DERANGEMENTS IN PATIENTS WITH NEWLY DIAGNOSED SCHIZOPHRENIA

A COMPARATIVE STUDY ON HALOPERIDOL AND RISPERIDONE INDUCED METABOLIC

DERANGEMENTS IN PATIENTS WITH NEWLY DIAGNOSED SCHIZOPHRENIA

DISSERTATION SUBMITTED FOR THE DEGREE OF M.D BRANCH –VI

PHARMACOLOGY APRIL – 2017

THE TAMILNADU

Dr. M.G.R MEDICAL UNIVERSITY, CHENNAI.

TAMILNADU

Madurai .09.2016

CERTIFICATE

This is to certify that the dissertation entitled

A COMPARATIVE STUDY ON HALOPERIDOL AND RISPERIDONE INDUCED METABOLIC DERANGEMENTS IN PATIENTS WITH NEWLY DIAGNOSED SCHIZOPHRENIA” is a bonafide record of work done by Dr.S.KIRUTHIKA, under the guidance and supervision of Dr.S.VIJAYALAKSHMI, M.D., Professor, in the Institute of Pharmacology, Madurai Medical College, Madurai during the period of her postgraduate study of M.D Pharmacology from

2014-2017.

Dr. R. PARAMESWARI, M.D

Dr. M.R.VAIRAMUTHU RAJU, M.D

Director & Professor,

The Dean,

Institute of Pharmacology Madurai Medical College,

Madurai Medical College, Govt. Rajaji Hospital,

Madurai. Madurai.

Madurai .09.2016

CERTIFICATE

This is to certify that the dissertation entitled “A COMPARATIVE STUDY ON HALOPERIDOL AND RISPERIDONE INDUCED METABOLIC DERANGEMENTS IN PATIENTS WITH NEWLY DIAGNOSED SCHIZOPHRENIA” is a bonafide record of work done by Dr.S.KIRUTHIKA, under my guidance and supervision in the Institute of Pharmacology, Madurai Medical College, Madurai during the period of her postgraduate study of M.D Pharmacology from

2014-2017.

Dr.S.VIJAYALAKSHMI M.D., Professor,

Institute of Pharmacology,

Madurai Medical College,

Madurai

DECLARATION

I, Dr.S.KIRUTHIKA solemnly declare that the dissertation titled

A COMPARATIVE STUDY ON HALOPERIDOL AND RISPERIDONE INDUCED METABOLIC DERANGEMENTS IN PATIENTS WITH NEWLY DIAGNOSED SCHIZOPHRENIA

has been prepared by me under the able guidance and supervision of Dr. R. PARAMESWARI M.D, Director and Professor, Institute of Pharmacology, Madurai Medical College, Madurai, in partial fulfillment of the regulation for the award of M.D Pharmacology degree examination of The Tamilnadu Dr. MGR Medical University, Chennai to be held in April 2017.

This work has not formed the basis for the award of any degree or diploma to me, previously from any other university to anyone.

Place: Madurai Dr.S.KIRUTHIKA

Date:

ACKNOWLEDGEMENT

I am greatly indebted to Dr. M.R.Vairamuthu Raju, M.D

Dean, Madurai Medical College and Govt Rajaji hospital, Madurai who initiated this interdisciplinary work with generous permission.

It is with great pleasure I record my deep respects, gratitude and indebtedness to Dr.R.Parameswari M.D., Director and Professor, Institute of Pharmacology, Madurai medical college, Madurai for her remarkable guidance, encouragement and selfless support which enabled me to pursue the work with perseverance. Her contagious enthusiasm was a source of energy to me in successfully completing my dissertation under her generous guidance.

I am extremely thankful to my guide Dr.S.Vijayalakshmi M.D., Professor, Institute of Pharmacology, Madurai Medical College, Madurai, for her valuable suggestions and critical review at every stage for the successful completion of this study.

I record my sincere and heartfelt thanks to Dr.M.Shanthi M.D.,

Professor of Pharmacology, Madurai Medical College,Madurai for her

untiring support, continuous suggestions and enduring encouragement

throughout the study.

I am thankful to Dr.R.Sarojini M.D., Professor of Pharmacology, for her valuable suggestions and support. I am thankful to Dr.K.Raadhika M.D., Associate Professor of Pharmacology, for her valuable suggestions and support.

I wish to express my sincere thanks to Dr.T.Kumanan M.D, D.P.M., Head of Department, Department of Psychiatry, Government Rajaji Hospital, Madurai for the generous permission and complete co-operation to carry out the study. I express my heartful thanks to Dr.P.MohanKumaresh M.D, Head of Department, Department of Biochemistry, Government Rajaji Hospital, Madurai for his immense help during this study.

It is with a deep sense of gratitude, I wish to express my sincere thanks to Assistant Professors Dr.K.Geetha M.D, Dr.M.S.Ahil M.D., Dr.B.Jeyapriya M.D., Dr.M.Malathi M.D., Dr.V.Theivanai M.D., Dr.M.Sheik Davooth M.D.

It is my duty to express my appreciation to my colleagues

Dr.S.Yeshodha, Dr.M.Vijayalakshmi, Dr.J.Arunkumar, Dr.S.Vasanth,

Dr.R.Vijayarani, Dr.G.Muthukavitha, Dr.C.Umamaheshwari,

Dr.R.Mangaladevi, Dr.V.Vinothini, Dr.S.Prasanakumari,

Dr.S.Meenambal for their assistance.

I thank my family members and staff members of the Institute of Pharmacology for their kind support and encouragement throughout the study.

I thank the almighty who had bestowed his mercy and kindness all throughout my study and my carrier.

CONTENTS

S.NO TITLE PAGE NO.

1. INTRODUCTION 1

2. AIM AND OBJECTIVES 5

3. REVIEW OF LITERATURE 6

4. MATERIALS AND METHODS 53

5. RESULTS 60

6. DISCUSSION 82

7. SUMMARY & CONCLUSION 88

ANNEXURES

1. BIBLIOGRAPHY

2. PROFORMA

3. INFORMED CONSENT IN TAMIL & ENGLISH

4. PATIENT INFORMATION SHEET

5. MASTER CHART

6. ABBREVIATION

7. ETHICAL CLEARANCE LETTER

8. ANTI PLAGIARISM CERTIFICATE

INTRODUCTION

Schizophrenia is a common chronic psychotic disorder characterized by splitting of perception and interpretation from reality and inability to think coherently. According to the Global Burden of Diseases, following cardiovascular diseases, schizophrenia is the second major disabling disorder in the world. It is an early onset disease, affecting people in their most crucial part of life either in late adolescence or early adulthood and thereby it creates a major impact on their family and society.

The burden of its morbidity and disability is better exemplified by its disability-adjusted life year (DALY) and years lost to disability (YLD) which are about 2.6 % and 4.9% respectively. Schizophrenic patients more commonly face challenges in their day to day functioning like difficulty in leading an independent living and in carrying out their school, workplace and parental responsibilities.¹ The negative symptoms such as anhedonia, attentional deficit and social withdrawal along with cognitive symptoms contribute to chronic disability and the worsening of positive psychotic symptoms like delusions and hallucinations leading to acute relapses in disease spectrum of schizophrenia. In order to diagnose a person with schizophrenia, he or she must have atleast two of the above symptoms for a duration of one month according to International Classification of Diseases 10 (ICD 10) and according to Diagnostic and Statistical Manual of Mental Disorders (DSM 5), the symptoms must be present for 6 months. If negative symptoms predominate in some patients, then it might be an indicator of poor outcome and a poor response to drug therapy.

The three major phases in spectrum of schizophrenia are acute, stabilization and maintenance phase, depending on which the pharmacotherapy is started for a patient. The acute stage might be a first psychotic episode or a relapse of the chronic illness which needs immediate clinical care. The acute phase usually lasts for 4 to 8 weeks, and it is followed by the stabilization phase during which if there is an interruption of patients treatment schedule, they are at a high risk for relapse.

The maintenance phase is the third phase where the patient is relatively in a remission stage.

In earlier days at the time of late 19th and early 20th centuries, for psychotic patients the available therapeutic interventions were mainly palliative.

The patients were under longer periods of hospitalization, under the influence of calming measures like physical treatments with wet sheet packs, hydrotherapy and other measures with unproven efficacy such as insulin coma, prefrontal lobectomy and electroconvulsive therapy (ECT). The main pharmacological tools used were the sedating agents like bromides and barbiturates. The most ancient antipsychotic used was reserpine, obtained from the extracts of the rauwolfia plant.

In the year 1952 the era of antipsychotic therapy began with the introduction of the first typical antipsychotic chlorpromazine after which a wide range of antipsychotic medications have been added to the therapeutic armamentarium.²

In schizophrenia, the central role of pharmacotherapy is played by the antipsychotic drugs which are very effective for reducing the impact of psychotic

symptoms on the quality of life of patients. The choice of antipsychotic drugs depends on the patient symptomatology, behaviour and drug resistance.³

The antipsychotic drugs are classified into two groups –typical or conventional or first generation antipsychotics and second generation or atypical antipsychotics. But these drugs act as a double edged sword, apart from controlling the symptoms, they also cause serious adverse effects which might be due to the extension of their pharmacological actions or by a different mechanism.

They cause several side effects like neurological deficits and metabolic derangements. The typical or first generation antipsychotics have more propensity to cause extra pyramidal symptoms. On the other hand the atypical or second generation antipsychotics have lower risk of causing extra pyramidal symptoms (EPS) and are more effective on negative symptoms and are also useful in refractory cases. Thus they appear to have several advantages over the typical antipsychotics.

Currently the atypical antipsychotics are most commonly prescribed not only for schizophrenia but also for other psychotic disorders like bipolar mood disorder .This rampant use of second generation antipsychotics is also associated with a newer group of adverse effects like increased risk of developing metabolic syndrome and cardiovascular diseases.⁴

Several long term prospective studies have been done in western countries as well as in India comparing the prevalence of metabolic syndrome between first generation antipsychotics (FGA) and second generation antipsychotics (SGA).

They have reported the first generation antipsychotics to carry lower risk of causing metabolic abnormalities.

But studies on the comparison of the prevalence of metabolic syndrome caused by the two groups of antipsychotics in schizophrenic patients among the South Indian population are scarce.

In our government tertiary care hospital, haloperidol and risperidone were the most commonly used antipsychotics in the psychiatric department for treating schizophrenia. So a comparative study was planned between the two groups of patients with newly diagnosed schizophrenia who were treated with either one of the candidate drugs namely haloperidol (typical) or risperidone (atypical) antipsychotic. The metabolic derangements were kept as the main parameter for the comparison of side effect profile of the two groups of antipsychotics.

AIM AND OBJECTIVES

AIMS AND OBJECTIVE

 To compare the metabolic derangements induced by a typical

antipsychotic – Haloperidol and an atypical antipsychotic – Risperidone in patients with newly diagnosed schizophrenia in a tertiary care hospital.

REVIEW OF LITERATURE

Psychosis is a cluster of symptoms like delusions and hallucinations which are associated with various psychiatric disorders, but it is not specifically diagnosed as a disorder by Diagnostic and Statistical Manual (DSM) and ICD International Classification of Diseases criteria.

The group of disorders in which psychosis is a part of the specific diagnostic criteria includes:

 Schizophrenia

 Substance-induced psychotic disorders

 Schizophreniform disorder

 Schizoaffective disorder

 Delusional disorder

 Brief psychotic disorder

 Psychotic disorder due to a general medical condition

The other disorders, where psychosis is only an associated feature but it is not a specific feature to make a diagnosis includes conditions like Mania, Depression, Cognitive disorders and Alzheimer‟s dementia.⁵

EPIDEMIOLOGY ⁶

Schizophrenia - “schizo” (fragmented or split) + “phrenia” (mind), it is named so as the patients suffering from this illness are often not able to think clearly and to feel normal emotions. According to World Health Organisation, schizophrenia is one among the top ten causes of disability affecting humans mostly in their early part of life around the second decade.

Its worldwide prevalence is about 0.5% – 1%.The overall incidence of schizophrenia ranges from 0.1 in western countries to 0.5 per 1000 people in India.

Usually the age at the time of first psychotic episode ranges between 18–25 years for men and 21–30 years for women. There is a high risk of suicidal behavior in them with one-third of them attempting suicide and suicide death rate being one out of ten schizophrenic patients. The disease has a highly variable outcome. Some of the factors which influence a poor disease outcome are insidious early onset of illness, male gender, strong family history of schizophrenia and a long prodromal phase present from childhood.

HISTORY ⁷

Charaka in his early documents in Ayurveda has described about schizophrenic patient as a person “who is filthy, walks naked, has lost his memory and moves about in an uneasy manner”. In 1896 Emil Kraepelin introduced the concept of „Dementia precox‟ where schizophrenia was characterized to be a condition with mental deterioration starting early in life.

In 1911 Eugen Bleuler coined the term schizophrenia and described its four primary symptoms autism, ambivalence, loosening of association, affective flattening and the secondary symptoms like delusions and hallucinations.

This was followed by Kurt Schneider description of „First Rank Symptoms‟. It consisted of various forms of hallucinations, thought withdrawal, thought insertion thought broadcasting, delusional perceptions, experiencing feelings and actions as made or influenced by external agents which helped in the diagnosis of schizophrenia.

At present the two major diagnostic criteria followed are the DSM –V

„Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association (APA) and ICD -10 „International Classification of Diseases (ICD)‟

SUBTYPES OF SCHIZOPHRENIA ⁸ • Paranoid

• Disorganized /Hebephrenic • Catatonic

• Undifferentiated • Residual

• Simple

DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS DSM-5 CRITERIA FOR SCHIZOPHRENIA

Symptoms

Two or more of the following for at least one month:

1. Delusions 2. Hallucinations 3. Disorganized speech

4. Disorganized or catatonic behaviour 5. Negative symptoms

Duration: The symptoms should be present for atleast 6 months or more

The other psychotic disorders excluded under this criteria are • Schizoaffective disorder

• Bipolar disorder

• General medical disorders like temporal lobe epilepsy • Substance induced

INTERNATIONAL CLASSIFICATION OF DISEASES 10 ICD-10 CRITERIA FOR SCHIZOPHRENIA

The first version of the ICD appeared in 1900, in order to establish comparable nomenclature among different countries. At present ICD-10 criteria (WHO, 2003) is followed which includes the following symptoms:

Symptoms At least one of:

1. Thought echo, insertion, withdrawal, broadcast 2. Passivity phenomena or delusional perception

3. Third-person conversing or running commentary hallucinations.

At least two of:

1. Persistent hallucinations in any modality, with delusions 2. Disorganized speech

3. Catatonia

4. Negative symptoms (must be „primary‟)

Duration: The symptoms should be present for atleast 1 month

Exclusions

• Mood disorder

• Organic brain disease

• Alcohol/drug-related intoxication ETIOLOGY

a. GENETIC FACTORS⁹

The life time inheritance risk of schizophrenia is 0.8 to 1.2% depending on the interaction between genes guiding neuronal development, plasticity and neurotransmission. Schizophrenia is a complex trait, with very high etiological heterogeneity. The candidate genes playing a central role in the development of schizophrenia include the following:

i. A hyperfunctioning allele for the dopamine metabolizing enzyme catechol- O- methyl transferase (COMT), leading to dopamine deficiency in prefrontal cortex causing the cognitive and negative symptoms.

ii. Mutations in genes like neuregulin 1 (NRG1) and D-amino acid oxidase activator (DAOA).

iii. Hypoactive alleles for dysbindin gene, which interfere at the post synaptic level with glutamate neurotransmission.

iv. Underactive alleles of the genes G72 and GRM3 leading to alteration of glutamate neurotransmission in the hippocampus and prefrontal cortex v. Mutations in the gene coding for (BDNF) brain-derived neurotrophic

factor.

b. NON-GENETIC FACTORS¹⁰ ENVIRONMENTAL FACTORS

The major risk factors for schizophrenia depend on the influence of several events which occur during the pre and perinatal period of development.

These factors are

 exposure to in utero infections like rubella, influenza, toxoplasmosis .

 late winter or early spring birth

 maternal anaemia , low level of maternal vitamin D

 maternal stress during pregnancy due to starvation, substance abuse, flood, unwanted pregnancy and depression

 pregnancy and birth complications like low birth weight, preeclampsia, foetal hypoxia and rhesus factor incompatibility

 urban birth or upbringing

 history of migration

 ethnic minorities

 advancing paternal age PATHOPHYSIOLOGY¹¹

Schizophrenia like other pathological states as cancer, diabetes and cardiovascular diseases is better elucidated by the “multiple-hit” theory. The vulnerable genes along with environmental, neurodevelopmental, biological and psychological factors influence the pathophysiology of schizophrenia.

1. NEURODEVELOPMENTAL MODEL

Schizophrenia is considered to be a neuro-developmental disorder , where in some patients, the structural and functional changes in the brain might be present since in utero or develop during childhood and adolescence or both involving multiple genes . With the help of neurodevelopmental model there is a better understanding of the effect of obstetric complications on developing brain, leading to the increased incidence of schizophrenia in late adolescence and early adulthood.

According to this model, patients with this disease have either too many or very few unnecessary synaptic connections which are normally eliminated during adolescence through a process called synaptic pruning. Hence this alteration in the synaptic connectivity, which beyond a threshold manifests as fragmented or disconnected brain.

This neurodevelopmental model is further substantiated by the presence of certain minor anatomical defects of the head, face, hands and feet in schizophrenic patients. The loss of neuronal connectivity also gets reflected as a reduction in the neuropil count as observed in postmortem studies done on schizophrenic patients.

2. BIOLOGICAL THEORIES OF SCHIZOPHRENIA a. NEUROCHEMICAL HYPOTHESES¹²

(i) THE DOPAMINE HYPOTHESIS

The dopamine hypothesis puts forth that the clinical manifestations of schizophrenia are due to alteration in dopamine levels in the CNS.

According to this model, four dopaminergic anatomical pathways are described.

- The mesolimbic pathway is the one which projects from the ventral tegmental area (VTA) to limbic areas. If there is excess of dopamine in this pathway it may lead to the development of positive symptoms like delusions and hallucinations.

- The mesocortical pathway projects from VTA to cortex, especially prefrontal cortex. Dopamine deficiency in the mesocortical pathway can cause the negative symptoms and cognitive deficits of schizophrenia.

- The nigrostriatal pathway extends from the substantia nigra to the striatum and it regulates body movements, low nigrostriatal dopamine leads to parkinsonism.

- The tubero infundibular pathway from the hypothalamus to the pituitary gland inhibits prolactin secretion, the blockade of dopaminergic receptors in this pathway leads to elevated prolactin, resulting in galactorrhoea and amenorrhoea.

Dopamine agonists like levodopa, cocaine and amphetamines exaggerate psychotic symptoms in normal persons as well in people with schizophrenia, likewise on the other hand neuroleptics block the D₂ dopamine receptors.

Positron emission tomography (PET) imaging studies have shown increased synthesis and release of dopamine in response to stressors. But some cases of schizophrenia are resistant to D₂ blockade effect and atypical antipsychotics like clozapine which have poor affinity to D₂ receptor are effective indicating that other neurotransmitters or receptors may also be involved.

(ii) THE GLUTAMATE HYPOTHESIS

The glutamate hypothesis states that malfunctioning of the major excitatory neurotransmitter N-methyl-D-aspartate (NMDA) glutamate receptor might be the trigger for the positive, negative, and cognitive symptoms of schizophrenia. It is

further substantiated by the finding that the level of glutamate is low in CSF of schizophrenic patients.

Glutamate receptors

The blockade of glutaminergic NMDA receptor by drugs like ketamine, phencyclidine produce some symptoms of schizophrenia.

Postmortem studies also show changes in the expression of NMDA receptors in schizophrenic patients. NMDA receptor hypofunction causes decreased activation of inhibitory neurotransmitter GABA, hence leading to glutamate excitotoxicity. NMDA receptor hypofunction also causes hyperactivity

of mesolimbic pathway leading to positive symptoms and hypoactivity of mesocortical pathway causing negative and cognitive symptoms of schizophrenia.

(iii) THE SEROTONIN HYPOTHESIS

Serotonin has important influences over dopamine and its role in pathophysiology of schizophrenia came to light with the observation that the hallucinogen lysergic acid diethylamide (LSD) produces a profound psychotic state.

It is further substantiated by the pharmacological evidence that drugs such as clozapine and risperidone have high affinity for specific serotonin receptors like 5-HT_2A and 5-HT_2C when compared with dopamine D₂ binding affinity. One of the main metabolites of serotonin is (5-HIAA) 5-hydroxy indole acetic acid and low levels of 5-hydroxy indole acetic acid in the cerebrospinal fluid were found in schizophrenics with suicidal ideation and depression.

b. NEUROANATOMICAL ABNORMALITIES¹³

The neuroimaging studies using techniques like computed tomography, magnetic resonance imaging ,magnetic resonance spectroscopy, positron emission tomography, functional magnetic resonance imaging, electroencephalography and magnetoencephalography done on schizophrenic patients have shown certain typical structural brain abnormalities which includes

 ventricular enlargement

 medial and superior temporal lobe abnormalities

 prefrontal cortex dysfunction

 parietal lobe and sub cortical abnormalities

COMORBID MEDICAL ILLNESS¹⁴

Nearly fifty percent of schizophrenic patients tend to have one or more comorbid medical conditions and these illness are commonly missed out due to improper medical care given to them. Among the endocrine disorders hypothyroidism is three times more common in schizophrenics than the general population. The major health issue is metabolic syndrome and cardiovascular diseases like coronary artery disease.

Hyperprolactinaemia caused by antipsychotics leads to an increased risk of osteoporosis. Infectious diseases like HIV (human immunodeficiency virus), hepatitis and respiratory infections like tuberculosis, chronic obstructive pulmonary disease are associated with schizophrenics. The prevalence of epilepsy is two times increased in schizophrenics. Ankylosing spondylitis and uro-arthritis are commonly seen in patients with atypical psychoses.

DIFFERENTIAL DIAGNOSIS OF SCHIZOPHRENIA

The various conditions that can resemble or mimic schizophrenia include the following

PSYCHIATRIC DISORDERS - Schizoaffective disorder - Bipolar disorder

- Major depression

- Brief psychotic disorder

MANAGEMENT

The successful management of schizophrenia involves a multidisciplinary approach integrating the current therapeutic options in psychosocial interventions and pharmacotherapy.

I. NON- PHARMACOLOGICAL TREATMENT¹⁵

 Psychosocial approaches:

o Cognitive-Behavioral Therapy For Psychosis

- The cognitive-behavioral therapy (CBT) approaches are moderately effective to medication resistant, positive symptoms of psychosis such as delusions and hallucinations, especially if continued for atleast 6 months

o Individual psychotherapy o Group psychotherapy o Compliance therapy

o Motivational interviewing or shared decision making o Cognitive remediation

o Social skills training

o Assertive community treatment (ACT) o Cognitive adaptation training (CAT) o Supported employment and housing o Family therapies

II. PHARMACOTHERAPEUTIC AGENTS ¹⁶ ANTIPSYCHOTIC DRUGS (NEUROLEPTICS) CLASSIFICATION

FIRST GENERATION / CONVENTIONAL / TYPICAL ANTIPSYCHOTICS

 PHENOTHIAZINES :

- Aliphatic side chain : Chlorpromazine Triflupromazine - Piperidine side chain : Thioridazine - Piperazine side chain : Trifluoperazine Fluphenazine

 BUTYROPHENONES :

Haloperidol Trifluperidol Penfluridol

 THIOXANTHENES :

Flupenthixol

 OTHER HETEROCYCLICS : Pimozide Loxapine Sulpiride

Zuclopenthixol

SECOND GENERATION / ATYPICAL ANTIPSYCHOTICS

 Clozapine

 Aripiprazole

 Risperidone

 Ziprasidone

 Olanzapine

 Amisulpiride

 Quetiapine

 Zotepine

 Asenapine

 Iloperidone

 Sertindole

 Paliperidone

 Lurasidone

 Cariprazine

The treatment of schizophrenia has significantly evolved since the early 20th century. The discovery of chlorpromazine in 1954 revolutionized psychopharmacology.

PHARMACOKINETICS

1. First-generation antipsychotics¹⁷

They are also known as typical or conventional antipsychotic.

They are further subdivided into low-potency, medium-potency and high- potency agents.

 High-potency agents : - Haloperidol, - Fluphenazine

 Medium-potency agents - Loxapine,

- Molindone

 Low-potency agents - Chlorpromazine, - Thioridazine

All of them have a similar mechanism of action by blocking dopamine receptors in the mesolimbic pathway and thereby reducing positive symptoms.

Hence they are called Dopamine receptor antagonists – DRA.

The high-potency drugs have strong affinity for dopamine receptor, and show effective antipsychotic action at low doses. They carry high risk of causing EPS and low risk of anticholinergic side effects.

The low-potency drugs are also dopamine receptor antagonists, but they also alter the other neurotransmitters leading to their anticholinergic, alpha- blocking, and antihistaminic properties. They carry low risk of causing extra pyramidal symptoms (EPS) and high risk of orthostatic hypotension, sedation and anticholinergic side effects. If the psychotic patient is not adherent to the medications, compliance can be improved by using depot preparations.

The two first-generation antipsychotics available as long-acting, intramuscular, injectable form are haloperidol and fluphenazine

ADDITIONAL BINDING PROPERTIES OF FIRST GENERATION ANTIPSYCHOTIC

M₁ – Anticholinergic, α₁ - Alpha-blocking, and H₁ - Antihistaminic properties

Second-generation antipsychotics

These drugs are often referred to as atypical antipsychotics. These agents also antagonize dopamine (D₂) receptors in the mesolimbic pathway and additionally they block serotonin (5-HT_2A) receptors in the mesocortical pathway.

They have a relatively loose binding to dopamine D₂ receptors and minimal antihistaminic properties when compared with the typical antipsychotics. Hence they are also named as Serotonin-Dopamine Antagonist SDA. Risperidone is available as long-acting, intramuscular injectable form. The other important advantage with their use is lower risk of EPS.

ATYPICAL ANTIPSYCHOTIC

MECHANISM OF ACTION

All conventional antipsychotics have potent dopamine D₂ receptor blocking action. Additionally D₁, D₃ and D₄ receptors are also blocked by phenothiazines and thioxanthenes but not correlating with their antipsychotic potency .The blockade of overactive dopaminergic receptors in mesolimbic area and mesocortical areas produces the antipsychotic action, while the same action in the basal ganglia produces the parkinsonian adverse effects.

Dopamine released by the neurons in tuberoinfundibular system physiologically inhibits prolactin secretion from the anterior pituitary, and thus the typical antipsychotics cause hyperprolactinemia as adverse effect by blocking the dopamine receptors located here.

The DA overactivity in mesolimbic areas are closely linked to positive symptoms (hallucinations, aggression) but not to the negative symptoms (apathy, cognitive deficit, withdrawal). The typical antipsychotic drugs produce EPS extrapyramidal symptoms when they occupy 80% or more of striatal D₂ receptors.

The phenothiazines have α adrenergic blocking, weak anticholinergic property, H1- antihistaminic and anti-5-HT actions ¹⁸.

The other affected neurotransmitter in schizophrenia is the serotonergic system (5-HT), 5-HT₂ receptors especially 5- HT_2A and 5-HT_2C receptors are blocked by clozapine and other atypical antipsychotics. Eventhough5-HT_2A receptors are widely distributed, the antagonism in prefrontal and basal ganglia exerts the maximum effect on DA release and midbrain noradrenergic outflow.

DOPAMINE RECEPTORS

Most of the newer atypical antipsychotic agents have higher affinity for the 5-HT_2A receptor than for the D₂ receptor. Thus, antipsychotic property depends on a specific profile of action of the drugs on several neurotransmitter receptors. By virtue of their impact on noradrenergic neurotransmission, 5-HT _2C antagonists and 5-HT _1A partial agonists also exhibit some antidepressant property.

Current research is directed towards discovering atypical antipsychotic compounds that are either more selective for the mesolimbic system (to reduce their effects on the extrapyramidal system) or to have effects on central neurotransmitter receptors like on acetylcholine and excitatory amino acids glutamate. ¹⁹

GENERAL GOALS OF PHARMACOTHERAPY²⁰

Short-term antipsychotic treatment is given to patients with delirium, dementia, mania or major depressive disorder with psychotic features, substance- induced psychoses, and brief psychotic disorder. Depending on the underlying etiology the duration of treatment varies and the antipsychotics are discontinued after resolution of psychotic symptoms.

On the other hand chronic diseases like schizophrenia, schizoaffective disorder and delusional disorder require long-term antipsychotic treatment, where the main goal is to minimize symptom and functional impairment and to facilitate the individuals to pursue social life as best as possible.

The choice of antipsychotic agents for long-term schizophrenia treatment depends primarily on avoidance of adverse effects and the amount of patient response. The atypical antipsychotic agents offer significant advantages over the typical antipsychotics. Due to their decreased affinity for D₂ receptors, they carry lower risk of EPS, tardive dyskinesia and hyperprolactinemia.

Eventhough they offer these advantages, they tend to cause increased risk of metabolic side effects like weight gain, dyslipidemia (especially

hypertriglyceridemia), impaired glucose tolerance, including new-onset type 2 DM, and diabetic ketoacidosis (DKA).

Response to drug therapy is usually seen within hours after drug administration in case of acute psychosis. The analyses of symptom response in several clinical trials, has shown 6 weeks as the adequate time for antipsychotic trial, while if there is failure of response after 2 weeks, then there should be a prompt clinical reassessment and determination of medication adherence, before increasing the current dose or before switching to another agent.

CLINICAL RESPONSE AND DRUG RESISTANCE TO ANTIPSYCHOTICS ²¹

A schizophrenic patient can be considered as a poor responder, when there is no adequate clinical response, to the therapeutic dose of an antipsychotic (eg chlorpromazine or its equivalent at a dose of 600-800mg) for a sufficient time period (minimum of 6 weeks).

The other measures which can be implemented as alternatives in case of poor responders for duration 6 to 8 weeks include:

 The dose of the first line drug might be increased to the maximum tolerated dose (eg chlorpromazine can be escalated up to 1000 mg)

 Switching over to another drug from a different class and it has to be used in its therapeutic range.

 The second-line drug can also be increased upto its maximum tolerated dose

 Switching over to a different formulation like depot preparations, thereby the large fluctuations in plasma concentration can be avoided. When there is no clinical response to one or at least two of these above alternative steps, then the patient can be considered to be „treatment resistant‟.

ADJUNCTIVE TREATMENTS²²

The psychotropic medications that are used as adjuncts are:

FIRST-LINE ADJUNCTIVE MEDICATIONS

 Antidepressants can be used to treat depression in schizophrenic patients.

SECOND-LINE ADJUNCTIVE MEDICATIONS

 Anxiolytics like benzodiazepines.

 Mood stabilizers like lithium salts, valproate, and carbamazepine

which are used during periods of impulsive, aggressive behaviors, hyperactivity or mood swings.

- LITHIUM SALTS

This anti-manic drug is the preferred choice of agents for schizoaffective disorder patients.

- CARBAMAZEPINE

This anti-epileptic agent can be used in schizoaffective disorder patients with electroencephalogram (EEG) abnormalities especially localized in the temporal area. Carbamazepine being an enzyme inducer, the dose of the antipsychotic has to be increased on concurrent administration with it.

- BENZODIAZEPINES

They are preferred during acute psychotic episodes.

- ELECTROCONVULSIVE THERAPY

Electroconvulsive therapy can be tried especially in cases with predominant depression and catatonic symptoms as a third-line treatment.

ANTIPSYCHOTIC DRUG COMPLIANCE²³

In the pharmacotherapy of chronic illness especially in psychiatric disorders like schizophrenia, maintenance of medication adherence is a Himalayan task.

About 40–60% of schizophrenics are on irregular treatment with antipsychotics.

The underlying reasons for non-compliance are lack of insight, adverse drug reactions and its effects on their day to day life, the daily pill burden and lack of support from family.

Several Methods that have been tried to enhance medication adherence are:

 Patient Education

- They can be trained to become aware about their illness, the beneficial effects of the medications and the risk of avoiding treatment.

 Depot formulations can enhance adherence and relapse rates can be reduced.

 Compliance therapy

- Here cognitive behavioral therapy targets on the measures to improve drug adherence.

 The family members can be taught about the exacerbation of symptoms, side effects of drug and the red alert situations which need immediate physician care.

 In the hospital setting, records can be maintained about the follow up schedule of patients, those patients who are missing the outpatient appointments can be given a home visit and other active outreach interventions might be tried.

DRUG INTERACTIONS²⁴

1. CNS depressants like hypnotics, anxiolytics, alcohol, opioids and antihistaminics are potentiated.

2. In parkinsonism patients the actions of levodopa and direct dopamine agonists like pramipexole and ropinirole are blocked by neuroleptics.

3. By their α2 adrenergic receptors blocking action, antipsychotics reduce the antihypertensive effect of clonidine and methyldopa.

4. The blood levels of neuroleptics are reduced by enzyme inducers barbiturates, anticonvulsants like phenytoin, carbamazepine and rifampicin.

5. Other significant pharmacokinetic interactions don‟t occur frequently because the neuroleptics are poor enzyme inducers.

6. Lithium on concurrent administration with haloperidol can cause aggravation on extrapyramidal symptoms like neurolept-malignant syndrome.

7. When clozapine is given along with anti-thyroid drugs, the risk of agranulocytosis is potentiated.

GENERAL ADVERSE EFFECTS OF ANTIPSYCHOTICS

Antipsychotics are very safe drugs in single or infrequent doses: deaths from overdose are uncommon.

I. Based on pharmacological actions (dose related) 1. CENTRAL NERVOUS SYSTEM

Drowsiness, lethargy, mental confusion is common with low potency typical antipsychotics and atypical ones like quetiapine and clozapine. There is a risk of aggravation of seizures in epileptics and occurrence of seizures in nonepileptics with high doses of some antipsychotics like clozapine and olanzapine. The high potency, phenothiazines, risperidone, quetiapine, aripiprazole and ziprasidone have only less effect on seizure threshold.

2. CARDIOVASCULAR SYSTEM

The α adrenergic blockade is more common with low potency phenothiazines and thus they cause postural hypotension, palpitation, inhibition of ejaculation (especially with thioridazine). Overdose of thioridazine, pimozide and ziprasidone increases the risk of Q-T prolongation and cardiac arrhythmias.

3. ANTICHOLINERGIC

Due to their antimuscarinic action low potency antipsychotics cause dry mouth, blurring of vision, constipation, urinary retention in elderly males.

Thioridazine has the highest cholinergic blocking property. Inspite of its anticholinergic action, clozapine due to its central action induces hypersalivation.

4. ENDOCRINE

The typical neuroleptics because of their D₂ blockade in tuberoinfundibular pathway cause hyperprolactinemia. The elevated prolactin levels lower Gn levels leading to amenorrhoea, infertility, galactorrhoea and gynaecomastia. Except risperidone, other atypical antipsychotics do not cause hyperprolactinemia.

5. EXTRAPYRAMIDAL SIDE EFFECTS

Extrapyramidal sypmtoms are the major dose-limiting side effects of antipsychotics. High potency typical antipsychotics like fluphenazine, haloperidol, pimozide have the highest propensity to cause these EPS, while thioridazine and the atypical antipsychotics carry a lower risk. The extrapyramidal disturbances are categorized as the following into

(a) Parkinsonism

(b) Acute muscular dystonias (c) Akathisia

(d) Malignant neuroleptic syndrome (e) Tardive dyskinesia

(a) Parkinsonism

The classical features like rigidity, tremor, hypokinesia, mask like facies, short shuffling gait, begin to appear within 1 to 4 weeks of starting the therapy.

Once drug induced parkinsonism has set in, the following steps have to be taken;

- dose of the antipsychotic has to be reduced

- centrally acting anticholinergic can be given concurrently, but not from the initiation of antipsychotic as they can worsen memory, cause intellectual deficit , dry mouth and urinary retention

- typical antipsychotic can be substituted by an atypical agent. Other alternative treatment option is amantadine.

After a few years of antipsychotic therapy, a rare form of extrapyramidal side effect that can occur is „rabbit syndrome‟- perioral tremors, with good response to central anticholinergic drugs.

(b) Acute muscular dystonias

Torticollis, locked jaw, bizarre muscle spasms predominantly involving linguo-facial muscles manifesting as grimacing, tongue thrusting can occur on parenteral administration of a single dose mostly within hours or during the first week of therapy. The overall incidence is 2%.

These dystonic reactions are more common in girls below 10 years, usually lasting for one to few hours and they resolve spontaneously. Drugs like central anticholinergics promethazine, hydroxyzine when injected intramuscularly might be useful.

(c) Akathisia

In some patients within 1–8 weeks of therapy, occurs motor restlessness with apparent agitation as a compelling desire to move about without anxiety.

These symptoms are about 20% common and can be mistaken for exacerbation of

psychosis. The first choice of treatment for this condition is a benzodiazepine like clonazepam or diazepam. In non-responsive cases, dose reduction of neuroleptic, or drugs like propranolol and atypical antipsychotic quetiapine, can be tried.

(d) Malignant neuroleptic syndrome

This fatal syndrome is rarely seen with high doses of potent agents and with the manifestations of marked rigidity, immobility, tremor, hyperthermia, semiconsciousness, fluctuating BP and heart rate, presence of myoglobin in blood.

It lasts for 5–10 days even after drug withdrawal. Immediately the offending antipsychotic has to be stopped and the drug of choice is intravenous dantrolene.

(e) Tardive dyskinesia

It is characterized by purposeless involuntary facial and limb movements like constant chewing, pouting, puffing of cheeks, lip licking and choreoathetoid movements. This syndrome is seen more commonly in elderly women, occuring late during treatment course and even after stopping the neuroleptic.

The mechanism of this effect might be due to neuronal supersensitivity to DA. It is worsened by anticholinergics and transiently reduced by high doses of the neuroleptic. Overall incidence of tardive dyskinesia is 10–20%.

6. METABOLIC EFFECTS

There is an increasing incidence of metabolic derangements like weight gain, rise in blood sugar and triglyceride levels with chronic antipsychotic therapy.

Especially low potency phenothiazines (CPZ, thioridazine) and atypical antipsychotics like olanzapine and clozapine have high risk of precipitating

diabetes. High potency drugs like trifluperazine, fluphenazine, haloperidol and atypical antipsychotics like risperidone, aripiprazole and ziprasidone have low risk. These metabolic side effects might be due to weight gain or insulin resistance.

Due to the antipsychotic drug induced changes in metabolic parameters, there is increased risk of cardiovascular diseases among schizophrenics.

7. MISCELLANEOUS

On long-term use of high doses of phenothiazines, especially more common with thioridazine occurs blue pigmentation of exposed skin, corneal and lenticular opacities and retinal degeneration. ²⁵

METABOLIC SYNDROME

The concept of metabolic syndrome was first highlighted by Kylin in 1920 and the term metabolic syndrome was introduced in 1988 by Gerald M. Reaven at the Banting lecture. It is also known as Syndrome X, Insulin Resistance syndrome, Beer-belly syndrome, Dysmetabolic syndrome and Reaven‟s syndrome. It describes a cluster of cardiovascular disease risk factors and metabolic alterations associated with excess body fat and insulin resistance.

About 20–25% of the world‟s adult population are diagnosed to have metabolic syndrome. The underlying causes of the syndrome are physical inactivity, genetic factors, overweight and drugs. Patient who have the metabolic syndrome are at an increased risk for stroke, type 2 diabetes, and coronary heart disease.

The three commonly accepted definitions of metabolic syndrome are those proposed by

 WHO – World Health Organisation,

 NCEP – ATP III - third report of the National Cholesterol Education Program - Adult Treatment Panel

 IDF - International Diabetes Federation.

People with features of metabolic syndrome are likely to benefit the most from early life style modifications which can prevent the development of CVD in later life.

According to IDF criteria, for a person to be defined as having metabolic syndrome, they must have:

1. Central obesity : waist circumference ≥ 90 cm in South Asian men (ethnicity specific ) ≥ 80 cm in South Asian women 2. Hypertriglyceridemia : ≥ 150 mg/dl (1.7 mmol/l)

or on specific treatment for this lipid abnormality 3. Low HDL cholesterol : < 40 mg/dl (1.03 mmol/l) in men and

< 50 mg/dl (1.29 mmol/l) in women

or on specific treatment for this lipid abnormality 4. High blood pressure : ≥ 130/85 mmHg or on treatment of previously diagnosed hypertension

5. High fasting glucose : ≥ 100 mg/dl or on treatment of previously diagnosed type 2 diabetes mellitus

Diagnosis of metabolic syndrome: Central obesity and other 2 or more features of the criteria IDF definitions of metabolic syndrome uses ethnic-specific cut off points of waist circumference (WC) for example people of Asian origin it recommends waist circumference cut-off values of 90 cm in men and 80 cm in women.

The modified NCEP ATP III definition recognizes abdominal obesity has a component of metabolic syndrome, but does not include it as a prerequisite for the diagnosis. Whereas IDF definition emphasizes abdominal obesity to be a specific factor along with the any two of the other four criteria for diagnosing metabolic syndrome.

The role of metabolic syndrome as an independent predictor of cardio metabolic diseases is well known. Cases of premature cardiovascular disease mortality are being reported in schizophrenic patients. ²⁶

The multiple causes of cardiometabolic risk in patients with schizophrenia includes genetic and lifestyle habits like smoking, unhealthy diet, sedentary life and also the other major contributor being treatment with some antipsychotic drugs.²⁷

ANTIPSYCHOTICS INDUCED METABOLIC SYNDROME²⁸

The drugs like antipsychotics are strongly associated metabolic derangements. The extent of mean weight gain is variable among the first and second generation antipsychotics.

Risk Of Weight Gain Antipsychotic Drug

High

Clozapine Olanzapine

Moderate

Chlorpromazine Quetiapine Risperidone Paliperidone Iloperidone

Low

Amisulpride Asenapine Aripiprazole

Haloperidol Lurasidone Trifluoperazine

Ziprasidone

The mechanisms by which these drugs cause metabolic alterations are not clearly elucidated at present. The possible explanations for weight gain induced by antipsychotics might be due to histamine-H₁ antagonism, changes in neural control of appetite and satiety leading to increased caloric intake and altered glucose metabolism , drug induced rise in serum prolactin levels, leptin resistance along with life style habits like smoking, substance abuse, poor fiber diet intake along with reduced energy expenditure.

Antipsychotics and the risk of glucose intolerance Degree of risk Antipsychotic drug

High risk

Clozapine, Olanzapine

Moderate risk

Quetiapine, Risperidone, Phenothiazines

Low risk Haloperidol

Minimal risk

Aripiprazole, amisulpride,

asenapine, lurasidone, ziprasidone

The antipsychotics might cause either new onset type 2 diabetes mellitus or it can worsen the glycemic control in patients already diagnosed to have diabetes.

The mechanisms by which it causes alteration in glucose homeostasis are due to weight gain, leptin resistance, rise in plasma lipids and also 5HT_2A/5HT_2C antagonism. Deaths due to diabetic ketoacidosis have also been reported with drugs like clozapine and olanzapine.

Apart from causing weight gain, and glucose intolerance antipsychotics also increase the risk of coronary artery disease by causing dyslipidemia. Drugs like phenothiazines, clozapine, olanzapine and quetiapine induce rise in LDL

cholesterol and fall in HDL cholesterol. Among the second generation antipsychotics the risk of hyperlipidemia is maximum with olanzapine, moderate risk with quetiapine and risperidone and lowest risk with aripiprazole, lurasidone and ziprasidone.

The rise in blood pressure caused by antipsychotics can be by the following two mechanisms:

1. A slow steady rise in blood pressure over time: due to increase in weight 2. A sudden fast sharp increase in blood pressure on intiating drug therapy

or during dose escalation .

About 30-40% of schizophrenic patients tend to develop hypertension on prolonged treatment with antipsychotics. Among the second generation antipsychotics, drugs with maximum affinity for α₂ adrenergic receptors like clozapine, olanzapine, risperidone carry the highest risk of causing hypertension.

Postural hypotension is common with first generation antipsychotics like chlorpromazine due to their α₁ receptorblocking property.

MANAGEMENT OF ANTIPSYCHOTIC INDUCED METABOLIC SYNDROME:

MONITORING:

When a patient is started on antipsychotics, thorough recording of the anthropometric parameters like weight, waist circumference, body mass index and metabolic parameters like oral glucose tolerance tests (OGTT), fasting blood glucose, fasting lipid profile, blood pressure which determine the presence of

metabolic syndrome must be done compulsorily at baseline and it has to be repeated at three months or six months intervals.

FOR WEIGHT GAIN:

If weight gain occurs, the current drug can be switched over to antipsychotics like aripiprazole, ziprasidone which have the least potential to cause weight gain. Other option would be adding aripiprazole or ziprasidone as adjuvants to the current antipsychotic drug. Life style modifications like diet and exercise programmes, cessation of smoking also play an important role in the treatment and prevention of metabolic syndrome. If all the above measures have failed and if there is morbid obesity then the patient might be started on pharmacotherapy. The drugs used for antipsychotic-induced weight gain includes

- Metformin - Orlistat - Amantadine - Bupropion - Fluoxetine - Melatonin - Reboxetine - Topiramate - Zonisamide - H₂ blockers

- Carboxy methyl cellulose

FOR DYSLIPIDAEMIA:

When the patient is started on clozapine and if moderate to severe rise occurs in the triglyceride levels then the clozapine can be replaced with aripirprazole, ziprasidone or iloperidone along with life style modifications and hypolipidaemic agents like statins can be started to reduce the risk of occurrence of coronary artery disease.

FOR ANTIPSYCHOTICS INDUCED GLUCOSE INTOLERANCE &

HYPERTENSION

Blood glucose level has to be monitored with tests like oral glucose tolerance tests, fasting blood glucose, HbA_1C, and urine glucose at periodic intervals of 3 or 6 months. If the patient develops diabetes mellitus then the treatment options would be switching over to antipsychotic with least propensity to cause glucose intolerance. If glycaemic control is not achieved then the patient should be started on anti-diabetic agents like oral-hypoglycaemic agents or insulin.

The treatment protocol of antipsychotic related hypertension is similar to the standard guidelines followed for secondary hypertension. Antihypertensive agents like angiotensin receptor blockers especially valsartan and telmisartan have shown to be effective in antipsychotic induced hypertension.

HALOPERIDOL²⁹

It is a more potent conventional antipsychotic drug and also lacks potent antimuscarinic and antihistaminic binding activities. It is a 4-[4-(4-chlorophenyl)- 4-hydroxypiperidino-]-4‟-fluorobutyrophenone and white powder practically

insoluble in water, slightly soluble in alcohol. It is a butyrophenone with general pharmacological actions resembling that of phenothiazines with piperazine side chain

STRUCTURAL FORMULA OF HALOPERIDOL

PHARMACOKINETICS:

It is readily absorbed from the gastrointestinal tract. It is metabolized in liver and is excreted in the urine and via the bile, in the faeces, with some amount enterohepatic cycling.

Due to its first pass metabolism on oral route, plasma concentrations are lower when compared with intramuscular injection. There is wide inter subject variation and in practice there is no strong correlation between its plasma concentration and therapeutic effect.

Haloperidol is metabolized by oxidative N- dealkylation mediated mainly through CYP2D6 and 3A4, and also by the formation of reduced haloperidol where the ketone group is reduced to form alcohol.

On oral dosing, the elimination half –life ranges from 12-38 hours. It is about 92% plasma protein bound. It has a wide body distribution and crosses blood-brain barrier. It also gets secreted in breast milk. Therapeutic drug monitoring can be done by measuring the scalp hair concentration of haloperidol or its metabolite reduced haloperidol.

The decanoate ester of haloperidol is preferred for depot injection as it gets slowly absorbed from the injected site. After getting gradually released into blood stream, it is rapidly cleared off by getting hydrolysed to haloperidol. Haloperidol produces few autonomic effects, is less epileptogenic and jaundice is rare.

PRECAUTIONS

i. Haloperidol is unsafe in porphyria patients.

ii. It might cause toxic encephalopathy on high intravenous dose.

iii. It can cause retroperitoneal fibrosis on long term use.

iv. Its use in breast feeding mother, might cause decline of developmental scores in the infant.

v. On concurrent use with lithium, an encephalopathy syndrome has been noted.

vi. There is increased risk of dystonic reactions in patients with hyperthyroidism.

OVERDOSAGE

Haloperidol overdosing causes symptoms like drowsiness, restlessness, confusion, marked extrapyramidal features, hypothermia, bradycardia and also episodes of severe, delayed hypertension.

DRUG INTERACTION

On concurrent use with carbamazepine and phenytoin, haloperidol clearance is increased by ~32% and thereby its plasma concentration gets reduced.

USES

- Schizophrenia

- Tourette‟s syndrome - Severe Tics

- Huntington‟s Chorea - Anti emetic

- Ballism

- Stuttering and sneezing - Intractable hiccups - Taste disorder - Dystonia

DOSING

- For psychosis, the usual initial oral dose is 0.5 to 5 mg in two or three divided doses upto a maximum dosage of 30 mg daily in severe or resistant cases. Maintenance doses frequently used is in the range of 3 to 10 mg daily. Gradually the dose has to be titrated depending on the clinical response. In children, the initial dose is 25 to 50 micrograms/kg twice daily.

- In case of acute psychosis, it is given intramuscularly in dose of 2-10 mg every 4-8 hours upto 18 mg per day. In emergency control of severely disturbed patients, intravenous route can be tried.

- For patients requiring long-term therapy who are stabilized on oral dosing, can be switched on to long acting decanoate ester by deep intramuscular injection.

- Haloperidol is given in the dose of 0.5 to 2 mg im or oral dose of 1 mg for the control of nausea and vomiting. In case of intractable hiccups, the preferred oral dose is 1.5mg in three divided doses per day.

- The therapeutically effective dose in Tourette‟s syndrome is 0.5 -1.5 mg tds orally. The oral dose of 500 micrograms bd it can be tried as an adjunct for the short term control of severe anxiety disorders. A subcutaneous infusion of 5-15mg over 24 hours might be useful for palliative care of restless and confused patients.

RISPERIDONE³⁰

It is 3-{ 2-[4-(6-fluoro-1,2 –benzisoxazol-3-yl)piperidino]ethyl}-6,7,8,9- tetrahydro-2-methylpyridol [1,2-] pyrimidin-4-one. On comparing with the other atypical antipsychotics it has a different chemical structure and a simpler pharmacologic profile.

Risperidone is especially atypical at lower doses but at high doses it can cause EPS and rise in serum prolactin levels equivalent to the conventional antipsychotics.

STRUCTURAL FORMULA OF RISPERIDONE

PHARMACOKINETICS:

It is well absorbed orally, within 1-2 hours peak plasma concentration is reached. It undergoes hydroxylation mediated by the cytochrome P450 isoenzyme CYP2D6 in the liver and gets metabolized to a major active metabolite, 9-hydroxy risperidone (paliperidone). Its minor metabolic pathway is through oxidative N- dealkylation.

Risperidone is 90% plasma protein bound and its metabolite 9-hydroxy risperidone is 77 % plasma protein bound. Both risperidone and its metabolite are secreted in breast milk. Its elimination half -life is 19.5 hours. Though it doesn‟t block histamine H₁ receptors, it causes α₁, α₂ blockade, and is less epileptogenic than clozapine.

Cases of genetic polymorphism due to variations in CYP2D6 are also being reported with risperidone intake. It is excreted mainly in the urine and also to a lesser extent in faeces.

PRECAUTIONS

i. It has to be cautiously used in patients with cardiovascular disease, QT_c prolongation, hypotension, parkinson‟s disease, epilepsy, renal and liver disease.

ii. In elderly patients with dementia, its use is associated with the risk of transient ischaemic attacks and stroke.

iii. Like other atypical antipsychotics, risperidone can cause weight gain, glucose intolerance and hyperlipidaemia.

OVERDOSAGE

On accidental overdosage, the patient might develop hypotension, hypothermia, extra pyramidal side effects, first degree heart block, prolonged QT interval.

DRUG INTERACTION

i. CYP inhibitors like fluoxetine and paroxetine, increase the concentration of risperidone whereas carbamazepine reduces its concentration by 50%.

ii. In AIDS patients on ritonavir and indinavir, concurrent use of risperidone causes dystonia and tremors.

USES

- Schizophrenia - Mania

- Irritability associated with autistic disorder - AIDS related psychosis

- Anxiety disorders - Bipolar disorders

DOSING

- In schizophrenic patients, risperidone is started at a dose of 2 mg twice daily. The usual maintenance dose is 4-6 mg and maximum recommended dose is 16 mg/day. Its depot preparation is given by deep intramuscular injection at 2 weeks interval.

- For treating manic episodes in bipolar patients, allowed dose is 2-6 mg orally.

- In autistic children aged 5 to 16 years it may be tried for the treatment of irritability in the following doses depending on the body weight :

< 20 kg: initial oral dose is 250 µg, increased to 500 µg after 4 days.

≥ 20 kg: starting dose is 500 µg and can be escalated upto 1 mg orally

FUTURE ANTIPSYCHOTICS

1. GLUTAMATE-LINKED MECHANISMS³¹ AMPAkines

Positive allosteric modulators of AMPA receptor, which is one of the subtype of glutamate receptor are being developed to improve the cognitive symptoms without signs of neurotoxicity.

mGluR presynaptic antagonists/postsynaptic agonists

Metabotropic glutamate receptors (mGluRs), are another subtype of glutamate receptor which regulate the transmission at synaptic cleft as an auto receptor. Thereby drugs acting at this might prevent the glutamate release and can tried in schizophrenia.

Glycine agonists

Drugs having agonistic action at the glycine site of NMDA receptors might reduce the negative symptoms.

GlyT1 inhibitors

Glycine transporters GlyT1 present on glial cells terminate the action of glycine at the glutamate synaptic cleft. Sarcosine and bitopertin might be effective against negative, cognitive and depressive symptoms. They are in their last phases of clinical trial.

2. PHOSPHODIESTERASE 10A INHIBITORS³²

Due to dopamine blockade the levels of intracellular cyclic adenosine monophosphate cAMP are altered. Phosphodiesterase (PDE) enzyme has a central role in regulation of cAMP levels and PDE 10A subtype is present in cells with