine or mianserin with SSRIs in depressed patients (discussed below) is due to α2-adrenergic blocking activity of these compounds. Blockade of 5-HT2 receptors is an alternative hypothesis to explain the clinical reports.
MIRTAZAPINE AND MIANSERIN: CLINICAL ACTIVITY IN MAJOR DEPRESSION, OCD, AND PDD
Augmentation of SSRIs with 5-HT2 antagonists lacking appreciable dopamine D2 blocking properties has been investigated. An initial open-label trial reported significant improvement in nearly half of 20 depressed patients in whom mirtazapine was added to ongoing treatment with SSRIs, venlafaxine, desipramine+SSRI, or desipramine+venlafaxine (Carpenter et al, 1999). A follow-up double-blind placebo-controlled study corroborated the earlier open-label trial (Carpenter et al, 2002). In the controlled study, 84% of the moderate to severely depressed patients randomized either to placebo or mirtazapine (15–30 mg/day) were on SSRIs for a minimum of 4 weeks but did not have a satisfactory response. Using a 50% decrease in the Hamilton Depression Rating Scale (HDRS) as the primary outcome measure, 64% of the mirtazapine-treated patients were considered responders, compared with only 20% of the placebo-treated patients.
Efficacy in enhancing the action of SSRIs in depressed patients has also been examined for mianserin, a compound with a similar chemical structure as mirtazapine. Maes et al (1999) studied the combination of the SSRI fluoxetine (20 mg/day) with mianserin (30 mg/day) compared to fluoxetine alone in an in-patient setting using a double-blind controlled design. Using a 50% decrease in HDRS ratings as the outcome criterion, they observed a 60% response rate in patients given the fluoxetine+mianserin combination from day 1 compared to a 9% response rate in patients treated with fluoxetine monotherapy. A significant separation between groups was observed as early as the first week. A double-blind placebo-controlled comparison of mianserin (30 mg/day)+fluoxetine (20 mg/day) vs placebo+fluoxetine found a significant advantage for the combined treatment group only when excluding the drop-outs from the first 2 weeks of the 6-week trial (Dam et al, 1998).
Mianserin may also enhance the efficacy of SSRIs in refractory patients as well. A double-blind, placebo-controlled study comparing addition of mianserin (60 mg/day) or placebo to fluoxetine (20 mg/day) or placebo in patients with ≥25 score on the 17-item Hamilton Depression Rating (Ham-D) Score observed a significant 5-point advantage for the mianserin+fluoxetine group compared to the placebo+fluoxetine group. The mianserin+placebo group was intermediate between the other two groups. The remission rate was also over twice as great in the mianserin+fluoxetine group vs the placebo+fluoxetine group (Ferreri et al, 2001). A recent double-blind study (mianserin+sertraline vs placebo+sertraline) failed to observe beneficial effects of adding mianserin (30 mg/day) to sertraline (100 mg/day) in patients failing to respond to an initial open 6-week treatment with sertraline (50 mg/day×4 weeks; 100 mg/day×2 weeks; Licht and Qvitzau, 2002). Differences in depression severity may have contributed to these differences. The 17-item HAM-D scores required for study entry was ≥25 for the fluoxetine augmentation study after initial fluoxetine treatment (Ferreri et al, 2001), whereas the entry criterion was ≥18 for the sertraline augmentation study before the initial sertraline treatment (Licht and Qvitzau, 2002).
Literature regarding the efficacy of mirtazapine in OCD is limited to a single open-label trial. Only two of 10 patients (or 2/6 completers) improved during a 10-week course of treatment with mirtazapine (Koran et al, 2001). Four patients in the study had not had a previous unsuccessful trial with SSRIs, and both of the patients who improved were in this subgroup. To date, there have been no published studies in which mirtazapine was used to augment SSRI monotherapy in treatment-refractory OCD.
A recent open-label study of mirtazapine (mean dose, 32 mg/day) in children, adolescents, and young adults with PDDs (aged 4–24 years) found a 35% response rate in 26 patients, similar to the response rate generally observed in this population with SSRIs (Posey et al, 2001). This was a naturalistic study in which the nine mirtazapine responders were on either no concomitant medications (four patients); methylphenidate (two patients); clonidine and pimozide (one patient); paroxetine and risperidone (one patient); or clonazepam and guanfacine (one patient). As with risperidone (see above), clinical improvement was noted for aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia, with no improvement in core symptoms of socialization or communication impairment. Confirmation of these preliminary results under double-blind placebo-controlled conditions would support the hypothesis that blockade of 5-HT2A receptors plays an important role in the therapeutic effects of risperidone for autistic patients. The efficacy of 5-HT2 antagonists in combination with SSRIs for the treatment of PDDs remains to be explored.
OTHER 5-HT2 ANTAGONISTS: SPECTRUM OF CLINICAL ACTIVITY
While SSRIs have become the mainstay for the pharmacological treatment of major depression, a number of drugs are effective in monotherapy minus the ability to appreciably block either monoamine uptake or monoamine oxidase. These ‘atypical’ drugs (mirtazapine, mianserin, nefazodone, and trazodone) have been shown to have antidepressant efficacy in multiple double-blind, placebo-controlled studies (Pinder and Fink, 1982; Marek et al, 1992; Davis et al, 1997; Fawcett and Barkin, 1998). The common potent pharmacological target for these agents is blockade of the 5-HT2 family of receptors. Interestingly, there have been no controlled studies published suggesting that nefazodone or trazodone might enhance in a synergistic fashion the therapeutic effects of SSRIs. If the 5-HT1A and 5-HT2C receptors are important targets that SSRIs indirectly activate via blockade of the 5-HT transporter, then the lack of selectivity of nefazodone and trazodone at the 5-HT1A or the 5-HT2C vs the 5-HT2A receptors may limit the usefulness of these drugs as augmenting agents for patients refractory to SSRIs (Wander et al, 1986; Eison et al, 1990; Richelson, 2001). In addition to the well-known ‘atypical’ antidepressants listed above, there are double-blind studies demonstrating antidepressant activity of other potent 5-HT2 antagonists as well, such as ritanserin, pipamperone, pizotifen, danitracen, and etoperidone (Matussek et al, 1976; Ansoms et al, 1977; Standal, 1977; Kern and Richter, 1985; Bersani et al, 1990).
In contrast to the preliminary evidence that blockade of 5-HT2 receptors may augment the therapeutic effects of SSRIs in OCD, evidence from monotherapy with potent 5-HT2 antagonists in this disorder is generally negative. For example, the atypical neuroleptic clozapine, at doses (400–500 mg/day) that would provide significant blockade of 5-HT2A receptors (Nordstrom et al, 1993), did not improve any of 10 treatment-refractory patients participating in a 10-week open-label trial (McDougle et al, 1995a). Clinical experience with other available 5-HT2 antagonists in the treatment of OCD has been similarly unrewarding.
In contrast to the apparent benefit of atypical neuroleptic drugs for SSRI-refractory patients with OCD, a number of case reports (generally involving schizophrenic patients) have suggested that addition of atypical neuroleptic drugs can worsen obsessive–compulsive symptoms while simultaneously improving psychotic symptoms (Lykouras et al, 2000; Khullar et al, 2001; De Haan et al, 2002). The magnitude of this clinical problem remains to be fully explored as clozapine may be implicated more frequently than other antipsychotic drugs (De Haan et al, 1999). Obsessive–compulsive symptoms have been reported to be improved in schizophrenic patients treated with olanzapine (Poyurovsky et al, 2000). Addressing both the issue of clozapine and the primary psychiatric diagnosis, the open-label trial of clozapine in treatment-refractory OCD patients failed to observe worsening of obsessive–compulsive symptoms for any of the 10 patients treated for 10 weeks (McDougle et al, 1995a). The frequency for which exacerbation of obsessive–compulsive symptoms is observed in schizophrenic patients remains to be quantified. Thus, primary OCD vs obsessive–compulsive symptoms in patients with other diagnoses may be an important factor in whether addition of 5-HT2A antagonists improves patients' refractory to SSRI treatment.
The improvement of aggression in autism by both risperidone and mirtazapine is suggestive that blockade of 5-HT2A receptors may play a role in this response. This is interesting in light of a double-blind placebo-controlled crossover trial in which the selective 5-HT2A antagonist pipamperone decreased episodes of anger, aggressiveness, and impulsivity, and increased alertness and responsiveness in adult females with mental retardation (van Hemert, 1975). While this report did not specify the clinical diagnoses of the patients, PDDs are known to be over-represented in the population of mentally retarded individuals with prominent behavioral disturbances. This efficacy in treating aggression is consistent with previous open-label trials of pipamperone in diverse groups of patients (DeBerdt, 1976; Van Renynghe de Voxvrie and De Bie, 1976; Noordhuizen, 1977; Haegeman and Duyck, 1978). Pipamperone has since been shown to have significant in vitro selectivity as an antagonist at the 5-HT2A receptor compared to other receptors (dopamine D2, 20-fold; dopamine D3, 46-fold; 5-HT1A, 512-fold; 5-HT1Dα, 30-fold; 5-HT2C, 100-fold; histamine H1, 444-fold; α2A-adrenergic, 159-fold; α2B-adrenergic, 6.5-fold; α2C-adrenergic, 54-fold) (Schotte et al, 1996).
THERAPEUTIC EFFICACY OF SSRIS: WHICH 5-HT RECEPTORS ARE ACTIVATED?
The central thesis argued above is that 5-HT2A receptors actually oppose the therapeutic effects of activating non-5-HT2A receptors in diverse neuropsychiatric syndromes such as depression, OCD, and PDDs. This broad range of clinical effects may be caused by localization of 5-HT2A receptors at critical sites in the prefrontal cortex regulating cortico-striatal-pallidal-thalamic loops. The target receptor(s) that actually mediate the therapeutic effects of increased synaptic 5-HT caused by SSRIs is far from clear and may be different for these and other psychiatric syndromes.
5-HT1A receptors may be involved in both the treatment (Pineyro and Blier, 1999) and the pathophysiology of major depression (Arango et al, 1995; Stockmeier et al, 1998). There have been some positive double-blind placebo-controlled studies with the azapirone class of drugs, such as buspirone and gepirone, which are partial 5-HT1A agonists that are not as effective as 5-HT itself in maximally activating postsynaptic 5-HT1A receptors (Robinson et al, 1990; Jenkins et al, 1990). However, these agents are not used as front-line monotherapeutic agents for patients with mood disorders. Furthermore, no positive double-blind placebo-controlled reports of antidepressant activity in depressed patients have been reported for the 5-HT1A partial agonists tandospirone and flesinoxan. A large multicenter, double-blind, placebo-controlled trial for ipsapirone failed to observe a significant antidepressant response, despite a placebo response rate of only 35% (Lapierre et al, 1998). Finally, it should be noted that no 5-HT1A partial agonists have been approved by the FDA for the treatment of major depression. It is not clear if the relative lack of success with 5-HT1A agonists in depression and OCD is caused by the following: (1) lack of compounds with sufficient agonist efficacy for postsynaptic receptors, (2) unfavorable pharmacokinetics of presently available drugs, or (3) inadequate therapeutic benefit from stimulation of 5-HT1A receptors alone.
The clinical overlap between migraine headache and major depression also raises the question of whether 5-HT1B/1D agonists might be useful in depression. Again, a central problem with 5-HT1B/1D receptors, as with 5-HT1A receptors, is that optimal clinical action might require blockade of presynaptic autoreceptors on the axon terminals of serotonergic neurons and activation of heteroceptors on the axon terminals of nonserotonergic neurons. Regarding presynaptic autoreceptor antagonists, the lack of efficacy of the 5-HT1A somatodendritic autoreceptor antagonist pindolol in augmenting the effects of SSRIs in SSRI-resistant depression (Perez et al, 1999) may simply mean that 5-HT1B terminal autoreceptors must also be targeted when attempting to increase serotonergic neurotransmission by blocking the 5-HT1A autoreceptors. Moreover, it has been argued that pindolol itself is a suboptimal tool for blocking 5-HT1A somatodendritic autoreceptors on serotonergic neurons (Kinney et al, 2000). Significant potential remains for potent and selective blockade of somatodendritic (5-HT1A) and terminal (5-HT1B/1D) autoreceptors on serotonergic neurons as a means to enhance the efficacy of SSRIs.
Activation of 5-HT2C receptors appears to cause effects that functionally oppose the effects resulting from activation of 5-HT2A receptors (see above). These two receptors are differentially regulated by antidepressants in a manner that could have clinical relevance (Berendsen and Broekkamp, 1991). Other preclinical work in rodents has found that 5-HT2C agonists have antidepressant-like action in the forced swim test, the olfactory bulbectomy model, and the DRL 72-s schedule (Martin et al, 1998; Cryan and Lucki, 2000). Moreover, a polymorphism for the 5-HT2C receptor has been linked to mood disorders (Lerer et al, 2001). This might result in an alteration of 5-HT2C function independent of receptor abundance. Alterations in RNA editing of 5-HT2C receptors has been reported in suicide victims (Niswender et al, 2001). Thus, simultaneous blockade of 5-HT2A receptors and activation of 5-HT2C receptors could result in an improved therapeutic benefit over either of these actions in isolation.
Blockade of 5-HT2C receptors could contribute to the enhanced efficacy of augmentation or combination therapy with mirtazapine, mianserin, or olanzapine. If blockade of 5-HT2C receptors mediates the antidepressant augmenting effects of 5-HT2 antagonists, then one might expect an SSRI with potent 5-HT2C receptor antagonist potency to have a faster onset of action. Fluoxetine has been suggested from extrapolations of preclinical data to block 5-HT2C receptors at doses used in the clinic (Bymaster et al, 2002). However, meta-analysis suggests that fluoxetine may have a slower onset of antidepressant action than other SSRIs (Edwards and Anderson, 1999). It remains to be determined if this is because of pharmacodynamic and/or pharmacokinetic considerations. Alternatively, suggestions that risperidone or pipamperone may augment the action of antidepressant drugs at doses with a measure of selectivity for blockade of 5-HT2A receptors might reflect the complex actions of 5-HT in mediating the therapeutic actions of antidepressant drugs (Ostroff and Nelson, 1999; Ansoms et al, 1977). In fact, the failure of the pharmaceutical industry to produce an effective antidepressant that selectively activates a single 5-HT receptor is consistent with the likelihood that indirect activation of multiple 5-HT receptor subtypes mediates the therapeutic actions of SSRIs.
The 5-HT5A/5B receptor is still poorly understood; indeed, its in situ postreceptor transduction pathway is not known. This receptor is most closely related to some of the 5-HT1 receptor subtypes on a pharmacological basis. Furthermore, in vitro studies have demonstrated that the 5-HT5A receptor, like the 5-HT1 family of receptors, can couple to Gi/Go proteins (Francken et al, 1998). The 5-HT5A/5B receptors are not known to be a target of antidepressant or neuroleptic drugs (Matthes et al, 1993). There is presently little data to indicate whether 5-HT5A/5B receptors mediate any of the clinical effects of increased synaptic 5-HT subsequent to blockade of 5-HT transporters. Interestingly, a recent report has implicated a polymorphism for this receptor in altered susceptibility to schizophrenia and mood disorders (Birkett et al, 2000).
There is some evidence suggesting that activation of 5-HT6 receptors might oppose the effects of 5-HT2A receptor activation in the frontal cortex. Activation of 5-HT2A receptors increases glutamate release from thalamocortical afferents, as discussed above. In contrast, blockade of 5-HT6 receptors has recently been shown to increase extracellular levels of glutamate measured using in vivo dialysis in the prefrontal cortex, hippocampus, and striatum (Dawson et al, 2000,2001). Activation of 5-HT6 receptors might, therefore, be expected to suppress extracellular levels of glutamate in the frontal cortex. Consistent with the hypothesis that functional relationships exist between 5-HT6 receptors and glutamate, blockade of ionotropic glutamate receptors decreases the expression of 5-HT6 receptor mRNA (Healy and Meador-Woodruff, 1999).
5-HT7 agonists might also be in functional opposition to the effects of 5-HT2A receptor activation in the prefrontal cortex. For example, high concentrations of 8-OH-DPAT (10 μM) suppressed delayed late EPSPs induced by concurrent activation of 5-HT2A receptors and electrical stimulation of the white matter in a delayed manner with only partial efficacy followed by complete recovery (G Marek, unpublished observations). However, effects of 8-OH-DPAT at 5-HT1A receptors in slice preparations are usually brisk in onset and only slowly fade away. Thus, these 8-OH-DPAT responses do not appear to be mediated by activation of 5-HT1A receptors. This action of 8-OH-DPAT was probably the result of activating a 5-HT1D/5A/5B/7 receptor. As discussed for the 5-HT6 receptor, blockade of ionotropic glutamate receptors also alters 5-HT7 receptor mRNA exprression (Healy and Meador-Woodruff, 1999). Further support for the hypothesis that activation of a Gqs-coupled receptor (positively coupled to adenylyl cyclase) might actually suppress glutamate release induced by 5-HT2A receptor activation comes from experiments in which the suppressant action of epinephrine or norepinephrine on DOI-induced late EPSPs is blocked by β2-adrenergic antagonists (B Ramos and G Marek, unpublished observations). β2-Adrenergic, like 5-HT4/6/7 receptors are well-known to be coupled to Gqs proteins. Activation of members of the 5-HT or adrenergic receptor superfamily that increase cAMP formation (eg 5-HT4/6/7), with subsequent upregulation of neurotrophins and transcription factors, has also been proposed to play an important role in the long-term effects of antidepressant drugs (Duman et al, 1997). Thus, activation of 5-HT6/7 receptors might have both acute and long-term effects that could contribute to the therapeutic actions of SSRIs.
CONCLUSIONS AND FUTURE DIRECTIONS
SSRIs have been found to exert clinical efficacy in a wide variety of psychiatric syndromes, including major depression, OCD, autism and other PDDs, panic disorder, and PTSD. Drugs that block the 5-HT2 family of receptors, such as risperidone, olanzapine, mirtazapine, and mianserin, have been found to either augment the action of SSRIs in treatment-refractory patients or to demonstrate therapeutic efficacy as stand-alone agents. The most parsimonious explanation for these findings is that blockade of 5-HT2A receptors and activation of non-5-HT2A receptors may have similar effects. Further evidence relevant to this hypothesis will come from the systematic examination of other ‘atypical’ neuroleptics with respect to their clinical profile of action across diverse psychiatric syndromes. For example, ziprasidone is even more selective for the 5-HT2A receptor vs dopamine D2 or 5-HT2C receptors than is risperidone or olanzapine (Schotte et al, 1996; Tandon et al, 1997). Unlike most other neuroleptics, ziprasidone is a 5-HT1A partial agonist (Sprouse et al, 1999) that also blocks monoamine transport with sub-μM potency. This drug is relatively weak at displacing binding to histamine H1 receptors compared to other ‘atypical’ neuroleptics. A further difference from other ‘atypical’ compounds is the high potency that ziprasidone possesses for the 5-HT1D receptor, and blockade of the 5-HT1D autoreceptor enhances the effects of SSRIs on extracellular 5-HT levels (Rollema et al, 1996).
Support for the hypothesis that blockade of 5-HT2A receptors coincident with activation of non-5-HT2A receptors results in more robust clinical activity than either drug alone could come from clinical testing of highly selective 5-HT2A antagonists, such as M100907 (Kehne et al, 1996), in combination with SSRIs. Evaluation of novel compounds that combine equal and potent blockade of both 5-HT2A receptors and 5-HT transporters would also provide critical data (Puller et al, 2000; Schmidt et al, 2001). An appreciation of the opposing effects of different 5-HT receptor subtypes in mediating the therapeutic effects of drugs will be important in better defining the neurocircuitry involved in the pathogenesis of these disorders, and in developing treatments with more rapid onset and greater efficacy.
Aghajanian GK, Marek GJ (1997). Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36: 589–599.
Aghajanian GK, Marek GJ (1999). Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825: 161–171.
Ansoms C, De Backer-Dierick G, Vereecken JLTM (1977). Sleep disorders in patients with severe mental depression: double-blind placebo-controlled evaluation of the value of pipamperone (Dipiperon). Acta Psychiatr Scand 55: 116–122.
Araneda R, Andrade R (1991). 5-Hydroxytryptamine2 and 5-Hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience 40: 399–412.
Arango V, Underwood MD, Gubbi AV, Mann JJ (1995). Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res 688: 121–133.
Arnt J, Hyttel J (1989). Facilitation of 8-OHDPAT-induced forepaw treading of rats by the 5-HT2 agonist DOI. Eur J Pharmacol 161: 45–51.
Ashby CR, Edwards E, Wang RY (1994). Electrophysiological evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex: an iontophoretic study. Synapse 17: 173–181.
Bengtsson HJ, Kele J, Johansson J, Hjorth S (2000). Interaction of the antidepressant mirtazapine with α2-adrenoceptors modulating the release of 5-HT in different rat brain regions in vivo. Naunyn-Schmiedebergs Arch Pharmacol 362: 406–412.
Berendse HW, Groenewegen HJ (1990). Organization of the thalamostriatal projections in the rat, with special emphasis on the ventral striatum. J Comp Neurol 299: 187–228.
Berendse HW, Groenewegen HJ (1991). Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat. Neuroscience 42: 73–102.
Berendsen HHG, Broekkamp CLE (1991). Attentuation of 5-HT-1A and 5-HT-2 but not 5-HT-1C receptor mediated behaviour in rats following chronic treatment with 5-HT receptor agonists, antagonists or anti-depressants. Psychopharmacology 105: 219–224.
Berendsen HHG, Jenck F, Broekkamp CLE (1990). Involvement of 5-HT1C receptors in drug induced penile erections in rats. Psychopharmacology 101: 57–61.
Bersani G, Pozzi F, Marini S, Grispini A, Pasini A, Ciani N (1990). 5-HT2 receptor antagonism in dysthymic disorder: a double blind placebo-controlled study with ritanserin. Acta Physiol Scand 83: 244–248.
Birkett JT, Arranz MJ, Munro J, Osbourn S, Kerwin RW, Collier DA (2000). Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuro Report 11: 2017–2020.
Bogetto F, Bellino S, Vaschetto P, Ziero S (2000). Olanzapine augmentation of fluvoxamine-refractory obsessive–compulsive disorder (OCD): a 12-week open trial. Psychiatry Res 96: 91–98.
Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC et al (1996). Radioceptor binding profile of the atypical antipsychotic olazepine. Neuro psychopharmacology 14: 87–96.
Bymaster FP, Zhang W, Carter PA, Shaw J, Chernet E, Phebus L et al (2002). Fluoxetine, but not other selective serotonin uptake inhibitors, increases extracellular norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology 160: 353–361.
Carpenter LL, Jocic Z, Hall JM, Rasmussen SA, Price LH (1999). Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry 60: 45–49.
Carpenter LL, Yasmin S, Price LH (2002). A double-blind placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry 51: 183–188.
Cryan JF, Lucki I (2000). Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine(2C) receptors. J Pharmacol Exp Ther 295: 1120–1126.
Dam J, Ryde L, Svejso J, Lauge N, Lauritsen B, Bech P (1998). Morning fluoxetine plus evening mianserin versus morning fluoxetine plus evening placebo in the acute treatment of major depression. Pharmacopsychiatry 31: 48–54.
Davis R, Whittington R, Bryson HM (1997). Nefazodone: a review of its pharmacology and clinical efficacy in the management of major depression. Drugs 53: 608–636.
Dawson LA, Nguyen HP, Li P (2000). In vivo effects of the 5-HT6 antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate. Br J Pharmacol 130: 23–26.
Dawson LA, Nguyen HQ, Li P (2001). The 5-HT6 receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology 25: 662–668.
De Boer T (1996). The pharmacologic profile of mirtazepine. J Clin Psychiatry 57: 19–25.
De Boer T, Nefkens F, Van Helvoirt A, Van Delft AML (1996). Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan. J Pharmacol Exp Ther 277: 852–860.
De Haan L, Linszen DH, Gorsira R (1999). Clozapine and obsessions in patients with recent-onset schizophrenia and other psychotic disturbances. J Clin Psychiatry 60: 364–365.
De Haan L, Bevk N, Hoogenboom B, Dingemans P, Linzen D (2002). Obsessive-compulsive symptoms during treatment with olanzapine and risperidone: a prospective study of 113 patients with recent onset schizophrenia as related disorders. J Clin Psychiatry 63: 104–107.
DeBerdt R (1976). Pipamperone (Dipiperon) in the treatment of behavioural disorders: a large scale multicentre evaluation. Acta Psychiatr Belg 76: 157–166.
Delgado PL, Chamey DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990). Serotonergie function and the mechanism of antidepressant action. Reversal of antidepressant induced remission by rapid depletion of plasma typtophan. Arch Gen Psychiatry 47: 411–418.
Delgado PL, Miller HL, Salomon RM, Licinio J, Krystal JH, Morens FA et al (1999). Tryptophan-depletion challange in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry 46: 212–220.
Duman RS, Heninger GR, Nestler EJ (1997). A molecular and cellular theory of depression. Arch Gen Psychiatry 54: 597–606.
Edwards JG, Anderson I (1999). Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 57: 507–533.
Eison AS, Eison MS, Torrente JR, Wright RN, Yocca FD (1990). Nefazodone: preclinical pharmacology of a new antidepressant. Psychopharmacol Bull 26: 311–315.
Fawcett J, Barkin RL (1998). Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord 51: 267–285.
Ferreri M, Lavergne F, Berlin I, Payan C, Peuch AJ (2001). Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatr Scand 103: 66–72.
Francken JB, Jurzak M, Vanhauwe JFM, Luyten WHML, Leysen JE (1998). The human 5-HT5A/5B receptor couples to Gi/Gi proteins and inhibits adenylate cyclase in HEK 293 cells. Eur J Pharmacol 361: 299–309.
Fuster JM (1997). The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal Lobe, 3rd edn. Lippincott-Raven: Philadelphia, New York.
Granhoff MI, Lee L, Jackson A, Patel K, Martinez Y, Ashby CR et al (1992). The interaction of 5-HT1A and 5-HT2 receptors in the medial prefrontal cortex: behavioral studies. Soc Neurosci Abstr 18: 1380.
Grossman F, Potter WZ, Brown EA, Maislin G (1999). A double-blind study comparing idazoxan and bupropion in bipolar depressed patients. J Affect Disord 56: 237–243.
Haddjeri N, Blier P, de Montigny C (1997). Effects of long-term treatment with the α2-adrenoceptor antagonist mirtazepine on 5-HT neurotransmission. Naunyn-Schmiedebergs Arch Pharmacol 355: 20–29.
Haegeman J, Duyck E (1978). A retrospective evaluation of pipamperone (Dipiperon) in the treatment of behavioural deviations in severely mentally handicapped. Acta Psychiatr Belg 78: 393–398.
Healy DJ, Meador-Woodruff JH (1999). Ionotropic glutamate receptor modulation of 5-HT6 and 5-HT7 mRNA expression in rat brain. Neuropsychopharmacology 21: 341–351.
Hoyer D, Schoeffter P, Waeber C, Palacios JM (1990). Serotonin 5-HT1D receptors. Ann NY Acad Sci 600: 168–181.
Jacobsen FM (1995). Risperidone in the treatment of affective illness and obsessive–compulsive disorder. J Clin Psychiatry 56: 423–429.
Jenkins SW, Robinson DS, Fabre LF, Andary JJ, Messina ME, Reich LA (1990). Gepirone in the treatment of major depression. J Clin Psychopharmacol 10: 77S–85S.
Jolly DC, Richards JB, Seiden LS (1999). Serotonergic mediation of DRL 72s behavior: receptor subtype involvement in a behavioral screen for antidepressant drugs. Biol Psychiatry 45: 1151–1162.
Kapur S, Zipursky RB, Remington G (1999). Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 156: 286–293.
Kehne JH, Baron BM, Carr AA, Chaney SR, Elands J, Feldman DJ et al (1996). Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a!potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther 277: 968–981.
Kern U, Richter (1985). Clinical comparison of etoperidone and amitriptyline in endogenous depressive patients. Pharmacopsychiatry 18: 94–95.
Khullar A, Chue P, Tibbo P (2001). Quetiapine and obsessive–compulsive symptoms (OCS): case report and review of atypical antipsychotic-induced OCS. J Psychiatry Neurosci 26: 55–59.
Kinney GG, Taber MT, Gribkoff VK (2000). The augmentation hypothesis for improvement of antidepressant therapy. Mol Neurobiol 21: 137–152.
Koran LM, Quirk T, Lorberbaum JP, Elliott M (2001). Mirtazapine treatment of obsessive–compulsive disorder. J Clin Psychopharmacol 21: 537–538.
Lapierre YD, Silverstone P, Reesal RT, Saxena B, Turner P, Bakish D et al (1998). A Canadian multicenter study of three fixed doses of controlled-release ipsapirone in outpatients with moderate to severe major depression. J Clin Psychopharmacol 18: 268–273.
Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, Blairy S et al (2001). Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder. Mol Psychiatry 6: 579–585.
Licht RW, Qvitzau S (2002). Treatment strategies in patients with major depression not responding to first-line sertraline treatment. Psychopharmacology 161: 143–151.
Lykouras L, Zervas IM, Gournellis R, Malliori M, Rabavilas A (2000). Olanzapine and obsessive-compulsive symptoms. Eur Neuropsychopharmacol 10: 385–387.
Maes M, Libbrecht I, Van Hunsel F, Campens D, Meltzer HY (1999). Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance. J Clin Psychopharmacol 19: 177–182.
Malone RP, Cater J, Sheikh RM, Choudhury MS, Delaney MA (2001). Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J Am Acad Child Adolesc Psychiatry 40: 887–894.
Marek GJ, Li AA, Seiden LS (1989a). Selective 5-hydroxytryptamine2 antagonists have antidepressant-like effects on differential-reinforcement-of-low-rate 72-second schedule. J Pharmacol Exp Ther 250: 52–59.
Marek GJ, Li AA, Seiden LS (1989b). Evidence for involvement of 5-hydroxytryptamine1 receptors in antidepressant-like drug effects on differential-reinforcement-of-low-rate 72-second behavior. J Pharmacol Exp Ther 250: 60–71.
Marek GJ, Martin-Ruiz R, Abo A, Artigas F (2001a). Synergistic ‘antidepressant-like’ action between a highly selective 5-HT-2A antagonist (M100907) and the SSRI fluoxetine on DRL 72-s behavior. Soc Neurosci Abstr 27: 975.8.
Marek GJ, Wright RA, Gewirtz JC, Schoepp DD (2001b). A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in neocortex. Neuroscience 105: 113–126.
Marek GJ, McDougle CJ, Price LH, Seiden LS (1992). A comparison of trazodone and fluoxetine: implications for a serotonergic mechanism of antidepressant action. Psychopharmacology 109: 2–11.
Marek GJ, Seiden LS (1988). Effects of selective 5-hydroxytryptamine-2 and nonselective 5-hydroxytryptamine antagonists on the differential-reinforcement-of-low-rate 72-second schedule. J Pharmacol Exp Ther 244: 650–658.
Marek GJ, Seiden LS (1994). Antidepressant drug screens and the serotonin system. In: Palomo T, Archer T (eds). Strategies for Studying Brain Disorders: Depressive, Anxiety and Drug Abuse Disorders. Farrand Press: London. Vol 1, pp 23–40.
Martin JR, Bos M, Jenck F, Moreau J, Mutel V, Sleight AJ et al (1998). 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 286: 913–924.
Martin P, Waters N, Carlsson A, Carlsson ML (1997). The apparent antipsychotic action of the 5-HT2A receptor antagonist M100907 in a mouse model of schizophrenia is counteracted by ritanserin. J Neural Transm 104: 561–564.
Matthes H, Boschert U, Amlaiky N, Grailhe R, Plassat J-L, Muscatelli F et al (1993). Mouse 5-hydroxytryptamine5A and 5-hydroxytryptamine5B receptors define a new family of serotonin receptors: cloning, functional expression, and chromosomal localization. Mol Pharmacol 43: 313–319.
Matussek VN, Benkert O, Fidetzis K, Flach D, Hermann HU, Kaumeier S et al (1976). Wirkung des Anthracenderivats danitracen (WA 335-BS) im vergleich zu amitriptylin bie depressiven patienten. Arzneim Forsch (Drug Res) 26: 1160.
McDougle CJ, Barr LC, Goodman WK, Pelton GH, Aronson SC, Anand A et al (1995a). Lack of efficacy of clozapine monotherapy in refractory obsessive–compulsive disorder. Am J Psychiatry 152: 1812–1814.
McDougle CJ, Fleischmann RL, Epperson CN, Wasylink S, Leckman JF, Price LH (1995b). Risperidone addition in fluvoxamine-refractory obsessive–compulsive disorder: three cases. J Clin Psychiatry 56: 526–528.
McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH (2000). A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibition-refractory obsessive–compulsive disorder. Arch Gen Psychiatry 57: 794–801.
McDougle CJ, Goodman WK, Leckman JF, Lee NC, Heninger GR, Price LH (1994). Haloperidol addition to fluvoxamine-refractory obsessive–compulsive disorder: a double-blind, placebo-controlled study in patients with and without tics. Arch Gen Psychiatry 51: 302–308.
McDougle CJ, Holmes JP, Carlson DC, Pelton GH, Cohen DJ, Price LH (1998). A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders [see comments]. Arch Gen Psychiatry 55: 633–641.
McDougle CJ, Naylor ST, Cohen DJ, Aghajanian GK, Heninger GR, Price LH (1996). Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 53: 993–1000.
Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tanredi A et al (2000). Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citaloporam. Eur J Neurosci 12: 1079–1095.
Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA et al (2001). RNA editing of the human serotonin 5-HT2C receptor: alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsychopharmacology 24: 478–491.
Noordhuizen GJM (1977). Treating severe maladjustment with pipamperone (Dipiperon). Acta Psychiatr Belg 77: 754–760.
Nordstrom A-L, Farde L, Halldin C (1993). High 5-HT2 receptor occupancy in clozapine treated patients demonstrated by PET. Psychopharmacology 110: 365–367.
Nyberg S, Eriksson B, Oxenstierna G, Halldin C, Farde L (1999). Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenia patients. Am J Psychiatry 156: 869–875.
O'Connor M, Silver H (1998). Adding risperidone to selective serotonin reuptake inhibitor improves chronic depression. J Clin Psychopharmacol 18: 89–90.
Osman OT, Rudorfer MV, Potter WZ (1989). Idazoxan: a selective α2-antagonist and effective sustained antidepressant in two bipolar depressed patients. Arch Gen Psychiatry 46: 958–959.
Ostroff RB, Nelson JC (1999). Risperidone augmentation of SSRIs in major depression. J Clin Psychiatry 60: 256–259.
Perez V, Soler J, Puigdemont D, Alvarez E, Artigas F (1999). A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch Gen Psychiatry 56: 375–379.
Pinder RM, Fink M (1982). Mianserin. Mod Probl Pharmacopsychiatry 18: 70–101.
Pineyro G, Blier P (1999). Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev. The American Society for Pharmacology and Therapeutics. Vol. 51: 533–591.
Posey DJ, Guenin KD, Kohn AE, Swiezy NB, McDouble CJ (2001). A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders. J Child Adolesc Psychopharmacol 11: 267–277.
Potenza MN, Holmes JP, Kanes SJ, McDougle CJ (1999). Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study. J Clin Psychopharmacol 19: 37–44.
Potter WZ, Grossman F, Dawkins K, Manji HK (1994). Initial clinical psychopharmacological studies of alpha-2 adrenoceptor antagonists in volunteers and depressed patients. In: Montgomery SA, Corn TH (eds). Psychopharmacology of Depression, Vol British Association for Psychopharmacology Monograph No. 13. Oxford University Press: New York.
Poyurovsky M, Dorfman-Etrog P, Hermesh H, Munitz H, Tollefson GD, Weizman A (2000). Beneficial effect of olanzapine in schizophrenic patients with obsessive–compulsive symptoms. Int Clin Psychopharmacol 15: 169–173.
Puller IA, Carney SL, Colvin EM, Lucaites VL, Nelson DL, Wedley S (2000). LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine2A receptor antagonist: a comparison with the antidepressant, nefazodone. Eur J Pharmacol 407: 39–46.
Ravizza L, Barzega G, Bellino S, Bogetto F, Maina G (1996). Therapeutic effect and safety of adjunctive risperidone in refractory obsessive–compulsive disorder (OCD). Psychopharmacol Bull 32: 677–682.
Research Units on Pediatric Psychopharmacology Autism Network (2002). A double-blind placebo-controlled trial of risperidone in children with autistic disorder. N Engl J Medicine (in press).
Richelson E (2001). Pharmacology of antidepressants. Mayo Clin Proceed 76: 511–527.
Richelson E, Nelson A (1984). Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther 230: 94–102.
Richelson E, Souder T (2000). Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 68: 29–39.
Robinson DS, Rickels K, Feighner J, Fabre LF, Gammans RE, Shrotriya RC et al (1990). Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. J Clin Psychopharmacol 10: 67S–76S.
Rollema H, Clarke T, Sprouse JS, Schulz DW (1996). Combined administration of a 5-hydroxytryptamine (5-HT)1D antagonist and a 5-HT reuptake inhibitor synergistically increases 5-HT release in guinea pig hypothalamus in vivo. J Neurochem 67: 437–439.
Saxena S, Wang D, Bystritsky A, Baxter Jr LR (1996). Risperidone augmentation of SRI treatments for refractory obsessive–compulsive disorder. J Clin Psychiatry 57: 303–306.
Schmidt CJ, Fox CB, Harms JF, Wylie P, Seeger TF, Guanowsky V et al (2001). CP-646,781: a potent dual SSRI/5-HT2A receptor agonist. Soc Neurosci Abstr 27: 665.17.
Schotte A, Janssen PFM, Gommeren W, Luyten WHML, Van Gompel P, Lesage AS et al (1996). Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124: 57–73.
Schreiber R, Brocco M, Audinot V, Gobert A, Veiga S, Millan MJ (1995). (1-(2,5-Dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine(5-HT)2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. J Pharmacol Exp Ther 273: 101–112.
Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG et al (2001). A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 158: 131–134.
Sprouse JS, Reynolds LS, Braselton JP, Rollema H, Zorn SH (1999). Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation. Neuropsychopharmacology 21: 622–631.
Standal JE (1977). Pizotifen as an antidepressant Acta Physiol Scand 56: 276–279.
Stein DJ, Bouwer MB, Hawkridge S, Emsley RA (1997). Risperidone augmentation of serotonin reuptake inhibitors in obsessive–compulsive and related disorders. J Clin Psychiatry 58: 119–122.
Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Fredman L, Raj Kowska G et al (1998). Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression—postmortem evidence for decreased serotonin activity. J Neurosci 18: 7394–7401.
Stoll AL, Haura G (2000). Tranylcypromine plus risperidone for treatment-refractory major depression. J Clin Psychopharmacol 20: 495–496.
Su HS, Bentivoglio M (1990). Thalamic midline cell populations projecting to the nucleus accumbens, amygdala, and hippocampus in the rat. J Comp Neurol 297: 582–593.
Talvik-Lofti M, Nyberg S, Nordstrom AL, Ito H, Halldin C, Brunner F et al (2000). High 5-HT2A receptor occupancy in M100907-treated schizophrenia patients. Psychopharmacology 148: 400–403.
Tanaka E, North RA (1993). Actions of 5-hydroxytryptamine on neurons of the rat cingulate cortex. J Neurophysiol 69: 1749–1757.
Tandon R, Harrigan E, Zorn SH (1997). Ziprasidone: a novel antipsychotic with unique pharmacology and therapeutic potential. J Serotonin Res 4: 159–177.
van Hemert JCJ (1975). Pipamperone (Dipiperon, R3345) in troublesome mental retardates: a double-blind placebo-controlled cross-over study with long-term follow-up. Acta Physiol Scand 52: 237–245.
Van Renynghe de Voxvrie G, De Bie M (1976). Character neuroses and behavioural disorders in children: their treatment with pipamperone (Dipiperon): a clinical study. Acta Psychiatr Belg 76: 688–694.
Vickers SP, Easton N, Malcolm CS, Allen NH, Porter RH, Bickerdike MJ et al (2001). Modulation of 5-HT2A receptor-mediated head-twitch behavior in the rat by 5-HT2C receptor agonists. Pharmacol Biochem Behav 69: 643–652.
Wander TJ, Nelson A, Okazaki H, Richelson E (1986). Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro. Eur J Pharmacol 132: 115–121.
Weiss EL, Potenza MN, McDougle CJ, Epperson CN (1999). Olanzapine addition to obsessive–compulsive disorder refractory to selective serotonin reuptake inhibitors: an open-label case series. J Clin Psychiatry 60: 524–527.
Willins DL, Meltzer HY (1997). Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J Pharmacol Exp Ther 282: 699–706.
About this article
Cite this article
Marek, G., Carpenter, L., McDougle, C. et al. Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders. Neuropsychopharmacol 28, 402–412 (2003). https://doi.org/10.1038/sj.npp.1300057
- 5-HT2A receptors
- obsessive–compulsive disorder
This article is cited by
A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine
Translational Psychiatry (2022)
Association between autism spectrum disorder and polymorphisms in genes encoding serotine and dopamine receptors
Metabolic Brain Disease (2021)
Expression of serotonin 1A and 2A receptors in molecular- and projection-defined neurons of the mouse insular cortex
Molecular Brain (2020)
Mapping the physiological and molecular markers of stress and SSRI antidepressant treatment in S100a10 corticostriatal neurons
Molecular Psychiatry (2020)
Molecular Psychiatry (2019)