Journal Reading FK UKI (Partial Dopamine D2 Serotonin 5-HT1A Receptor Agonists As New Therapeutic Agents)

JOURNAL READING
Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents
Clinical Instructor
dr. Sabar Siregar, Sp.KJ
Ariyo Riyadi Rangga Putra 0861050028
The Open Neuropsychopharmacology Journal, 2010, 3, 1-12
Partial Dopamine D2/ Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents
Adeline Etievant, Ccile Btry, and Nasser Haddjeri
Laboratory of Neuropharmacology, Faculty of Pharmacy, University Lyon I, EAC CNRS 5006, 8 Avenue Rockefeller 69373 LYON Cedex 08 France
Journal Reading from Medical Students of Christian University of Indonesia Clinical Instructor dr. Sabar Siregar, Sp.KJ Magelang, 28 September 2012
CONTENTS (1)
ABSTRACT INTRODUCTION - Regulation of brain DA and 5-HT transmission DA system DA partial agonist 5-HT system PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA - Therapeutic Agent for Schizophrenia - Partial D2-Like Receptor Agonists in Schizophrenia - 5-HT1A Receptor Agonists in Schizophrenia
Abstract
The therapeutic efficacy of current antipsychotic or antidepressant agents still present important drawbacks, such as delayed onset of action and a high percentage of non-responders. The present review discusses the usefulness of partial dopamine D2/serotonin 5-HT1A receptors agonists in the treatment of schizophrenia, major depression and bipolar disorder as well as in Parkinsons disease.
Abstract
Partial agonists can behave as modulators since their intrinsic activity or efficacy of a partial agonist depends on the target receptor population and the local concentrations of the natural neurotransmitter. These drugs may restore adequate neurotransmission while inducing less side effects.
Abstract
In schizophrenia, partial DA D2/5-HT1A receptor agonists (like aripiprazole or bifeprunox), by stabilizing DA system via a preferential reduction of phasic DA release, reduce side effects i.e. extrapyramidal symptoms and improve cognition by acting on 5-HT1A receptors. Aripiprazole a promising agent for the treatment of depression since it potentiates the effect of SSRIs in resistant treatment depression. Concerning bipolar disorders, aripiprazole may have only a benefit effect in the treatment of manic episodes.
Abstract
Treatment of Parkinsons disease with partial DA D2/5-HT1A receptor agonists remains still experimental. Several studies suggest that these drugs decrease usually observed side effects (dyskinesia, psychotic-like symptoms) in Parkinsons disease treatment.
INTRODUCTION
Regulation of Brain DA and 5-HT Transmission
DA SYSTEM
INTRODUCTION
DA SYSTEM
INTRODUCTION
DA SYSTEM
1. THE MESOLIMBIC DOPAMINERGIC PATHWAY Located within the ventral tegmental area. Efferent target in the ventral striatum including nucleus accumbens (Nacc) and limbic structures (e.g amygdala and hippocampus). Involved in emotional and motivational processing. In schizophrenia, the hyperactivation of this pathway seems to lead to positive symptoms like hallucinations.
INTRODUCTION
DA SYSTEM
2. THE MESOCORTICAL DOPAMINERGIC PATHWAY Efferent targets in prefrontal cortex. This pathway is hypoactive in schizophrenia which can be responsible for cognitive and negative symptoms.
INTRODUCTION
DA SYSTEM
3. THE NIGROSTRIATAL DOPAMINERGIC PATHWAY Consists of the subst. nigra pars compacta (SNc-A9). Efferent targets in the dorsal striatum. Contains the majority of brain DA. This pathway is involved in motor learning and control. Degeneration of this pathway leads to Parkinsons disease. Blockade of this pathway is associated with movement disorders like EPS and dyskinesia.
INTRODUCTION
DA SYSTEM
4. THE TUBERO-INFUNDIBULAR DA PATHWAY Consists of DA neurons that project from the periventricular and arcuate nuclei of the hypothalamus to the intermediate lobe of the pituitary. Secretion of prolactine under the control of DA. Blockade of DA receptors hyperprolactinemia.
INTRODUCTION
DA PARTIAL AGONISTS
A partial agonist induces a reduced signaling response compared to the maximum achievable response by a full agonist. The intrinsic activity or efficacy of a partial agonist depends on the sensitivity and responsiveness of the receptors. A partial agonist can behave as an agonist or antagonist, depending on the target receptor population and the local concentration of the natural neurotransmitter.
INTRODUCTION
DA PARTIAL AGONIST
(Hypothetic of the mechanism of action of partial D2/5-HT1A agonists)
INTRODUCTION
5-HT SYSTEM
Located in the brainstem near or on the midline. There is nine 5-HT nuclei in the brainstem. The superior group : the caudal linear nucleus, median raphe nuclei (MRN), dorsal raphe nuclei (DRN), lateral nucleus. The inferior group : the nuclei raphe obscursus, raphe pallidus, raphe magnus. Efferent 5-HT projections to the forebrain originate mainly from the superior group of raphe nuclei.
INTRODUCTION
5-HT SYSTEM
The DRN contains about 50-60% of 5-HT neurons in human CNS, whereas the MRN contains about 5%. In the DRN, about 70% of the cells are 5-HT neurons. Non-5-HT cells found in the DRN : peptidergic neurons (Substance P) and non-peptidegric neurons (DA and GABA).
INTRODUCTION
5-HT SYSTEM
INTRODUCTION
5-HT SYSTEM
5-HT1A receptors
Located presynaptically on 5-HT neurons in the raphe nuclei and post-synaptic neurons in the brain and spinal cord. Exert negative feedback on firing activity. Abundant in limbic structures, exert an inhibitory function on neuronal activity.
PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA
SCHIZOPHRENIA
SCHIZOPHRENIA
SCHIZOPHRENIA
SCHIZOPHRENIA
THERAPEUTIC AGENTS FOR SCHIZOPHRENIA

All antipsychotics reduce DA neurotransmission by blocking DA receptors. Divided in two generations : 1. The first-generation typical antipsychotics 2. The second-generation atypical antipsychotics

The First-Generation Typical Antipsychotics
Reduce DA neurotransmission by blocking DA receptors, predominantly the D2 subtypes. Reduce positive symptoms. Causing important side effects : EPS. EPS are directly related to D2 receptor blockade (up to 80% od D2 receptor blockade) of the nigrostriatal pathway. Other possible effect : hyperprolactinaemia.

The Second-Generation Atypical Antipsychotics
Have less side effects on the motor function. Decrease both negative and positive symptoms. Have important metabolic side effects : weight gain or diabetes. Have a higher affinity for 5-HT2A receptors than for D2 receptors and blocks both receptor types. Interact with a large range of other receptors, including cholinergic and serotoninergic receptors.
PARTIAL D2-LIKE RECEPTOR AGONISTS IN SCHIZOPHRENIA

Currently, aripiprazole is the only partial D2-like receptor agonist used for schizophrenia. Other agents showing in vivo or in vitro partial D2-like receptor activity represent putative antipsychotics, e.g. bifeprunox, sarizotan, 3PPP, ACR16, OSU6162. Interestingly, the N-desmethylclozapine, the major metabolites of clozapine, is also a partial D2-like agonist.

Haloperidol : At low dose increase firing activity. At high dose depolarization block. Chronic treatment decrease number of spontaneous active DA neurons in the VTA reducing mesolimbic DA transmission. Aripiprazole : Moderately decrease VTA DA neuronal firing. Chronic treatment does not affect neuronal firing. It also can induce a stabilization of the DA neurotransmission.
5-HT1A RECEPTOR AGONISTS IN SCHIZOPHRENIA

Several compounds including clozapine, ziprasidone, and quetiapine have a partial agonistic effect on 5HT1A receptors. Recent drugs (bifeprunox, aripiprazole) are more potent 5-HT1A receptor agonistic effect.

5-HT1A receptor agonist 8-OH-DPAT increased the effect of the D2-like antagonist raclopride in the conditioned avoidance response. Clinical studies have shown a beneficial effect on psychotic syndromes by simultaneous administration of haloperidol (a typical antipsychotic) and buspirone (a partial 5-HT1A receptor agonist).

Cognitive impairments are associated with a decrease of DA release in PFC. Direct or indirect 5-HT1A receptor stimulation may increase DA release in prefrontal cortex. Clinical studies have reported a beneficial effect of the simultaneously administration of typical or atypical antipsychotic and a 5-HT1A agonist (like tandospirone or buspirone) on cognitive deficits, including verbal learning and memory.

5-HT1A agonists induce anxiolytic and antidepressive effects in clinical studies, which makes them potentially interesting for treatment of major depression. In this regard, compounds such as aripiprazole present anxiolytic effects in preclinical tests of anxiety.

65% of D2 receptors occupancy is necessary for clinical efficacy of treating psychotics, while it must not exceed 90% in order to avoid EPS. Important to develop compounds able to increase this narrow window. 5-HT1A agonist 8-OH-DPAT reversed the catalepsy induced by D2 receptor antagonists or antipsychotics, by stimulation of the 5-HT1A autoreceptor in the median raphe nuclei.
CONTENTS (2)
PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS - Major Depression - Therapeutic Agents for Major Depression - D2-Like Receptor Agonists in Major Depression - 5-HT1A Receptor Agonists in Major Depression - Bipolar Disorder - Therapeutic Agents for Bipolar Disorder - Partial D2-Like Receptor Agonists in Manic Episodes PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND PARKINSONS DISEASE - Therapeutic Agents for Parkinsons Disease - Partial D2-Like Receptor Agonists in PD - 5-HT1A Receptor Agonists in PD
PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS
MAJOR DEPRESSION
Prevalence rate 12% men and 20% women Changes in mood Several psychosiological Decreased ability to concentrate Reccurent thought of death
MAJOR DEPRESSION
THERAPEUTIC AGENTS FOR MAJOR DEPRESSION

First generation antidepressant therapy (Tricyclic anti-depressants and IMAO)
Side effects : hypotension, retention urinary, sexual and sleep impairment, toxicity lead to the search for more tolerable

SSRIs, selective noradrenaline reuptake inhibitors, noradrenaline and serotonin reuptake inhibitors or atypical antidepressants
Have fewer and less severe side effects than these first generation drugs due to their lack of affinity for amines and acetylcholine receptors

Two major problems remain unresolved:
1. One-third of the patients does not respond to any treatment and one-third shows only a partial response to any first agent used at an adequate dose for a sufficient time 2. There is an undesirable 3-8 weeks delay before the onset of therapeutic response to antidepressant drugs
D2-LIKE RECEPTOR AGONISTS IN MAJOR DEPRESSION

Atypical antipsychotics can be effective as anti-manic or antidepressant agents, and therefore they are increasingly popular as adjunctive agents in clinical therapy, for example: 1. Olanzapine + Fluoxetine 2. Risperidone + Citalopram 3. Aripiprazole
5-HT1A RECEPTOR AGONISTS IN MAJOR DEPRESSION

5-HT neurons gradually recover their normal firing rate as a result of 5-HT1A autoreceptor desensitization. This gradual recovery of 5-HT neuronal activity may explain the therapeutic delay of clinical action of these drugs. Preclinical data suggest that postsynaptic 5-HT1A receptors are particularly important for the antidepressant response.

First, the activation of these receptors leads to behavioral changes in several animal models, such as the forced swim test (FST), similar to those observed with conventional antidepressants
Second, there is evidence tha neurogenesis, which is a crucial phenomenon in the antidepressant action, can be mediated via 5-HT receptor activation.

The azapirones (gepirone, buspirone, tandospirone and ipsapirone) which act as partial 5-HT1A eceptor agonist have shown efficacy in the treatment of anxiety and major depression. Buspirone is a commercially agent available but used as a single agent appears to be non-effective. Early clinical trials conducted with an immediate release (IR) formulation of gepirone, buspirone and ipsapirone showed antidepressant efficacy after eight weeks, but has the disadvantages of poor tolerability (dizziness, nausea, insomnia, headache and asthenia and a limited efficacy (short half-life and rapid absorption from the gastrointestinal tract).

Azapirones have been reformulated as an extended-release (ER) tablet which increases their half life, allowing more gradual and sustained absorption from the gastrointestinal tract while lowering peak plasma gepirone concentration
Wilcox et al. showed that gepirone ER administration had antidepressant efficacy 1 week until 6 weeks of treatment with a daily dose of 70mg but not with 40mg

While these results from clinical trials support the efficacy and the tolerability of ER formulation of gepirone in major depressive disorder, it should be noted that results are less conclusive concerning other azapirones (buspirone and ipsapirone). In addition, azapirones are rapidly metabolized into 1-(2pyrimidinyl)-piperazine (1-PP) which is an alpha-2 adrenoreceptor antagonist, like mirtazapine an effective antidepressant drug. However, the antidepressantlike effect of 1-PP is not well established
BIPOLAR DISORDER
Bipolar disorder is a severe chronic illness associated with abnormal structure and function of the central nervous system with high rates of recurrence, disability, social impairment1-6% of the population.
Specifically, the depressive episodes are more numerous,last longer, and are less responsive to treatment than the manic episodes
THERAPEUTIC AGENTS FOR BIPOLAR DISORDER

The goals of pharmacological treatments for bipolar disorder are:
First, to decrease this hyperexcitability and Stabilize mood Second, to prevent the recurrence of depressive and manic episodes

Traditional mood-stabilizing: Lithium Anticonvulsive agents (valproate or lamotrigine)
20%-40% patient have side effects such as : Tremors Gastrointestinal disorders, Tiredness Somnolence, and cognitive Impairment in memory and concentration

Short-term studies (3-4 weeks) suggest that atypical antipsychotics (olenzapine, risperidone, ziprasidone) have beneficial effects on manic and depressive episodes. Longer-term management of bipolar disorder For example, a placebocontrolled study showed maintenance of the efficacy of risperidone monotherapy over 12 weeks and aripiprazole seems to have simila effects.
PARTIAL D2-LIKE RECEPTOR AGONISTS IN MANIC EPISODE

Studies have demonstrated that aripiprazole is effective and well tolerated in the treatment of acute bipolar mania. Aripiprazole had superior efficacy to haloperidol in response rates and tolerability in a 12-week acute mania trial in patients with bipolar I disorder in acute manic or mixed episode side effects aripripazole such as akathisia, insomnia, nausea,restless or dry mouth

Aripiprazole monotherapy was superior to placebo in maintaining efficacy in patients with a recent manic/mixed episode who were stabilized and maintained on a regimen of aripiprazole for 12 weeks, 26 weeks and 100 weeks Vieta et al. demonstrated that adjunctive aripiprazole therapy to lithium or valproate showed significant improvement in mania symptoms from one week in bipolar patients with manic or mixed episodes who were partiall nonresponsive to lithium/valproate monotherapy.

The same result has been observed with other atypical antipsychotics. The use of isperidone, olanzapine and quetiapine as adjunctive agent enhanced the response to classical treatment. While the beneficial effect of aripiprazole was clear in the treatment of manic episodes, there is no evidence that aripiprazole monotherapy has superior efficacy compared to placebo treatment at the end of the treatment in bipolar depression at the dose use.
PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND PARKINSONS DISEASE
PARKINSONS DISEASE
THERAPEUTIC AGENTS FOR PARKINSONS DISEASE

L-dihydroxyphenylalanine (L-DOPA) is presently the most effective treatment for PD. Its use is associated with a high probability of motor complications, including abnormal involuntary movements (dyskinesia) and motor fluctuations in 50% of PD patients.
PARTIAL D2-LIKE RECEPTOR FOR PD

Full DA receptor agonists can induce dyskinesia and psychotic-like symptoms including hallucinations (probably due to the overstimulation of extra-striatal DA receptors) or somnolence. It has been suggested that such side-effects could be counteracted by the use of partial D-like receptor agonists. These compounds might stimulate D2 and D3 receptors when the dopaminergic tone is low, while counteracting excessive stimulation of the DA D2 and D3 receptor when the dopaminergic tone is high. It is also possible that partial agonists would modulate dopaminergic transmission in a specific region, resulting in the restoration of dopaminergic transmission which is perturbed in PD patient.
5-HT1A RECEPTOR FOR PD

5-HT1A receptor agonists could reduce the incidence of dyskinesia. The 5-HT1A receptor agonist tandospirone reduced dyskinesia in L-DOPA treated PD patient Preclinical and clinical studies suggest that sarizotan, a 5-HT 1A receptor agonist that possesses weak D3 and D4 receptor agonist activity, could ameliorate dyskinetic symptoms in association with L-DOPA.

Studies with 5-HT1A agonists have suggested a reduction in L-DOPA-induced dyskinesia but a worse PD disability. Carta et al. have shown that dyskinesia induced by chronic L-DOPA treatment in rats with 6-OHDAinduced lesions of the nigrostriatal DA pathway is critically dependent on the integrity and function of the serotonergic system

Synergistic effect of low doses of 5-HT1A and 5-HT agonists to suppress dyskinesia, without affecting the antiparkinsonian effect of L-DOPA in presence of spared DA terminals, suggests that early use of these drugs could counteract the development of dyskinesia in PD patients. Wang et. al. have shown that unilateral lesion of the rat nigrostriatal pathway induces an increase of neuronal firing of 5-HT neurons associated with desensitized 5-HT autoreceptors.
High frequency stimulation of the subthalamus nucleus, a well admit antiparkinsonian therapy, has been shown to reduce 5-HT neuronal firing , further suggesting the involvement of 5-HT system in the pathophysiology of PD.
CONCLUSION
Several studies are in accordance with the marked interest of partial D2/5-HT1A agonists in reducing side effects i.e. extrapyramidal symptoms and cognitive impairments in schizophrenia, various researches are still needed to emphasize their beneficial utility in major depression, bipolar disorders and Parkinsons disease.
CONCLUSION
Treatment with aripiprazole in major depression as monotherapy or as adjuvant with a classical antidepressants seems to improve the antidepressant response whereas, in bipolar disorder, only partial dopamin D2 1A receptors agonists show advantages in the treatment of manic episodes. Differently, if treatment of Parkinsons disease with partial D2 and 5-HT receptors agonists is still at the experimental phase, increasing studies report a decrease of side effects with these drugs. Hence, these relatively recent researches provide an exciting future in the discovery of novel stabilizators agents for the management of the latter diseases.
JOURNAL READING
Partial Dopamine D2/ Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents
CRITICAL APPRESIAL
THE STRUCTURE AND CONTENT OF THE JOURNAL

The Title of Journal
1. 2. 3. 4. Not too long or too short : Yes (9 words) Describe the whole of the journal : Yes Interestingly enough : Yes Without abbreviations : Yes
The Author and Institution

Appropriate with the guidelines : Yes
Abstrak
1. 2. 3. The structure : Consist of 1 part Informative : Yes Less than 250 word : No (255 word)
Introduction
1. 2. 3. 4. Consist of 2 paragraph or part : No (10 paragraph, 3 parts) The first paragraph explain background of the research : Yes The second paragraph explain hypothesis or objective : Not pattern Less than 1 page : Yes (3 pages)
The Literature Review

1. 2. 3. 4. The present state of play in relation to the topic : Yes A range of up-to-date sources was reviewed : Yes Key themes in the literature discussed and their significance was shown : Yes Gaps in the literature was identified : No
The Research Methods

1. The context of the research is clear : Yes 2. The research methods are appropriate to the research questions : Not pattern 3. Methods are clearly justified : Not pattern 4. The research sample was selected, and is it an appropriate sample for the research questions : Not pattern 5. The methods are well executed : Not pattern 6. Ethical issues was addressed : Not pattern
The Data Analysis

1. The main findings was described clearly : Yes 2. They was clearly related to the original research questions : Yes 3. They was presented in a format that is appropriate for the findings : Not pattern 4. The interpretation of the data was consistent with the evidence : Yes 5. The findings is significant : Yes 6. If quantitative: The data was analyzed using appropriate statistical tools : Not pattern 7. If qualitative: Selection of data was presented : Not pattern
The Discussion
1. The data from the research related back to the literature and to other findings : Yes 2. The research support or challenge existing thinking or practice : Yes 3. The research suggest recommendations for practice, or areas for further research : Yes 4. The author reflective on her/his work or self-critical : Not pattern
The Conclusion
1. The threads of the argument was drawn together clearly : Yes 2. The research questions was answered and research aims fulfilled : Yes 3. The research contribute to the field : Clinicians, Psychiatrist
Thank You

Journal Reading FK UKI (Partial Dopamine D2 Serotonin 5-HT1A Receptor Agonists As New Therapeutic Agents)

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JOURNAL READING

Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents

dr. Sabar Siregar, Sp.KJ

Ariyo Riyadi Rangga Putra 0861050028

The Open Neuropsychopharmacology Journal, 2010, 3, 1-12

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

Regulation of Brain DA and 5-HT Transmission

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

THERAPEUTIC AGENTS FOR SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

THERAPEUTIC AGENTS FOR SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

THERAPEUTIC AGENTS FOR SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

THERAPEUTIC AGENTS FOR SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

PARTIAL D2-LIKE RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

PARTIAL D2-LIKE RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

PARTIAL D2-LIKE RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

PARTIAL D2-LIKE RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

5-HT1A RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

5-HT1A RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

5-HT1A RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

5-HT1A RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

5-HT1A RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

5-HT1A RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND SCHIZOPHRENIA

5-HT1A RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS

THERAPEUTIC AGENTS FOR MAJOR DEPRESSION

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS

THERAPEUTIC AGENTS FOR MAJOR DEPRESSION

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS

THERAPEUTIC AGENTS FOR MAJOR DEPRESSION

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS

D2-LIKE RECEPTOR AGONISTS IN MAJOR DEPRESSION

PARTIAL DOPAMINE D2/SEROTONIN 5-HT1A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS

5-HT1A RECEPTOR AGONISTS IN MAJOR DEPRESSION