Providing an overview of antipsychotic drugs: is schizophrenia a psychiatric challenge?

Providing an overview of antipsychotic drugs: is schizophrenia a psychiatric challenge? Abstract Natalie Schellack, BCur, BPharm, PhD(Pharmacy), Senior Lecturer Moliehi Matlala, BPharm, MSc(Med) Pharmacy, Senior Lecturer Department of Pharmacy, Faculty of Health Sciences, University of Limpopo (Medunsa Campus) Correspondence to: Natalie Schellack, e-mail: natalie.schellack@ul.ac.za Keywords: antipsychotic drugs, first-generation antipsychotic drugs, second-generation antipsychotic drugs, schizophrenia Psychosis is an umbrella term used in the description of various conditions that involve delusions and hallucinations. This article will focus on the management of schizophrenia. Schizophrenia is a complex disorder, which provides many pharmacotherapy-related challenges. Advances have been made in the treatment of the condition. However, this requires a team approach, with the pharmacist monitoring treatment, both for safety and efficacy. The involvement of medicines that might possibly modulate the N-methyl- D-aspartate receptors is an exciting development that should be monitored. Medpharm S Afr Pharm J 2014;81(4):28-33 Introduction Psychosis has various definitions. The most basic definition of a psychotic episode refers to delusions and prominent hallucinations, with the hallucinations occurring without the affected patient being aware of their pathological nature. Some definitions include the positive symptoms experienced in schizophrenia, e.g. disorganised speech, gross behavioural disorganisation, or the display of catatonic behaviour. The term psychotic also differs in schizophrenia, schizophreniform disorder, schizoaffective disorder, brief psychotic disorder and a psychotic disorder due to a general medical condition, or a substance-induced psychotic disorder, whereby the term refers to delusions or hallucinations unaccompanied by insight. 1 Schizophrenia is described as a mental disturbance of a minimum of six months duration, and includes at least a month of active Acute phase A worsening of signs and symptoms Patient seeks or is referred for medical attention Stabilisation phase The illness subsides after an acute episode Stable or chronic phase The acute symptoms subside Function is impaired phase symptoms: hallucinations, delusions, disorganised speech, disorganised behaviour and negative symptoms. 1 Three stages of schizophrenia are identified in the evolvement of the condition, and are of importance to the pharmacist when managing or evaluating treatment (Figure 1). 2 Neurotransmitter involvement Dopamine involvement The hypothesis that dopamine is involved in schizophrenia derives from two ideas: 3 Dopamine hypothesis involved in antipsychotic action: The dopamine D2 (D 2 ) receptors have shown increased densities in the caudate nucleus and decreased densities in the prefrontal cortex. The overactivity of these receptors in the mesolimbic part of the brain provides for the explanation of positive symptoms. These receptors provide the mechanistic basis for antipsychotic action when blocking these receptors. Decreased activity in the mesocortical dopaminergic pathway: It has been shown through neuroimaging studies that there is decreased D 1- receptor activity in the mesocortical dopamine pathway in patients diagnosed with schizophrenia and suffering from psychosis. To manage schizophrenia pharmacologically, the dopaminergic transmission has to be inhibited in the limbic pathway, and simultaneously enhanced in the prefrontal cortex. This makes the management of schizophrenia challenging. Figure 1: The evolvement of schizophrenia S Afr Pharm J 28

N-methyl-D-aspartate and glutamate Glutaminergic and gamma-aminobutyric acidergic neurons play an important role in controlling neuronal activity in the mesolimbic pathways, when there is also dopaminergic activity. 4 It is for this reason that the glutamate synapse has received widespread attention as an important target for pharmacological action. 4 The synapse is target rich as it contains a large number of presynaptic, postsynaptic and regulatory proteins that may be used in drug therapy to treat symptoms refractory to other drug therapy. 4 It has been postulated that some of the negative symptoms seen in schizophrenia might be due to a disruption in glutamate transmission at the N-methyl-D-aspartate (NMDA) receptors, because of the functional abnormality of these receptors. 4 Drug development for the management of schizophrenia might be steered towards the development of agents that enhance the function of the NMDA receptor by activating the glycine site. 4 Serotonin Serotonin does not seem to play a direct role in the pathogenesis of schizophrenia. However, the receptors are present on the dopaminergic axons. 5,6 Stimulation of these receptors decreases dopamine release, especially in the striatum. 5,6 Dugs with combined D 2 antagonistic effects and 5-hydroxytryptamine (5-HT) receptor activity have improved therapeutic effects, and will be discussed in more detail. 5,6 Management of psychosis Baseline investigations prior to the initiation of therapy All antipsychotic agents, to varying degrees, increase body weight. Some second-generation antipsychotic agents elevate lipid levels. 7 Some first-generation antipsychotic agents produce agranulocytosis (clozapine). 7 It is for this reason that patients undergo baseline investigations prior to the initiation of antipsychotic agents, including: 7 Body mass index, especially for olanzapine Waist-to-hip ratio Fasting blood glucose Liver function tests White cell count, especially acute neutrophil count, and particularly for clozapine An electrocardiogram. These baseline investigations can be modified according to the regimen on which the patient is going to be initiated, or if there is a change thereto. The pharmacist can assist in monitoring the side-effect profile. Pharmacological management Pharmacological treatment is the cornerstone and essential component of treatment, while psychosocial interventions are crucial in promoting recovery and improving the quality of life of patients with schizophrenia, as well as its clinical management through the different stages of the patient s illness. 7,8 Receptor Profile Efficacy in the treatmentresistant groups, and specifically clozapine Classification of antipsychotic agents Figure 2: The distinction between first- and second-generation antipsychotic agents 5,7 Monotherapy is recommended. There is no advantage to combining antipsychotics, which should only be performed for short periods when switching agents, or in the treatment-resistant setting. 7 Medication must be individualised as individual response is highly variable. The patient s immediate presenting problem must be considered first, as well as his or her prior response to pharmacotherapy, including efficacy and side-effects. Elderly patients and those experiencing their first episode of psychosis require lower doses. 7,8 Schizophrenia is managed by typical first-generation, or atypical second-generation, antipsychotic agents. Second-generation antipsychotic agents are increasingly replacing first-generation antipsychotic agents as first-line treatment. 2,7 The classification of and distinction between first- and secondgeneration antipsychotic agents is detailed in Figure 2. 5,7 First-generation antipsychotic agents First-generation antipsychotic agents are antagonists at the D 2 receptors in the mesocortex and limbic system, and are more selective to D 1, D 4 and the erotonin receptors than D 2. Firstgeneration antipsychotic agents inhibit the dopamine receptors in the nigrostriatal pathway, and have an inhibitory effect on the histaminic and muscarinic receptors, giving rise to characteristic extrapyramidal side-effects (EPS). 8 There is a strong correlation between the therapeutic doses of these drugs and their binding affinity to the D 2 receptor site. 8 Classification of first-generation antipsychotics Incidence of extrapyramidal side-effects (less with the second-generation antipsychotic agents) Efficacy against negative symptoms Phenothiazine derivatives: Chlorpromazine is the prototype for this group. Phenothiazine derivatives have antihistaminic, anticholinergic, antidopaminergic and adrenolytic properties. 9,10 The least potent of the group are the aliphatic derivatives (chlorpromazine) and piperadine derivatives (thioridazine). Piperazine derivatives are more potent (effective in lower doses), but are not necessarily more efficacious. 9,10 Butyrophenones: Haloperidol is an example. It is a potent neuroleptic agent. Butyrophenones largely lack antihistaminic, S Afr Pharm J 29

Table I: Recommended daily, maximum doses of typical first-generation antipsychotic agents, and the side-effects and management thereof 11 Name Brand name Usual dose Maximum dose Indications Side-effects Chlorpromazine Largactil 75-300 mg 1 000 mg Schizophrenia, intractable hiccups, and to reduce the manic phase of manic depressive disorders Postural hypotension, especially in the elderly, and anticholinergic effects Haloperidol Serenace 1.5-15 mg 20 mg Schizophrenia and secondary psychosis Oligomenorrhea or amenorrhea, and EPS Haloperidol decanoate Flupenthixol decanoate Fluphenazine decoanate Haloperidol LA 50 mg 300 mg Tourette s syndrome Orthostatic hypotension and seizures (rare) Fluanxol 40 mg 400 mg Mild to moderate depression, with or without anxiety Modecate 12.5 mg 100 mg Psychotic disorders, especially schizophrenia Zuclopenthixol Clopixol 200 mg 600 mg Schizophrenia, including agitation, psychomotor disturbances, hostility, being suspicious and aggressive, and affective reactions Sulpiride Eglonyl 200-800 mg 2400 mg Acute schizophrenic episodes, and the prevention of relapse in chronic cases Pimozide Orap 2-20 mg 20 mg Maintenance treatment of patients with chronic schizophrenia who respond to the anti-hallucinatory and anti-delusional effects of classical neuroleptics, but who do not need, or are handicapped by, the hyposedative action of such neuroleptics EPS: extrapyramidal side-effects Insomnia Blood dyscrasias Insomnia Fatigue, weight gain and erectile dysfunction Anorexia, akinesia, EPS, sedation, visual disturbance, constipation and a dry mouth anticholinergic and adrenolytic activity. They are also nonsedative in therapeutic doses, but have greater EPS than phenothiazines. 9,10 Haloperidol is the most widely used typical antipsychotic medicine. 9,10 Benzamides: Amisulpride, a substituted benzamide analogue of sulpiride, is a highly selective antagonist of the D 2 and D 3 receptors, with little affinity for D 1 -like or non-dopaminergic receptors. 8 First-generation antipsychotic agents differ in potency, not effectiveness, as per the following example: 10 High potency: Haloperidol and flufenazine Mild potency: Perphenazine and loxapine Low potency: Chlorpromazine. Table I provides an overview of the first-generation medicines used in the management of schizophrenia. Second-generation antipsychotic agents There are two theories on the mechanism of action of secondgeneration antipsychotic agents: the serotonin-dopamine (S 2 / D 2 ) antagonist theory and the fast-off D 2 theory. The S 2 /D 2 theory suggests that a second-generation antipsychotic agent has a higher affinity for the serotonin 5-HT 2A receptor relative to dopamine D 2. The fast-off D 2 theory suggests that a secondgeneration antipsychotic agent cannot function without some degree of binding to the D 2 receptor, but that dissociation from the D 2 receptor quickly makes the antipsychotic agent more accommodating to physiological dopamine transmission. 8-10 Generally, second-generation antipsychotic agents have a lower risk of EPS and tardive dyskinesia than first-generation antipsychotic agents, but they may be associated with higher rates of weight gain and metabolic disorders. 7 Table II provides an overview of the second-generation antipsychotic agents used in the management of schizophrenia. 11 General management principles in schizophrenia Second-generation antipsychotics agents, excluding clozapine, have become agents of choice when treating first-time episodes or younger patients owing to their lack of EPS and tardive dyskinesia, which are commonly experienced by this group of patients. 7,11 Monotherapy is recommended as there is no advantage to combining antipsychotic agents. 7 Respiridone, amisulpiride, olanzapine, quetiapine, aripiprazole, and ziprazidone are effective agents in the treatment of a first episode in patients with psychosis. When the response to the first-line agent is unsatisfactory, another second-generation antipsychotic agent can be considered, or alternatively a change can be made to a first-generation antipsychotic agent. The second agent should be tried for 4-6 weeks before third-line treatment is considered. 7 Clozapine is commonly recommended in the treatment of patients who are inadequately controlled following trials with two different classes of antipsychotic agents, or who display consistent aggression or persistent suicidal thoughts or behaviour. 2,5,10 However, the main safety concerns for clozapine are agranulocytosis, myocarditis and diabetes. 2 S Afr Pharm J 30

Table II: Recommended daily, maximum doses of second-generation antipsychotic agents, and their side-effects and the management thereof 11 Name Brand name Usual dose Maximum dose Indications Side-effects Amisulpiride Solian 400-800 mg 1 200 mg Acute and chronic schizophrenia Neuroleptic malignancy syndrome Aripiprazole Abilify 10-30 mg 30 mg Schizophrenia and bipolar mania Weight gain, anxiety, insomnia and headaches Clozapine Clozaril 200-450 mg 900 mg Schizophrenia Agranulocytosis, weight gain and hypotension Olanzapine Zyprexa 10-20 mg 20 mg Managing the manifestations of psychotic disorders, and preventing the recurrence of manic episodes of bipolar disorder Risperidone Risperdal 4-6 mg 16 mg Acute and chronic schizophrenia, and conduct and disruptive behaviour disorders in children aged 5-12 years Quetiapine Seroquel 300-450 mg 750 mg Bipolar mood disorder associated with mania and schizophrenia Ziprazidone Geodon 80 mg 160 mg Acute exacerbation and maintenance of clinical improvement during continuation therapy in schizophrenia Paliperidone Invenga t available in South Africa Asenapine Saphris iloperidone Fanapt EPS: extrapyramidal side-effects Bradycardia, xerostomia, weight gain (dose dependent), hypercholesterolaemia, EPS (dose dependent), hyperglycaemia and weakness Angio-oedema, body temperature dysregulation, hyperprolactinaemia in children and insomnia Abdominal, back, chest or ear pain, a dry mouth and somnolence Headaches, nausea, EPS, and generalised tonic-clonic seizures Clozapine is used as third-line therapy at the highest tolerable dose (< 900 mg daily) for six months. Switching requires tapering and stopping the previous agent before the initiation of clozapine, to reduce the risk of haematological side-effects. 7,11 Various adjunctive treatments, including benzodiazepines, lithium, anticonvulsant and antidepressant drugs, beta blockers and dopamine agonists, have been used to enhance the response to antipsychotic medication, or to treat the residual symptoms of chronic schizophrenia and co-morbid conditions associated with schizophrenia. 8 Studies performed to determine the efficacy and effectiveness of first-generation antipsychotic agents versus second-generation antipsychotic agent have delivered conflicting results. However, a lower incidence of EPS with second-generation antipsychotic agent weight gain is a significant problem with these agents. 6 Drugs from both groups are equally effective in treating psychosis. The second-generation antipsychotic agents provide greater treatment results in the management of negative symptoms. 7 The choice of drug is then determined by: 7 Availability and accessibility of the drug Shared patient-centred decision-making Previous experience (efficacy and side-effects) Tailoring the side-effect profile to meet the needs of the patient Choice of the mode of administration (oral or parenteral). The pharmacist can greatly assist in finding the right choice of drug for the patient. Figure 3 provides a treatment algorithm for the management of schizophrenia. 7 Conclusion Schizophrenia is a complex disorder and many aetiologies play a role therein. Management of the patient requires a multidisciplinary team, with each member of the team contributing to best-care management of the patient. Side-effect profiles differ between the two groups of antipsychotic agents. The decision as to which drug to use in the patient should involve patient characteristics, as well as the active involvement of the patient. Pharmacotherapy should be monitored with each patient visit according to the safety and efficacy of the drug in the patient. References 1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4 th ed. Washington: American Psychiatric Association; 2000. 2. Canadian Psychiatric Association. Clinical practice guidelines: treatment of schizophrenia. Can J Psychiatry. 2005;50(13 Supplement 1):7S-57S. 3. Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology and pharmacology in schizophrenia. Am J Psychiatry: 2003;160(1):13-23. 4. Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012;37(1):4-15. 5. Rang HP, Dale MM, Ritter JM, et al. Rang and Dale s pharmacology. 7 th ed. Edinburgh: Elsevier Churchill Livingstone; 2012. 6. Crismon LM, Argo TR, Buckley PF. Schizophrenia. In: DiPiro JT, editor. Pharmacotherapy: a pathophysiologic approach. 7 th ed. New York: The McGraw Hill Companies; 2008. 7. Swingler D. The South African Society of Psychiatrists (SASOP) treatment guidelines for psychiatric disorder: schizophrenia. South African Journal of Psychiatry. 2013;19(3). SAJP [homepage on the Internet]. Available from: http://www.sajp.org.za/index.php/sajp/article/viewfile/474/430 8. Miyamoto S, Duncan GE, Max CE, et al. Treatment for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005;10(1):79-104. 9. Leonard BE, editor. Drug treatment of schizophrenia and the psychoses. Fundamentals of psychopharmacology. 3 rd ed. New York: John Wiley & Sons; 2003. 10. Brenner G M, Stevens C. Pharmacology. 3 rd ed. Philadelphia: Saunders Elsevier; 2010. 11. South African medicines formulary. 9 th ed. Cape Town: Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town; 2012. S Afr Pharm J 32

Diagnosis using DSM-IV-TR History and examination Special investigations: Bedside, serology and drug screening First episode Oral monotherapy: SGAs: RIS, OLA, QUE, ARI, ZIP and AMI Lower dose in the range of 300-100 mg CPZ/E 4-6 weeks Multiple episodes or a relapse Oral monotherapy SGAs, RIS, QUE, ARI and AMI Or FGAs, HAL and CPZ Dose in the range of 300-1 000 mg CPZ/E 4-6 weeks BZD as required Poor response review Diagnosis correct? Drug trial of an adequate dose and duration? Adequate psychosocial interventions? Co-morbidities assessed and managed? Second-line (4-6 weeks) Oral monotherapy Second SGAs: RIS, OLA, QUE, ARI, ZIP and AMI Or FGAs: HAL, and CPZ only if failed first line was an SGA Dose in the range of 300-1 000 mg CPZ/E Third-line Oral CLO up to 900 mg daily WCC monitoring Seizure caution > 450 mg daily Fourth-line Combine CLO with a SGA Augment CLO with a mood stabiliser (LAM, VAL and Li) ECT (earlier in certain clinical situations) Maintenance AMI: amisulpiride, ARI: ariprazole, BZP: benzodiazepines, CLO: clozapine, CPZ: chlorpromazine, CPZ/E: chlorpromazine equivalents, DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ECT: electroconvulsive therapy, FGAs: first-generation antipsychotic agents, HAL: haloperidol, LAM: lamotrigine, Li: lithium, OLA: olanzapine, QUE: quetiapine, RIS: risperidone, SGAs: second-generation antipsychotic agents, VAL: valproate, WCC: white cell count, ZIP: ziprasidone Figure 3: Treatment algorithm S Afr Pharm J 33