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

7/30/2019 Journal Reading FK UKI (Partial Dopamine D2 Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents)

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Ariyo Riyadi Rangga Putra0861050028

JOURNAL READING

Partial Dopamine D2/Serotonin 5-HT1A Receptor

Agonists as New Therapeutic Agents

Clinical Instructor

dr. Sabar Siregar, Sp.KJ


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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

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

Journal Reading from Medical Students of Christian University of IndonesiaClinical Instructordr. Sabar Siregar, Sp.KJ

Magelang, 28 September 2012


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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 AGONISTSAND SCHIZOPHRENIA

- Therapeutic Agent for Schizophrenia

- Partial D2-Like Receptor Agonists in Schizophrenia

- 5-HT1A Receptor Agonists in Schizophrenia

Journal Reading from Medical Students of Christian University of IndonesiaClinical Instructordr. Sabar Siregar, Sp.KJMagelang, 28 September 2012


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Abstract

The therapeutic efficacy of current antipsychotic orantidepressant agents still present important drawbacks,such as delayed onset of action and a high percentage ofnon-responders.

The present review discusses the usefulness of partialdopamine D2/serotonin 5-HT1A receptors agonists in thetreatment of schizophrenia, major depression and bipolardisorder as well as in Parkinsons disease.




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Abstract

Partial agonists can behave as modulators since theirintrinsic activity or efficacy of a partial agonist depends onthe target receptor population and the local concentrationsof the natural neurotransmitter.

These drugs may restore adequate neurotransmission whileinducing less side effects.




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Abstract

In schizophrenia, partial DA D2/5-HT1A receptor agonists(like aripiprazole or bifeprunox), by stabilizing DA systemvia a preferential reduction of phasic DA release, reduceside effects i.e. extrapyramidal symptoms and improve

cognition by acting on 5-HT1A receptors.

Aripiprazole a promising agent for the treatment ofdepression since it potentiates the effect of SSRIs inresistant treatment depression.

Concerning bipolar disorders, aripiprazole may have only abenefit effect in the treatment of manic episodes.




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Abstract

Treatment of Parkinsons disease with partial DA D2/5-HT1Areceptor agonists remains still experimental.

Several studies suggest that these drugs decrease usuallyobserved side effects (dyskinesia, psychotic-like symptoms)in Parkinsons disease treatment.




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INTRODUCTION Regulation of Brain DA and 5-HT Transmission

DA SYSTEM




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DA SYSTEM


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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 motivationalprocessing.

In schizophrenia, the hyperactivation of thispathway seems to lead to positive symptoms likehallucinations.




DA SYSTEM


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2. THE MESOCORTICAL DOPAMINERGIC PATHWAY

Efferent targets in prefrontal cortex.

This pathway is hypoactive in schizophrenia

which can be responsible for cognitive andnegative symptoms.




DA SYSTEM


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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 Parkinsonsdisease.

Blockade of this pathway is associated with movementdisorders like EPS and dyskinesia.




DA SYSTEM


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4. THE TUBERO-INFUNDIBULAR DA PATHWAY

Consists of DA neurons that project from theperiventricular 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.




DA SYSTEM


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A partial agonist induces a reduced signaling responsecompared to the maximum achievable response by afull agonist.

The intrinsic activity or efficacy of a partial agonistdepends on the sensitivity and responsiveness of thereceptors.

A partial agonist can behave as an agonist orantagonist, depending on the target receptorpopulation and the local concentration of the naturalneurotransmitter.




DA PARTIAL AGONISTS


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(Hypothetic of the mechanism of action of partial D2/5-HT1A agonists)




DA PARTIAL AGONIST


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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.




5-HT SYSTEM


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The DRN contains about 50-60% of 5-HT neurons inhuman 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).




5-HT SYSTEM


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5-HT SYSTEM


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5-HT1A receptors Located presynaptically on 5-HT neurons in the raphe

nuclei and post-synaptic neurons in the brain andspinal cord.

Exert negative feedback on firing activity.

Abundant in limbic structures, exert an inhibitoryfunction on neuronal activity.




5-HT SYSTEM


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

SCHIZOPHRENIA


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SCHIZOPHRENIA


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Journal Reading from Medical Students of Christian University of Indonesia

Clinical Instructordr. Sabar Siregar, Sp.KJMagelang, 28 September 2012


SCHIZOPHRENIA


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SCHIZOPHRENIA


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All antipsychotics reduce DA neurotransmission byblocking DA receptors.

Divided in two generations :

1. The first-generation typical antipsychotics

2. The second-generation atypical antipsychotics




THERAPEUTIC AGENTS FOR SCHIZOPHRENIA


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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 to80% od D2 receptor blockade) of the nigrostriatalpathway.

Other possible effect : hyperprolactinaemia.






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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 ordiabetes.

Have a higher affinity for 5-HT2A receptors than for D2receptors and blocks both receptor types.

Interact with a large range of other receptors,including cholinergic and serotoninergic receptors.






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PARTIAL DOPAMINE D2/SEROTONIN 5-HT1ARECEPTOR AGONISTS AND SCHIZOPHRENIA

THERAPEUTIC AGENTS

FOR SCHIZOPHRENIA


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Currently, aripiprazole is the only partial D2-like receptoragonist used for schizophrenia.

Other agents showing in vivo or in vitro partial D2-likereceptor 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.




PARTIAL D2-LIKE RECEPTOR AGONISTS IN SCHIZOPHRENIA


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Haloperidol :At low dose increase firing activity. At high dose depolarization block. Chronic treatment decreasenumber of spontaneous active DA neurons in the VTA

reducing mesolimbic DA transmission. Aripiprazole :

Moderately decrease VTA DA neuronal firing. Chronictreatment does not affect neuronal firing. It also can

induce a stabilization of the DA neurotransmission.






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/


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Several compounds including clozapine, ziprasidone,and quetiapine have a partial agonistic effect on 5-HT1A receptors.

Recent drugs (bifeprunox, aripiprazole) are more

potent 5-HT1A receptor agonistic effect.




5-HT1A RECEPTOR AGONISTS IN SCHIZOPHRENIA

PARTIAL DOPAMINE D /SEROTONIN HT RECEPTOR AGONISTS AND SCHIZOPHRENIA


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5-HT1A receptor agonist 8-OH-DPAT increased theeffect of the D2-like antagonist raclopride in theconditioned avoidance response.

Clinical studies have shown a beneficial effect on

psychotic syndromes by simultaneous administrationof haloperidol (a typical antipsychotic) and buspirone(a partial 5-HT1A receptor agonist).





PARTIAL DOPAMINE D /SEROTONIN 5 HT RECEPTOR AGONISTS AND SCHIZOPHRENIA


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Cognitive impairments are associated with a decreaseof DA release in PFC.

Direct or indirect 5-HT1A receptor stimulation mayincrease DA release in prefrontal cortex.

Clinical studies have reported a beneficial effect of thesimultaneously administration of typical or atypicalantipsychotic and a 5-HT1A agonist (like tandospironeor buspirone) on cognitive deficits, including verbal

learning and memory.







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5-HT1A agonists induce anxiolytic and antidepressiveeffects in clinical studies, which makes thempotentially interesting for treatment of majordepression.

In this regard, compounds such as aripiprazole presentanxiolytic effects in preclinical tests of anxiety.







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65% of D2 receptors occupancy is necessary for clinicalefficacy of treating psychotics, while it must notexceed 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.






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CONTENTS (2)

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

- 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 ANDPARKINSONS DISEASE

- Therapeutic Agents for Parkinsons Disease- Partial D2-Like Receptor Agonists in PD

- 5-HT1A Receptor Agonists in PD



PARTIAL DOPAMINE D /SEROTONIN 5-HT A RECEPTOR AGONISTS AND AFFECTIVE DISORDERS


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Prevalence rate 12% men and 20% women

Changes in mood

Several psychosiological

Decreased ability to concentrate

Reccurent thought of death

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

MAJOR DEPRESSION





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MAJOR DEPRESSION



PARTIAL DOPAMINE D /SEROTONIN 5-HT RECEPTOR AGONISTS AND AFFECTIVE DISORDERS


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First generation antidepressant therapy(Tricyclic anti-depressants and IMAO)

Side effects : hypotension, retention urinary, sexual and

sleep impairment, toxicity lead to the search for moretolerable



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

THERAPEUTIC AGENTS FOR MAJOR DEPRESSION



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SSRIs, selective noradrenaline reuptake inhibitors,noradrenaline and serotonin reuptake inhibitors or atypical

antidepressants

Have fewer and less severe side effects than these firstgeneration drugs due to their lack of affinity for amines and

acetylcholine receptors







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Two major problems remain unresolved:

1. One-third of the patients does not respond to anytreatment and one-third shows only a partial responseto any first agent used at an adequate dose for asufficient time

2. There is an undesirable 3-8 weeks delay before theonset of therapeutic response to antidepressant drugs







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Atypical antipsychotics can be effective as anti-manic orantidepressant agents, and therefore they are increasinglypopular as adjunctive agents in clinical therapy, for example:

1. Olanzapine + Fluoxetine

2. Risperidone + Citalopram

3. Aripiprazole




D2-LIKE RECEPTOR AGONISTS IN MAJOR DEPRESSION



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5-HT1A RECEPTOR AGONISTS IN MAJOR DEPRESSION

5-HT neurons gradually recover their normal firing rateas a result of 5-HT1A autoreceptor desensitization.

This gradual recovery of 5-HT neuronal activity mayexplain the therapeutic delay of clinical action of these

drugs. Preclinical data suggest that postsynaptic 5-HT1A

receptors are particularly important for theantidepressant response.



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First, the activation of these receptorsleads to behavioral changes in severalanimal models, such as the forced swimtest (FST), similar to those observedwith conventional antidepressants

Second, there is evidence thaneurogenesis, which is a crucialphenomenon in the antidepressantaction, can be mediated via 5-HTreceptor activation.



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The azapirones (gepirone, buspirone, tandospirone andipsapirone) which act as partial 5-HT1A eceptor agonist have shownefficacy in the treatment of anxiety and major depression.

Buspirone is a commercially agent available but used as a singleagent appears to be non-effective.

Early clinical trials conducted with an immediate release (IR)formulation of gepirone, buspirone and ipsapirone showedantidepressant efficacy after eight weeks, but has thedisadvantages of poor tolerability (dizziness, nausea, insomnia,

headache and asthenia and a limited efficacy (short half-life andrapid absorption from the gastrointestinal tract).



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Azapirones have been reformulated as an extended-release(ER) tablet which increases their half life, allowing more

gradual and sustained absorption from the gastrointestinaltract while lowering peak plasma gepirone concentration

Wilcox et al. showed that gepirone ER administration hadantidepressant efficacy 1 week until 6 weeks of treatment with a

daily dose of 70mg but not with 40mg



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While these results from clinical trials support the efficacyand the tolerability of ER formulation of gepirone in majordepressive disorder, it should be noted that results are lessconclusive concerning other azapirones (buspirone and

ipsapirone). In addition, azapirones are rapidly metabolized into 1-(2-

pyrimidinyl)-piperazine (1-PP) which is an alpha-2adrenoreceptor antagonist, like mirtazapine an effective

antidepressant drug. However, the antidepressantlikeeffect of 1-PP is not well established



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Bipolar disorder is a severe chronic illness associated withabnormal structure and function of the central nervoussystem with high rates of recurrence, disability, social

impairment1-6% of the population.

Specifically, the depressive episodes are morenumerous,last longer, and are less responsive to treatment

than the manic episodes



BIPOLAR DISORDER



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The goals of pharmacological treatmentsfor bipolar disorder are:

First, to decrease this hyperexcitability andStabilize mood

Second, to prevent the recurrence ofdepressive and manic episodes



2 1A

THERAPEUTIC AGENTS FOR BIPOLAR DISORDER



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Traditional mood-stabilizing:

Lithium

Anticonvulsive agents(valproate or lamotrigine)

20%-40% patient have sideeffects such as :

Tremors

Gastrointestinal disorders,

Tiredness

Somnolence, and cognitive

Impairment in memory andconcentration



2 1A




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Short-term studies

(3-4 weeks) suggest thatatypical antipsychotics(olenzapine, risperidone,ziprasidone) have beneficial

effects on manic anddepressive episodes.

Longer-term managementof bipolar disorder

For example, aplacebocontrolled studyshowed maintenance ofthe efficacy of risperidonemonotherapy over 12weeks and aripiprazole

seems to have similaeffects.






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Studies have demonstrated that aripiprazole is effective andwell tolerated in the treatment of acute bipolar mania.

Aripiprazole had superior efficacy to haloperidol in responserates 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

2 5 1A

PARTIAL D2-LIKE RECEPTOR AGONISTS IN MANIC EPISODE





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Aripiprazole monotherapy was superior to placebo inmaintaining efficacy in patients with a recent manic/mixed

episode who were stabilized and maintained on a regimen ofaripiprazole for 12 weeks, 26 weeks and 100 weeks Vieta et al.

demonstrated that adjunctive aripiprazole therapy to lithium orvalproate showed significant improvement in mania

symptoms from one week in bipolar patients with manic ormixed episodes who were partiall nonresponsive to

lithium/valproate monotherapy.



2 1A




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The same result has been observed with other atypicalantipsychotics. The use of isperidone, olanzapine and

quetiapine as adjunctive agent enhanced the response toclassical treatment. While the beneficial effect of aripiprazole

was clear in the treatment of manic episodes, there is noevidence that aripiprazole monotherapy has superior efficacy

compared to placebo treatment at the end of the treatment inbipolar depression at the dose use.




PARTIAL DOPAMINE D2/SEROTONIN 5-HT1ARECEPTOR AGONISTS AND PARKINSONS DISEASE


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PARKINSONS DISEASE



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THERAPEUTIC AGENTS FOR PARKINSONS DISEASE

L-dihydroxyphenylalanine (L-DOPA) is presently the mosteffective treatment for PD.

Its use is associated with a high probability of motorcomplications, including abnormal involuntary movements

(dyskinesia) and motor fluctuations in 50% of PD patients.



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PARTIAL D2-LIKE RECEPTOR FOR PD

Full DA receptor agonists can induce dyskinesia and psychotic-like

symptoms including hallucinations (probably due to theoverstimulation of extra-striatal DA receptors) or somnolence. Ithas been suggested that such side-effects could be counteractedby the use of partial D-like receptor agonists.

These compounds might stimulate D2 and D3 receptors when thedopaminergic tone is low, while counteracting excessivestimulation of the DA D2 and D3 receptor when the dopaminergictone is high.

It is also possible that partial agonists would modulate

dopaminergic transmission in a specific region, resulting in therestoration of dopaminergic transmission which is perturbed inPD patient.



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5-HT1A RECEPTOR FOR PD

5-HT1A receptor agonists could reduce the incidence ofdyskinesia. The 5-HT1A receptor agonist tandospironereduced dyskinesia in L-DOPA treated PD patient

Preclinical and clinical studies suggest that sarizotan, a5-HT 1A receptor agonist that possesses weak D3 and D4receptor agonist activity, could ameliorate dyskineticsymptoms in association with L-DOPA.



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Studies with 5-HT1A agonists have suggested areduction in L-DOPA-induced dyskinesia but a worsePD disability.

Carta et al. have shown that dyskinesia induced by

chronic L-DOPA treatment in rats with 6-OHDA-induced lesions of the nigrostriatal DA pathway iscritically dependent on the integrity and function ofthe serotonergic system



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Synergistic effect of low doses of 5-HT1A and 5-HT agoniststo suppress dyskinesia, without affecting the anti-parkinsonian effect of L-DOPA in presence of spared DAterminals, 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 firingof 5-HT neurons associated with desensitized 5-HT

autoreceptors.



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High frequency stimulation of the subthalamusnucleus, a well admit antiparkinsonian therapy, has

been shown to reduce 5-HT neuronal firing , furthersuggesting the involvement of 5-HT system in the

pathophysiology of PD.


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CONCLUSION



Several studies are in accordance with the markedinterest of partial D2/5-HT1A agonists in reducing sideeffects i.e. extrapyramidal symptoms and cognitiveimpairments in schizophrenia, various researches arestill needed to emphasize their beneficial utility inmajor depression, bipolar disorders and Parkinsonsdisease.


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CONCLUSION



Treatment with aripiprazole in major depression asmonotherapy or as adjuvant with a classical antidepressantsseems to improve the antidepressant response whereas, inbipolar disorder, only partial dopamin D2 1A receptorsagonists 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 thesedrugs. Hence, these relatively recent researches provide an

exciting future in the discovery of novel stabilizators agentsfor the management of the latter diseases.

JOURNAL READING


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CRITICAL

APPRESIAL

Partial Dopamine D2/ Serotonin 5-HT1AReceptor Agonists as New Therapeutic Agents

THE STRUCTURE AND


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THE STRUCTURE ANDCONTENT OF THE JOURNAL

The Title of Journal1. Not too long or too short : Yes (9 words)

2. Describe the whole of the journal : Yes

3. Interestingly enough : Yes4. Without abbreviations : Yes

The Author and InstitutionAppropriate with the guidelines : Yes

Ab t k


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Abstrak1. The structure : Consist of 1 part

2. Informative : Yes

3. Less than 250 word : No (255 word)

Introduction

1. Consist of 2 paragraph or part : No(10 paragraph, 3 parts)

2. The first paragraph explain background of theresearch : Yes

3. The second paragraph explain hypothesis orobjective : Not pattern

4. Less than 1 page : Yes (3 pages)

The Literat re Re ie


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The Literature Review1. The present state of play in relation to the topic : Yes

2. A range of up-to-date sources was reviewed : Yes

3. Key themes in the literature discussed and their significancewas shown : Yes

4. Gaps in the literature was identified : No

The Research Methods1. The context of the research is clear : Yes

2. The research methods are appropriate to the researchquestions : Not pattern

3. Methods are clearly justified : Not pattern4. 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


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The Data Analysis1. The main findings was described clearly : Yes

2. They was clearly related to the original research

questions : Yes3. They was presented in a format that is appropriate for

the findings : Not pattern

4. The interpretation of the data was consistent with theevidence : Yes

5. The findings is significant : Yes6. If quantitative: The data was analyzed using

appropriate statistical tools : Not pattern

7. If qualitative: Selection of data was presented : Notpattern

The Discussion


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1. The data from the research related back to theliterature and to other findings : Yes

2. The research support or challenge existing thinking orpractice : Yes

3. The research suggest recommendations for practice, orareas for further research : Yes

4. The author reflective on her/his work or self-critical :

Not pattern

The Conclusion1. The threads of the argument was drawn together

clearly : Yes2. The research questions was answered and research

aims fulfilled : Yes

3. The research contribute to the field : Clinicians,Psychiatrist


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

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