Schizophrenia: Serotonin-Dopamine Antagonists

By | February 11, 2015

Serotonin-dopamine antagonists, together with dopamine partial agonists, are considered atypical antipsychotics. serotonin-dopamine antagonists have been used for the treatment of schizophrenia since the early 1990s, and currently marketed serotonin-dopamine antagonists include Novartis’s clozapine (Clozaril/Leponex, generics), Janssen’s risperidone (Risperdal), Eli Lilly’s olanzapine (Zyprexa), AstraZeneca’s quetiapine (Seroquel), and Pfizer’s ziprasidone (Geodon/Zeldox).

TABLE . Emerging Therapies in Development for Schizophrenia

Compound Development Phase Marketing Company
Serotonin-dopamine antagonists
Asenapine (ORG-5222)
United States III Organon/Pfizer
Europe III Organon/Pfizer
Olanzapine depot
United States III Eli Lilly
Blonanserin (Lonasen)
United States
Europe II Almirall Prodesfarma
Japan III Dainippon Pharmaceutical
United States II Sumitomo Pharmaceuticals
Japan II Sumitomo Pharmaceuticals
Iloperidone (Zomaril)
United States III Vanda Pharmaceuticals/Titan Pharmaceuticals/Novartis
Europe III Vanda Pharmaceuticals/Titan Pharmaceuticals/Novartis
United States II Johnson & Johnson
Dopamine partial agonists
Bifeprunox (DU-127090)
United States III Solvay/Wyeth
Europe III H.Lundbeck
Japan -(7) Solvay/Wyeth
United States
Europe I Merck
AMPA receptor modulators
CX-516 (Ampalex)
United States II Cortex Pharmaceuticals
United States II Organon/Cortex Pharmaceuticals
Glycline N-methyl-d-aspartate-associated agonists
United States III National Institutes of Mental Health
Nicotinic acetylcholine agonists
United States Spain Abbott Laboratories
Acetylcholinesterase inhibitors
Galantamine (Reminyl)
United States II Johnson & Johnson/ Shire/Janssen
Neurokinin antagonists
United States
Europe II Sanofi-Synthelabo
United States II GlaxoSmithKline

The phase of development for bifeprunox in Japan is unknown. Spain = Suspended.

Continued development of serotonin-dopamine antagonists has focused on two areas: (1) developing a more tolerable compound with efficacy similar to or better than that of clozapine, the gold standard in antipsychotic efficacy, and (2) offering delivery methods other than oral tablets (e.g., depot formulations) to expand the franchises of currently available agents.

Although new serotonin-dopamine antagonists have been introduced to the market since clozapine’s first launch in the 1970s, none has been able to match its efficacy. Clozapine is the only agent to gain approval for use in treatment-refractory and suicidal patients. Regulatory approvals for these difficult-to-treat populations along with clinical experience have prompted physicians to consider clozapine the most efficacious atypical antipsychotic.

Drug companies are developing alternative delivery methods for serotonin-dopamine antagonists to expand their drug’s franchises. Depot formulations ostensibly improve compliance, a major issue for schizophrenic patients. Several studies show that 40% or more of schizophrenic patients in the United States and Europe fail to take their medication as prescribed. To improve compliance, some physicians prescribe a depot, or long-acting injectable, formulation of an antipsychotic. Drug companies have also developed short-acting intramuscular formulations of atypical agents for use in acute-care settings. Currently, ziprasidone and olanzapine are available in these formulations. Intramuscular formulations have small market potential because they are used only as a last resort in acute settings and therefore have a limited patient population and duration of treatment. However, companies have pursued the development of intramuscular formulations in hopes that it will promote long-term oral therapy with their antipsychotic. (Physicians tend to keep a patient on the antipsychotic prescribed in the emergency room.)

Mechanism Of Action

Serotonin-dopamine antagonists are atypical antipsychotics and share a general mechanism of dual antagonism at the serotonin and dopamine receptors. One notable advantage all atypical antipsychotics share is that they have much reduced or no motor side effects like extrapyramidal symptoms or tardive dyskinesia compared with typical drugs. Theoretically, this lower risk of movement disorders could be the result of the blockade of 5-НТ2D receptors in addition to D2 receptors. This serotonin blockage prevents dopamine from being released in the mesolimbic dopamine pathway; hyperactivity of dopamine in this area is associated with extrapyramidal symptoms.

Serotonin-dopamine antagonists’ mechanism of action against positive symptoms is not well understood. The drugs are thought to improve positive symptoms by dual antagonism of D2 and 5-HT2A receptors. Dopamine hyperactivity is thought to be one of the main causes of psychosis. Based on observations made during antipsychotic treatment, decreased dopaminergic neurotransmission apparently reduces the symptoms of schizophrenia. Importantly, 5-НТ2А blockade seems to moderate the reduction in dopaminergic function caused by the D2antagonism of antipsychotics. Furthermore, serotonin-dopamine antagonists demonstrate selectivity for mesolimbic over nigrostriatal regions of the brain in their effects on the dopamine system. This selectivity is important because dopamine deficiency in the nigrostriatal pathway of the brain can cause extrapyramidal symptoms while hyperactivity of dopamine in the mesolimbic pathways is thought to cause psychosis. However, given the many receptors these drugs affect, it may be that unknown biochemical mechanisms or receptors are at work.

Serotonin-dopamine antagonists’ mechanism of action against the negative symptoms and cognitive dysfunction related to schizophrenia is also not well understood. Researchers have suggested cortical dopamine deficiency and/or mesocortical dopamine blockade may be involved in the etiology of negative symptoms. Based on these theories, it has been further proposed that serotonin-dopamine antagonists reduce negative symptoms by blocking serotonin receptors in the mesocortical region, thereby increasing the release of cortical dopamine. Mesocortical release of dopamine associated with 5-HT2A antagonism is also hypothesized to be a factor in the cognitive improvement associated with antipsychotic treatment. serotonin-dopamine antagonists’ ability to increase acetylcholine release in the prefrontal cortex — a neurotransmission that is implicated in cognitive dysfunction in many illnesses such as Alzheimer’s disease — could be important in schizophrenia as well. Some researchers have proposed that serotonin-dopamine antagonists’ 5-HT1a agonism activity may help alleviate depression, anxiety, negative symptoms, and cognitive dysfunction.


Organon/Pfizer’s asenapine (ORG-5222) is in Phase III development in the United States and Europe. In October 2003, Pfizer licensed exclusive worldwide codevelopment and commercial rights to the drug.

Organon and Pfizer are developing asenapine with hopes that it will have efficacy similar to that of clozapine but with less severe side effects. Unfortunately, nothing about asenapine’s pharmacological profile suggests that it will offer enhanced efficacy or tolerability compared with that of current or other emerging agents. This agent has high affinity for 5-НТ2А, 5- НТ2с, D1, D2, H1, and α1-adrenergic receptors and moderate affinity for a2-adrenergic, 5-HT1a, and 5-HT1b receptors. Unlike clozapine (and olanzapine), it has negligible affinity for D4 and muscarinic receptors. Because antipsychotics’ efficacy is not fully understood, the relevance of this difference between asenapine and clozapine is unknown at this time, although it suggests that asenapine may not be associated with side effects such as constipation and dry mouth, which are caused by the blockage of muscarinic receptors. Asenapine’s efficacy may stem from its affinity for adrenoceptors because some researchers suggest that blockage of a 1-adrenoceptors may help alleviate positive symptoms, although it may also increase the risk of orthostatic hypotension. Blockage of a2-adrenoceptors may help relieve negative and cognitive symptoms. Asenapine’s antagonism of histamine Hi receptors may cause somnolence.

At the fall 2003 financial analyst meeting, Organon presented consolidated data from three Phase II studies that suggested asenapine significantly reduces the positive and negative symptoms of schizophrenia. All three studies were placebo-controlled, and two trials used risperidone (6 mg/day) as an active control. After six weeks of treatment, patients taking asenapine had significant improvements in total Positive and Negative Syndrome Scale (Positive and Negative Syndrome Scale), positive Positive and Negative Syndrome Scale, and negative Positive and Negative Syndrome Scale compared with placebo-treated patients. According to study investigators, consolidated data from these three studies demonstrated that risperidone provided significant improvements only in positive Positive and Negative Syndrome Scale compared with placebo at six weeks. The company stated that asenapine improved cognitive functioning “in certain domains” but did not elaborate.

Consolidated data from these three studies also suggest that asenapine’s tolerability is similar to that of risperidone. The incidence of extrapyramidal symptoms was similar at the study end among asenapine-, risperidone-, and placebo-treated patients. The mean increase in body weight from baseline at six weeks was approximately 0.5 kg (1.1 lb) for asenapine, 1.9 kg (4.18 lb) for risperidone, and 0.3 kg (0.66 lb) for placebo. The fact that the weight gain associated with asenapine was similar to that of placebo and lower than that of risperidone is impressive; unfortunately, the statistical significance of these data was not presented. The percentage of patients with QTc prolongation ( > 450m/sec) was approximately 9% for asenapine, 17% for risperidone, and 10% for placebo. Organon also claims that asenapine did not significantly increase glucose and prolactin levels. Further details from these three Phase II studies have not been released.

In addition to treating positive and negative symptoms, some preclinical studies suggest that asenapine may have anxiolytic activity. However, in one comparative preclinical study, this effect was similar to the minimal anxiolytic activity of olanzapine. Asenapine’s anxiolytic activity has yet to be demonstrated in clinical trials.

Earlier studies suggest that asenapine is well tolerated. Data presented in abstract form from an earlier Phase I trial indicate that in doses as high as 4 mg per day, heavy headedness, dull headedness, and dull feelings were its major side effects. However, another adverse effect revealed in this abstract was a slight and transient increase in the level of the enzymes aspartate amino transaminase and alanine amino transferase. Significant increases in these enzymes can be indicative of liver disease, suggesting potential toxicity hurdles for this drug. In this Phase I study, asenapine did not appear to have any effect on prolactin.

Olanzapine Depot

Eli Lilly is developing a once-monthly depot formulation of olanzapine. This formulation is in Phase III development in the United States.

Olanzapine depot has the same mechanism of action as its oral counterpart. Like all serotonin-dopamine antagonists, olanzapine demonstrates dual antagonism of D2 and 5-HT2A receptors, where the 5-НТ2А activity is greater than the D2 activity. This activity is theorized to be important to its antipsychotic effect. Olanzapine closely resembles clozapine in structure but exhibits a different receptor profile. It demonstrates significant 5-НТ2А, 5-НТ2в, and 5-НТB receptor affinity as well as an increased ratio of D4 to D2 receptor affinity. The compound also has a high affinity for muscarinic M1 — 5, histamine H1, and α1-adrenergic receptors. Although the therapeutic effect of olanzapine’s affinities has not been clearly defined, they most likely contribute to its side-effect profile. Its antagonism of muscarinic receptors (which may be partly responsible for its lower risk of extrapyramidal symptoms) may explain its anticholinergic effects; its histamine-receptor antagonism may explain the somnolence observed with the drug; and its antagonism of a 1-adrenergic receptors, which may enhance its antipsychotic efficacy, may explain the orthostatic hypotension.

No clinical data on this formulation have been released. If launched, olanzapine will be the second atypical antipsychotic available in a long-acting formulation. (Risperidone depot launched in Germany and the United Kingdom in 2002 and in the United States in 2003.) Olanzapine’s depot formulation will likely have some competitive advantages over that of risperidone because olanzapine is more tolerable at higher doses — a feature that may render it more appealing in a long-acting formulation — and it will require less frequent administration (once monthly versus risperidone’s bimonthly).


Dainippon Pharmaceutical’s blonanserin (Lonasen) is in Phase III trials in Japan and Phase II evaluation in Europe. In June 2001, Dainippon announced that it had entered into a licensing agreement with the Spanish company Almirall Prodesfarma, which received exclusive global development and marketing rights, excluding Japan, China, Taiwan, and South Korea.

Blonanserin has strong affinity for both D2 and 5-НТ2D receptors and little or no affinity for Di, 5-HT1, 5-НТз, α1 and а2-adrenergic, H1, muscarinic, gamma-aminobutyric acid, benzodiazepine, and sigma receptors. In preclinical studies, the drug demonstrated antipsychotic activity consistent with dopamine and serotonin antagonism. Because its histaminergic and adrenergic blocking is weak, blonanserin is not expected to induce the somnolence or orthostatic hypotension associated with many other serotonin-dopamine antagonists. On the other hand, adrenergic activity is theorized to contribute toward the relief of positive and negative symptoms and cognitive dysfunction so, without this action, blonanserin may prove slightly less efficacious than currently marketed serotonin-dopamine antagonists. A preclinical study suggests that blonanserin is able to relieve both the positive and negative symptoms of schizophrenia but whether this efficacy is comparable to that of other atypical antipsychotics has not been determined.

A double-blind Phase II comparator trial evaluated blonanserin’s efficacy and safety. Patients with schizophrenia (n = 263) were randomized to receive blonanserin (flexible dosing; 8-24 mg/day) or haloperidol for eight weeks. The results showed that blonanserin was at least as effective at improving symptoms as haloperidol, as measured by the change in the Final Global Improvement Rating Scale (61.3% versus 51.3% of patients) and was associated with a significantly lower incidence of extrapyramidal symptoms (52.7% versus 75.4%). Although both treatments resulted in a high incidence of extrapyramidal symptoms, interpretation of these findings is limited by the absence of a placebo control. In earlier Phase II trials, the most commonly reported side effects associated with blonanserin were akathisia (29%), tremor (23%), insomnia (23%), rigidity (14%), and hyperprolactinemia (33%).


Sumitomo Pharmaceuticals’ SM-13496 (lurasidone) is in Phase II evaluation in Japan and in the United States by licensee Merck.

SM-13496 is a potent D2 and 5-HT2a receptor antagonist (Yabuchi K, 1999). In addition, the drug shows high affinity for 5-HT2A, 5-HTia, 5-HT7 and агс receptors but weak affinity for D1, 5-HT2C, and α2B and α1 receptors. It does not interact with Hi or muscarinic receptors. The drug’s ability to block a1-adrenoceptors may help alleviate negative symptoms and cognitive dysfunction. Unlike many other serotonin-dopamine antagonists, SM-13496 may not cause orthostatic hypotension because its blockage of a1-adrenoceptors is weak, and because it does not interact with Hi or muscarinic receptors, it may be devoid of the somnolence and anticholinergic effects that plague other serotonin-dopamine antagonists. Sumitomo claims that this receptor-binding profile suggests SM-13496 has a low potential for weight gain, central nervous system depression, and cardiovascular side effects (e.g., orthostatic hypotension) .

The drug has shown antipsychotic activity in standard animal models, including antagonism of apomorphine-related climbing and amphetamine-induced hyperactivity. Rodent studies also suggest that SM-13496 is less likely than several typical and atypical antipsychotics to induce extrapyramidal symptoms. Data to confirm SM-13496’s efficacy and safety in humans are not publicly available. Studies of animal models, presented in abstract form, suggest SM-13496 may have some antianxiolytic properties as well. In the Vogel conflict test, it increased punished water drinking with minimal effective doses of 10 mg/kg.


Iloperidone (Zomaril) was originally under development by Hoechst Marion Roussel (now Aventis), which licensed worldwide rights to Titan Pharmaceuticals in 1997. Titan subsequently granted Novartis worldwide development, manufacturing, and marketing rights. Novartis also conducted trials of a long-acting, once-monthly depot formulation of iloperidone. Titan and Novartis had originally planned to file for U.Spain. regulatory review of iloperidone in 2001, but in a press release dated July 22, 2002, Titan revealed that iloperidone causes a dose-dependent QTc prolongation similar to that of ziprasidone. The companies announced that development would be delayed so that they could conduct additional tests before submitting a new drug application (new drug application) to the FDA. In June 2004, Vanda Pharmaceuticals acquired worldwide rights to develop and commercialize iloperidone. Under this license agreement from Novartis, Vanda will pursue completion of the iloperidone Phase III trials and product registration, and Titan’s rights and economic interests in iloperidone remain unchanged.

Like available atypical agents, iloperidone has a stronger affinity for 5-HT2A receptors than for D2 receptors. This preference is thought to be an important factor for atypical antipsychotic activity and the reduction of extrapyramidal symptoms. Iloperidone also demonstrates binding potential for the D4, 5-HT1a, 5-НТ2D, 5-НТ2с, 5-НТб, а2с, and α1 receptors.

In September 2000, Titan released data from a study that enrolled 600 patients with schizophrenia or schizoaffective disorder in 40 centers in the United States, Europe, Canada, Australia, and South Africa. According to the company’s announcement, iloperidone achieved a statistically significant reduction in psychotic symptoms (assessed by the Brief Psychiatric Rating Scale) and statistically significant improvements in patients’ total scores on the Positive and Negative Syndrome Scale, compared with placebo. In addition, iloperidone demonstrated a good safety profile, with no extrapyramidal symptoms, little weight gain, and no elevation of serum prolactin. Adverse events included orthostatic hypotension, dizziness, and somnolence, but coadministration of food reduced their incidence and severity.

Abstract data presented at the 15th European College of Neuropsychopharmacology Congress held in Barcelona, Spain, in October 2002 also suggest that iloperidone has good efficacy. Its effect on psychotic symptoms is reportedly similar to that of haloperidol. A total of 557 patients diagnosed with either schizophrenia or schizoaffective disorder were randomized to receive either iloperidone or haloperidol for 52 weeks. At the end of the study, the average Positive and Negative Syndrome Scale score declined by 33% and 29% for iloperidone- and haloperidol-treated patients, respectively. In addition, 73% of patients treated with iloperidone were rated as very much or much improved on the Clinical Global Impression-Global Improvement scale, compared with 71% in the haloperidol-treated group. Further data including statistical significance have not been released.

In a press release dated July 23, 2001, Titan released long-term data from three double-blind safety studies involving approximately 1,200 patients. The results showed that patients in the iloperidone arm experienced a mean weight gain of only 1.6-3.7 kg and minimal extrapyramidal symptoms. No increase occurred in serum prolactin, and minimal effects on heart rate and blood pressure were noted over the course of these studies.


Johnson & Johnson (Japan&Japan), the marketer of risperidone, is developing paliperidone. The compound entered Phase II trials in August 2003 in the United States for schizophrenia. Japan&Japan claims that paliperidone, which is a major active metabolite of risperidone, possesses a better side-effect profile than that of risperidone. The company is developing an extended-release oral formulation (paliperidone ER) and a depot formulation (paliperidone palmitate).

Virtually no information has been released on paliperidone’s characteristics or its mechanism of action. Because it is an active metabolite of risperidone, it is assumed that this drug’s mechanism of action will be similar to that of other serotonin-dopamine antagonists.

The potential marketing advantage for this agent is the dosing frequency of its depot formulation. Japan&Japan claims that this formulation could be administered every 6-12 weeks. This dosing strategy would be a huge advantage over the depot formulations of risperidone and olanzapine, which are dosed every two and four weeks, respectively.