PREFACE The knowledge on schizophrenia is expending and one finds it difficult to keep pace with recent research and

studies carried out. Research findings of today form the basis of practice in years to come. My topic for this paperwork is pharmacologic treatment in schizophrenia patients. It gives basic understanding on how antipsychotic drugs work on schizophrenia patients around the world. As we all know schizophrenia is a chronic and unique health problem that can affect anyone from any race, culture, background or nation. Everyone 1 person in a group of 100 can be suffering from schizophrenia. My paper work is to enlighten the readers on how we can treat schizophrenia and live with the disease, since there is no cure found yet. I have also mentioned all the adverse effects of antipsychotic drugs and the basic guidelines on treatment.

CONTENT Chapter 1 : Introduction 1.1 : Background 1.2 : Problem identification 1.3 : Aims 1.4 : Benefits Chapter 2 : Literature Review 2.1 : Pathophysiology and Pharmacological treatment 2.2 : Typical antipsychotic 2.3 : Atypical antipsychotic 2.4 : Similarities between typical and atypical antipsychotic drugs 2.5 : Other medication 2.6 : Treatment guidelines 2.7 : The choice of an antipsychotic drug Chapter 3 : Conclusion References

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CHAPTER 1 : INTRODUCTION

1.1. Background

The term schizophrenia exist from a severe and prolonged mental disturbances manifested as a wide range of disturbed thought, speech, and behaviour. Schizophrenia is known and viewed as one disease, but in depth it is more appropriately considered as a group of disorders of uncertain cause with similar clinical manifestations. This group of disorders can vary in each patient, including thought disturbances, hallucinations, delusions, bizarre behaviour and deterioration in the general level of functioning. This chronic disease can effect about 1 in every 100 persons. [2] Schizophrenia ranks among the top 10 causes of disability worldwide. It usually manifests itself in late adolescence or early adulthood. [4] In the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) schizophrenia disorders were divided into four active and one residual subtypes. Residual type schizophrenia features current lack of active-phase symptoms but definite experiences of at least one schizophrenic episode in the past, with the continued presences of either negative symptoms or attenuated forms of two or more of the active phase symptoms. The disorganized type schizophrenia (hebephrenia) features include incoherence and the lack of systematized delusions, disorganized behaviour that is not catatonic, and blunted, inappropriate or silly affect. They normally poorly adapt to their surrounding and have extreme social impairment. [1] Catatonic type features either excitement or stupor and mutism, negativism, rigidity and posturing. Whereas in undifferentiated type there are presences of grossly disorganized behaviour hallucinations, incoherence, or prominent delusions. The last type is the paranoid type schizophrenia which features one or more fixed delusions and exclusion of the regressive symptoms such as prominent disorganization of speech and behavior or inappropriate affect. Patients suffering from paranoid schizophrenia have more stable clinical picture, with less deterioration and better prognosis than those with other subtypes. [1] Schizophrenia symptoms are classified in positive, negative and cognitive. Positive symptoms include disorganized speech or behaviour and psychotic characteristics such as delusions and hallucinations. Negative symptoms include 3

affective flattening (restricted emotional experiences), alogia (restricted speech), avolition (lack of goal-directed behaviour) and reduced social drive. Cognitive symptoms may include difficulty in verbal fluency, attention and working memory. According to DSM-IV, a patient can be diagnosed with schizophrenia if he or she presents with at least two of the following symptoms in addition to social dysfunction for a significant amount of time during a 1-month period, with some symptoms persisting for at least 6 months. [3] Meanwhile there are also 2 other schizophrenia which is characterized by the onset, which is early onset schizophrenia, occurring prior to age 17 and very early onset schizophrenia, occurring prior to age 13 [4]. There are three types of treatment for schizophrenia patient, which are psychosocial treatment, pharmacological treatment and combined treatment. My paper today is to see the depth of pharmacological treatment in schizophrenia patients.

1.2. Problem Identification

a. How does antipsychotic drug work on a patient suffering from schizophrenia? b. How many groups of drugs are there to treat schizophrenia? c. The differences between typical and atypical antipsychotic drugs? d. The treatment guidelines in schizophrenia patients? e. What side effects can the drugs cause? f. Can schizophrenia be cured?

1.3. Aims

a. To enlighten the reader on how does an antipsychotic drug treat schizophrenia patients. To enhance the reader about the pathophysiological effect of a schizophrenia patients and on how does pharmacological treatment help schizophrenia patients. b. To explain on the two types of antipsychotic drugs, which are the typical antipsychotic and the atypical antipsychotic. c. To bring fort the differences between the typical antipsychotic drugs and the atypical antipsychotic drugs. Helps the reader to differentiate between the first-generation antipsychotic drugs and the second-generation antipsychotic drugs. d. To explain about what drugs can be given at what dosage to a schizophrenia patients. e. To view in details all the side effects that can sometimes remain permanent and sometimes be temporary due to he usage of certain antipsychotic drugs. f. To state that schizophrenia cannot be cured but with the proper medication, a patients life can be prolonged and the disease can be controlled.

1.4. Benefits

a. The reader will be able to understand how does schizophrenia effect the human brain and what are pharmacological effects on a patients who is on antipsychotic drugs. b. To make the reader understand and locate a typical antipsychotic drug and an atypical antipsychotic drug. c. To understand the similarities and differences between the typical antipsychotic drugs and the atypical antipsychotic drugs and how they own their specific mechanism in controlling the disorder. d. It is beneficial for the reader to understand the dosage that they drug can be given and the severity of adverse effects if the treatment guidelines are not followed. e. It can help educate the reader on all the adverse effects that can be associated by using antipsychotic drugs and how to overcome these side effects whether they are permanent or temporary. f. To make them acknowledge the fact that even if schizophrenia cannot be cured but the patient can always have a good life by improving his or her quality of life with the medication in a appropriate dose.

CHAPTER 2 : LITERATURE REVIEW 2.1. Pathophysiology and Pharmacologic treatment

In patients with schizophrenia, it is observed that there is an increase in the neurotransmission of dopamine, which maybe due to responses to stress. This causes the loss of neuron and its connections, which results that brain to be hypersensitive to stimuli and unable to regulate its response through normal inhibitory mechanism. As the number of neurons decreases, the interneuronal connections that store and process information further diminished the brain loses its ability to sort the incoming information into what is known and what is unknown. [3] The pharmacological approach to this manifestation is centered on the neurotrasmitters that control the response of neurons to stimuli. Pyramidal neurons are found in the cerebral cortex, which stores and process information are regulated by many other neurons. The activities of the pyramidal neurons are monitored and inhibited by the interneurons. The activity of both pyramidal and inhibitory neurons is further modulated by dopaminergic neurons, as well as by serotonergic, cholinergic and noradrenergic neurons, which send afferents into the cortex. [2] Dopamine (DA) activates the D1 and D2 receptors that increase the neuronal responses to glutamate (GLU). Serotonin activates 5-hydroxytryptamine (5-HT) receptors that facilitate the release of glutamate from synaptic terminals. Antipsychotic drugs block the facilitative effects of both dopamine and serotonin. Whereas, interneurons regulate the release of glutamate and thus the excitation of pyramidal neurons, through presynaptic inhibitory GABA receptors. Clozapine increases interneurons activity by increasing the release of acetylcholine (ACH), which activates interneurons and by blocking norepinephrine (NE) receptors, which decreases interneuron activity. [2] Pharmacological agents that cause psychosis, hallucinations or delirium by increasing the responses of pyramidal neurons in the verebral cortex to incoming stimuli are stimulant (cocaine, amphetamine), hallucinogenic (lysergic acid diethylamide), dissociative anesthetic (phencyclidine), and anticholinergic (atropine). Whereas, antipsychotic agents that decreases neuronal response in the cerebral cortex to incoming stimuli are first-generation (haloperidol), second-generation (olanzapine, risperidone, quetiapine, ziprasidone), clozapine, aripiprazole and amisulpride. [2] 8

2.2. Typical antipsychotics

Typical antipsychotics, which are also known as conventional or firstgeneration antipsychotic, work through dopamine receptor antagonism. The examples of typical antipsychotics are chlorpromazine (Thorazine), fluphenazine (Prolixin), haloperidol (Haldol), perphenazine (Trilafon), thiothixene (Navane), and trifluoperazine (Stelazine)[3]. Chlorpromazine was the first antipsychotic drug used to treat schizophrenia [2]. Its antipsychotic effects were identified incidentally, when it was tested as an antihistamine in subjects who happened to have schizophrenia. Only after that it was came to know the therapeutic mechanism for effectiveness of chlorpromazine in schizophrenia was by blocking the dopamine receptors. Moreover haloperidol are 100 times as potent as chlorpromazine as antipsychotic agents, but they also are more likely to have parkinsonian side effects [2]. This effect is caused by the dopamine blockage in the basal ganglia thus causing movement disorders like pseudoparkinsonism. In the beginning, administration of typical antipsychotic such as haloperidol and chlorpromazine in patients with schizophrenia resulted in an immediate blockage of dopamine D2 receptors and a partial antipsychotic effect. Complete remission of symptoms was only seen in about 20 percent of patients, whereas most patients had some response but also had continuing symptoms. After an episode of psychosis, continued treatment with antipsychotic agents significantly decreased the chance of relapse in patients. [2] Typical antipsychotics are associated with movement disorders, including tardive dyskinesia (TD) and extrapyramidal symptoms (EPS) which are akathisia (uncontrollable motor restlessness), dystonia (abnormal muscle tone), and pseudoparkinsonism (drug-induced syndrome resembling parkinsonism). [3] Tardive dyskinesia (choreoathetotic movement disorder) presents as abnormal orofacial movements, normally occur in patients on long-term typical antipsychotic drugs. Tardive dyskinesia cannot be treated with medication and it may be irreversible even after the offending antipsychotic is discontinued but

they can be manageable if patients use good dental hygiene to retain their own teeth [2]. Whereas, extrapyramidal symptoms can be treated. For instant akathisia which is caused by noncompliance with the drug regimen can be treated either by lowering the antipsychotic dosage or with benzodiazepines or centrally acting beta-blockers suzh as propranolol (20 to 80 mg per day). In addition, dystonia and pseudoparkinsonism can be treated with anticholinergic agents such as benztropine or diphenhydramine. [3] Other than extrapyramidal symptoms, there are also a few other side effects due to the usage of typical antipsychotic drugs. Elderly patients may be at increased risk of hip fractures as a result of drug associated movement disorders. Bradykinesia (decrease in spontaneous movement and slows down voluntary movement) mimics the effects of depression which can be treated with anticholinergic, antiparkinsonian drugs, such as benztropine (2 to 6 mg per day in divided doses). [2] Antipsychotic drugs can rarely cause death, but if it is to happen, there are several mechanism which can be blamed. Temperature dysregulation can lead to severe neuroleptic malignant syndrome, whereby the patients temperature exceeds 40 degree Celsius and brain death ensues. Neuroleptic malignant syndrome is treated by rapid cooling, and dantrolene can be administered to inhibit the release of calcium in muscle cells and thus attenuate the metabolic changed caused by the hyperthermia. [2] Table 1. Dosage for typical antipsychotic Drug Name Chlorpromazine (Thorazine) Fluphenazine (Prolixin) Haloperidol (Haldol) Perphenazine (Trilafon) Thiothixene (Navane) Trifluoperazine (Stelazine) 5 mg 2-5 mg 4-8 mg 4-10 mg 4-10 mg 5-20 mg 2-20 mg 16-64 mg 15-20 mg 5-20 mg 3 times daily 1-3 times daily 3 times daily 2-3 times daily twice daily Starting Daily Dose 50-100 mg Target Daily Dose or Range 300-1000 mg Schedule 3 times daily

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2.3. Atypical antipsychotic drugs

Atypical antipsychotic drugs are also known as the second-generations antipsychotics. It has been introduced into clinical practice over the past 15 years in attempt to improve therapeutic effects and decrease the side effects associated with first-generation dopamine-blocking drugs. As mentioned above, typical antipsychotic work primarily as dopamine-2 receptor antagonists, whereas in atypical antipsychotic drugs the mechanism is much wider [2]. Atypical antipsychotic drugs not only have an antagonistic effect on dopamine, but it also antagonizes norepinephrine and serotonin receptors [3]. Even though atypical antipsychotic drugs have the same D2 dopamine-receptor antagonism of the typical antipsychotic drugs, but they are less tightly bound to the D2 receptors since D2-receptor antogonism is no longer the sole therapeutic mechanism [2]. For example, aripiprazole has and unique mechanism of action involving mixed dopaminergic agonism and antagonism in addition to antagonism of serotonergic receptors [3]. Thus, in a general scope and time course of the effects, there are similarities between the typical antipsychotic drugs and the atypical antipsychotic drugs but there are clinically important differences in both the therapeutic effects and the side effects [2]. Aripiprazole (abilify), clozapine (clozaril), iloperidone (fanapt), olanzapine (zyprexa), paliperidone (invega), risperidone (risperdal), quetiapine IR (seroquel IR), quetiapine XR (seroquel XR) and ziprasidone (geodon) are the list of atypical antipsychotic drugs [3]. Due to the association of atypical antipsychotic drugs with serotonergic antagonism, there are no high rates of extrapyramidal symptoms, with the exception of aripiprazole, which causes akathisia in approximately 10 percent of patients [3]. Although atypical antipsychotic drugs dont usually cause extrapyramidal symptoms but they may come with a new risk, which can negatively affect the patients adherence. Clozapine is the first atypical antipsychotic drugs, which has obtained antipsychotic effects without the adverse effects on movement of the firstgeneration drugs. In addition it also has an enhanced therapeutic efficacy, as

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compared to the first-generation drugs. It has significant antagonist effects at D1, D2, D4 dopamine receptors, as well as at norepinephrine and serotonin receptors. Due to these reasons it was introduces into the clinical practice despite a serious known adverse effect (increased incidences of agranulocytosis). Patients on this particular drug had to be frequently monitored on their leukocytes count (weekly for the first six months and every two weeks thereafter, including the first four weeks after the patient has discontinued the drug). Moreover all antipsychotic drugs lower the threshold for seizure, this effect is more pronounced with clozapine. In addition, it also carries antocholinergic effects, hypersalivation, and myocarditis. Clozapine is usually used in patient who do not response to other treatment, as a last resort. The enhanced antipsychotic action of clozapine are similar in risperidone, olanzapine, quetiapine and ziprasidone. These drugs hace an efficacy that is equivalent to or exceeds the efficacy of first-generation antipsychotic agents, without many extrapyramidal effects of the first-generation drugs and it also has a greatly reduced risk of tardive dyskinesia. Moreover there is also a significantly less rate of relapse in patients taking second-generation drugs. Aripiprazole is characterized by mixed agonism and antagonism at dopamine receptors and in certain investigation it has been stated that the drug enhanced low levels of dopaminergic transmission, thus improving cognition, but blocked higher levels of transmission that might cause psychosis. At the same time it has also affected the serotonergic receptors. Whereas, amisulpride is an antagonist at D2 and D3 dopamine receptors. Risperidone and paliperidone are associated with hyperprolectinemia, leading to acute adverse events such as galactorrhea (spontaneous flow of milk from nipple), amenorrhea (absence of menses) and sexual dysfunction. Other than that there are also weight gain in long term usage of second-generation antipsychotic drugs. Due to this weight gain the incidences of diabetes mellitus has also increased and there are also cases of insulin resistances in certain patients. In few cases there have been life-threatening ketoacidosis and high cholesterol levels. Thus, amisulpride and ziprasidone at recommended doses cause less weight gain than do other antipsychotic drugs.

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Table 2. Dosage for atypical antipsychotic Drug Name Aripiprazole (Abilify) Clozapine (Clozaril) Iloperidone (Fanapt) Olanzapine (Zyprexa) Paliperidone (Invega) Risperidone (Risperdal) Quetiapine IR (Seroquel IR) Quetiapine IR (Seroquel XR) Ziprasidone (Geodon) Starting Daily Dose 10-15 mg 12.5-25 mg 2 mg 5-10 mg 6 mg 2 mg 50 mg 300 mg 40 mg Target Daily Dose or Schedule Range 10-15 mg 300-450 mg 12-24 mg 20 mg 6 mg 2-8 mg 300-400 mg 400-800 mg 40-160 mg Once daily 1-2 times daily Twice daily Once daily Once daily 1-2 times daily 2-3 times daily Once daily Twice daily, with food

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2.4. Similarities between typical and atypical antipsychotic drugs Other than the fact that both typical and atypical antipsychotic drugs have the same mechanism to the dopamine-receptor antagonism, they also share some other similarities. Both typical and atypical agents, especially haloperidol, chlorpromazine, iloperidone, thioridazine, and ziprasidone, are associated with prolongation of the QTc interval, although thioridazine and ziprasidone have the highest incidences rate. There have been not much published literature clamming that atypical antipsychotic drugs are more or less efficient than typical antipsychotic drugs. Improvement in cognitive function has been seen in both the agents, but atypical agents show a higher percentage of improvement on neuropsychological tests of cognitive function, particularly in assessments of attention and short-term memory. Whereas the percentage in typical agents arent that high compared to atypical agents.

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2.5. Other medications Although antipsychotic remains as the primary pharmacological treatment in schizophrenia patients, there are a number of other medications that may be used as an alternative. These alternative drugs are commonly known as mood stabilizers, which are often used in patients that are experiencing increased agitation or aggression. Even though schizophrenia patients are not violent, but sometimes during an episode in which positive symptoms are exacerbated may lead to increased agitation. During this period of time mood stabilizers come in very handy Benzodiazepines have been studied for their benefits in augmenting antipsychotics. The studies done are in a very small number but they have shown some advantage over antipsychotic monotherapy in treating agitation on schizophrenia. But this effect is short-lived, since the symptoms return within 1 hour of a benzodiazepine dose.

Algorithm for treatment of schizophrenia Stage 1 : Atypical antipsychotic Stage 2 : Atypical or typical antipsychotic Not the same atypical antipsychotic drug from stage 1 Stage 3 : Clozapine May try earlier if history of recurrent suicidal, violence, or substances abuse Stage 4 : Clozapine plus Typical or atypical antipsychotic or ECT Stage 5 : Trial of single atypical or typical agent not tried in stage 1 and 2 Stage 6 : Combination therapy, such as atypical plus typical antipsychotic; Combination of atypical and/or typical agent plus ECT; Combination of atypical antipsychotic plus mood stabilizer

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2.6. Treatment guidelines Since schizophrenia is a unique disorder, the treatment of it needs experience differential diagnosis of mental disorders and in assessing the patients potential for suicide or violence. To provide optimal management for these patients, physicians have to look at all aspects such as, psychological, social and occupational therapies. Evidence-based recommendations are guidelines for psychopharmacological treatment of schizophrenia are regarded as important tools to improve the quality of clinical treatment, to guide decision-making and to reduce inappropriate variations in clinical practice [5]. The guidelines are intended to offer a more rational treatment strategy and thereby optimizing the therapeutic efficacy and reduce side effects. When a person has his or her first psychotic episode, immediate treatment improves his or her long-term outcome and does not obscure the later differential diagnosis. As mention above, the usual features of schizophrenia are hallucinations or delusions, or both, and they are usually accompanied by anxiety, behavioral withdrawal, anger and suicidal thoughts. In most cases, patients are treated with second-generation antipsychotic in divided doses. Within the first day or the second, slight improvement can be observed such as less sleep disturbances, decrease in anger and gradual improvement in other symptoms by a few weeks time. After a patient has been given antipsychotic drug, if they lack in improvement in the first one to four weeks, then the dosage of the drugs should be increased. If that fails then a change to another drug, usually clozapine or another second-generation drug. In schizophrenia patients, maintaining the treatment is very important to prevent relapse. After the first episode has resolved, continued treatment for at least one year should be maintained and reevaluated. It is also very important for physicians to know that clozapine is not the first-line drug due to the possibility of agranulocytosis. Clozapine should only be used on patients who has inadequate response to other second-generations or first-generation antipsychotic drugs and on those who are unable to tolerate side effects, such as akathisia, of other antipsychotic agents.

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Additionally, it is noted that the total daily dose of most antipsychotics can be administered once daily is tolerated, and this will improve adherence. Meanwhile, clozapine, quetiapine, and ziprasidone, which probably will require multiple daily doses to control symptoms. Finally, treatment with multiple antipsychotics should be considered a last resort and avoided if at all possible, as it often provides no additional efficacy and increases the risk of intolerable side effects.

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2.6. The choice of an antipsychotic drug All antipsychotic drugs are effective for positive symptoms of acute psychosis. Second-generation drugs are preferred because of their greater effects on negative symptoms and cognitive function and because they are associated with a lower rate of relapse and a lower incidence of movement disorders. First-generation antipsychotic agents administered as a depot injection, despite the risk of tardive dyskinesia, remain the optimal therapy for patients who have relapse because of poor adherence to a regimen of oral medication. Similarly, when patients have no responses to other antipsychotic drugs, it is necessary to choose clozapine despite its potentially fatal side effects, such as agranulocytosis and myocarditis. In addition, clozapine is associated with the decrease in suicidal incidences, if so the increase in agranulocytosis and myocarditis might be compensated for by the decrease in mortality from suicide, which make clozapine more freely to be prescribed. Whereas in some patients weight gain due to the antipsychotic drugs might be a factor of not choosing that drug because it might lead to diabetes mellitus. Due to that for patients with the development of diabetes are normally switched to ziprasidone as an alternative.

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CHAPTER 3 : CONCLUSION

Despite the fact that there is no cure for schizophrenia, providing patients with guideline-based treatments supported by primary literature will afford the best opportunity for controlling the symptoms of their illness. The process of choosing appropriate medications and monitoring for appropriate adverse reactions should be facilitated by the pharmacist whenever possible. Although psychosocial interventions are an important adjunctive treatment, antipsychotic medications continue to be the mainstay of treatment. careful monitoring of metabolic side effects and age-appropriate intervention is particularly important. Treatments for schizophrenia that are effective in reducing symptoms and improving overall function are currently available. However, these treatments, in particular antipsychotics, have side effects profiles that are concerning and require further investigation of immediate and long-term impact on health.

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References 1. Howard H. Golman, MD, MPH, PhD. Review of General Psychiatry. 5th ed. United States: McGraw-Hill. 2000. p 244-248 2. Robert Freedman, M.D. Schizophrenia [cited 2003 October]. Available from : http://www.nejm.org/doi/pdf/10.1056/NEJMra035458 3. Stacy Eon, PharmD; Jennifer Durham, PharmD. Schizophrenia: A Review of Pharmacological and Nonpharmacological Treatments [cited 2010 January]. Available from : http://www.medscape.com/viewarticle/713596_2 4. Anand K. Mattai; Julia L. Hill; Rhoshel K. Lenroot. Treatment of Earlyonset Schizophrenia [cited 2010 July]. Available from : http://www.medscape.com/viewarticle/723660 5. Albert Bolstad; Ole A Andreassen; Jan I RAssberg; Ingrid Melle; Lars Tanum. Previous Hospital Admissions and Disease Severity Predict the Use of Antipsychotic Combination Treatment in Patients With Schizophrenia [cited 2011 November]. Available from : http://www.medscape.com/viewarticle/751654

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