Classical versus atypical antipsychotics

DETAILED COMPARISON OF TYPICAL AND ATYPICAL ANTIPSYCHOTICS. COMPARED ON SIDE EEFECTS

1. TYPICAL VERSUS ATYPICAL ANTIPSYCHOTICS AKHIL JOSEPH PHARM.D 5 TH YEAR.

2. ANTIPSYCHOTICS First-generation antipsychotics, known as typical antipsychotics, were discovered in the 1950s. Chlorpromazine is the first Antipsychotic agent. It was synthesized by a French pharmaceutical company Rhône-Poulenc in 1951. Most second-generation drugs, known as atypical antipsychotics, have been developed more recently, although the first atypical antipsychotic,  Clozapine , was discovered in 1958 and introduced clinically in the 1970s. Clozapine was synthesized by Wander AG, a Swiss pharmaceutical company.

3. CHLORPROMAZINE CLOZAPINE (TYPICAL PROTOTYPE) (ATYPICAL PROTOTYPE) C 18 H 19 ClN 4 C 17 H 19 ClN 2 S PHENOTHIAZINE DIBENZODIAZEPINE

4. TYPICAL ANTIPSYCHOTICS Mechanism of action : The antipsychotic effect of these medications is primarily mediated through the blockade of dopamine receptors (D2 antagonists). Potency: Typical antipsychotic agents are classified by their potency for the dopamine receptor into high and low-potency antipsychotics. Low potency AP have low affinity for dopamine receptor thus low EPS. Efficacy : When dosed in equivalent doses, the various typical antipsychotics have similar efficacy. Equivalent doses are described using chlorpromazine (CPZ) equivalents . Typical antipsychotics are thought to be as effective as atypical antipsychotics for positive symptoms but are less effective for negative symptoms. ATYPICAL ANTIPSYCHOTICS The mechanism of action : The atypical antipsychotics are dopamine antagonists but also block 5-HT2A-receptors. They block 5-HT to a greater extent than dopamine. D2 partial agonist. Potency : All atypical antipsychotics have activity at the 5-HT2A-receptor and dopamine receptor. Different agents have different activity for histamine, α-, and muscarinic receptors. Efficacy : Atypical antipsychotics have increased efficacy for negative symptoms compared to typical antipsychotics. With the exception of clozapine, all antipsychotics are thought to have similar efficacy for positive symptoms. Clozapine has demonstrated efficacy for treatment-resistant schizophrenia.

5. PHARMACOKINETICS DRUG BIOAVAILABILITY (%) HALF LIFE (H) METABOLISM TYPICAL Chlorpromazine 10–30 8–35 CYP 3A4 Fluphenazine 20–50 14–24 CYP 2D6 Haloperidol 40–70 12–36 CYP 1A2, 2D6, 3A4 ATYPICAL Aripiprazole 87 48–68 CYP 3A4 Clozapine 12–81 11–105 CYP 3A4 Olanzapine 80 20–70 CYP 3A4 Quetiapine 9±4 6.88 CYP 3A4 Risperidone 68 3–24 CYP 2D6

6. General Adverse Effects of Antipsychotics Typical Antipsychotics Atypical Antipsychotics Sedation Sedation Anticholinergic effects Blurred vision Constipation Dry mouth Urinary retention Anticholinergic effects (clozapine, olanzapine) Orthostatic hypotension Moderate to severe weight gain Diabetes mellitus Hypercholesterolemia Extrapyramidal symptoms Extrapyramidal symptoms Lowered seizure threshold Lowered seizure threshold QT prolongation QT prolongation Hyperprolactinemia Hyperprolactinemia (risperidone) Moderate weight gain Extrapyramidal symptoms Sexual dysfunction Sexual dysfunction Neuroleptic malignant syndrome Neuroleptic malignant syndrome Photosensitivity Temperature dysregulation Elevated liver enzymes Orthostatic hypotension

7. Atypical : high rate of metabolic side effects. Typical : high rate of neurologic side effects. Hence variety of antipsychotics are available, using an alternative drug should be considered if patient complains of poor tolerability and side effects. Because medication side effects are the main reason for patient non-adherence.

8. ENDOCRINE SYSTEM TYPICAL GALACTORRHEA – 57% AMENORRHEA OR IRREGULAR MENSTRUAL CYCLE – 97% HYPERPROLACTINEMIA (D2 blockade in tuberoinfundibular tract) GYNECOMASTIA These effects are also seen with RISPERIDONE (atypical) Switching to atypical Quetiapine, Ziprasidone or Aripiprazole is the alternative choice. ATYPICAL WEIGHT GAIN – 40% patient taking CLOZAPINE / OLANZAPINE have significant weight gain ( blockade of 5HT2C receptor ). Risperidone and quetiapine also causes weight gain but low as compared to above. Weight gain (obesity) increase the risk of Cardiovascular diseases and DM, as well as is the reason for poor adherence. DIABETES – CLOZAPINE have 52% rate of onset. Switching to Quetiapine, Ziprasidone or Aripiprazole is less likely to cause weight gain.

9. CARDIOVASCULAR SYSTEM ORTHOSTATIC HYPOTENSION – 20mmHg drop in systolic pressure that causes syncope. Seen in low potency- typicals and atypicals , especially on IM & IV administration. High risk in patient with pre-existing cardiovascular diseases and DM. ECG CHANGES : In both typicals and atypicals . Thioridazine, Mesoridazine , Clozapine and Ziprasideone are most likely to cause ECG changes, it include increase in HR, flattened T wave, QT and PR interval prolongation. QT PROLONGATION : associated with ventricular arrhythmia including torsades de point syndrome. Thioridazine (20ms) & Ziprasidone (10ms). Its longer than haloperidol, risperidone, olanzapine and quetiapine.

10. LIPID CHANGES TYPICALS ( phenothiazines ) and ATYPICALS ( olanzapine & clozapine ) – elevation in serum TRIGLYCERIDES & CHOLESTEROL. Low risk of dyslipidemia in Aripiprazole, Ziprasidone and Risperidone. High risk for development of Metabolic Syndrome in ATYPICALS. TGL > 150mg/dl. HDL < 40mg/dl. FBS > 100mg/dl. BP > 135/85mmHg. AG > 102 cm in men. > 88 cm in women.

11. Patients receiving antipsychotics, or antipsychotics in combination with anticholinergics, may experience anticholinergic side effects (e.g., dry mouth, constipation, tachycardia, blurred vision, inhibition or impairment of ejaculation, urinary retention, or impaired memory). Particularly seen with low-potency typicals ( thioridazine and chlorpromazine ) among the elderly. Among the atypicals , clozapine and olanzapine have moderately high rates of anticholinergic effects. AUTONOMIC NERVOUS SYSTEM

12. CENTRAL NERVOUS SYSTEM EXTRAPYRAMIDAL SYSTEM DYSTONIA – a state of abnormal tonicity. Occurs primarily with Typical antipsychotics. High risk in males and with increase in dose. Usually occurs within 24-96 hours of dosage initiation or dose increase. Incidence rate is 64% with high potency antipsychotics, can be minimised by using low dose initiation. Risk is highly reduced with atypiclas . Olanzapine and Ziprasidone inj. gives rapid action with low risk of Dystonia. Anticholinergics can be used to treat dystonia – diphenhydramine 50mg IM/IV.

13. AKATHISIA – it’s the inability to sit still and being functionally motor restless. Occurs in 20-40% patients treated with high potency typical antipsychotics. Reduction in typical antipsychotics dosage is the best intervention or switching to an atypical antipsychotic. Akathisia may occur ocassionally with Atypical antipsychotics and is the most common EPS like symptom reported with atypical. Quetiapine and Clozapine have lowest risk of producing akathisia.

14. PSEUDOPARKINSONISM – akinesia. Bradykinesia, cogwheel rigidity, postural abnormalities. Occurs due to D2 blockade in nigrostriatum The incidence of pseudoparkinsonism from FGAs ranges from 15.4% to 36%. Akinesia alone can be seen in 59% of patients on high-potency FGAs. The onset of symptoms is typically 1 to 2 weeks after initiation of antipsychotic therapy or a dose increase. The risk of pseudoparkinsonism with SGAs is extremely low. When risperidone is used in doses greater than 6 mg/day, the risk of pseudoparkinsonism symptoms approaches that with FGAs. Quetiapine, aripiprazole, or clozapine are reasonable alternatives in a patient experiencing EPS with other SGAs.

15. TARDIVE DYSKINESIA – abnormal involuntary movements occuring late in onset to initiation of antipsychotic therapy. Classical description is Buccolingual Masticatory Syndrome (BLM). Late in onset in initiation to antipsychotics therapy. With FGA’s incidence rate is 0.5-63%. In elderly overall risk with 3 year FGA’s treatment, the prevalence is 53%. Risk with SGA’s is extremely low. SGA’s treatment lasting more than 1 year – risk is 0.8% / year in adult and 5.3% in elderly. Olanzapine – 0 - 0.5% incidence rate. Risperidone & Quetiapine – 0.6 -0.7% incidence rate. Prevention of TD is important.

16. SEDATION AND COGNITION Sedation is a common side effect in both Typical and Atypical Antipsychotics. Several studies shows that SGA’s have cognitive benefits over FGA’s. THERMOREGULATION Thermoregulatory problems are reportedly more common with use of low-potency FGA’s and may also occur with more anticholinergic SGA’s. Poikilothermia is important. Hyperpyrexia can be dangerous in extreme hot weather. Reduced sweating due to anticholinergic effect also causes elevated body temp.

17. SEIZURES Antipsychotics lower seizure threshold by GABA depletion. Increased risk of Seizures in Antipsychotic treatment in both FGA’s and SGA’s. Usually with high dose, upon initiation and rapid dose increase. When seizure occurs Rapid reduction in dose is recommended. High risk with clozapine and chlorpromazine, if change is required then Risperidone, Haloperidol and Fluphenazine is associated with lowest potential.

18. NEUROLEPTIC MALIGNANT SYNDROME ( NMS ) NMS is a life threatening reaction that occurs mainly with antipsychotic medication. Include symptoms like high fever, confusion, rigid muscles, variable BP, increased HR, sweating. NMS occur in 0.5 to 1% of patients receiving FGA’s. High incidence with high-potency, injectable / depot FGA’s. More commonly seen with Haloperidol and Chlorpromazine. Although less common than FGA’s NMS is also seen with SGA’s including Clozapine. Onset is 24-72 hrs. Also seen when Depot FGA’s are discontinued. Only SGA’s should be used for rechallenge following an episode of NMS. PSYCHIATRIC SIDE EFFECTS Delirium and Psychosis are reported with larger doses of FGA’s or combination of anticholinergics with FGA’s.

19. HEPATIC SYSTEM Cholestatic hepatocanalicular jaundice has been reported in up to 2% of patients receiving phenothiazines. LFT abnormalities ( ELEVATED AST, ALT & ALP ), often asymptomatic, were reported in up to 50% of patients. LFT abnormalities are uncommon with SGAs. Cholestatic hepatitis has been reported with risperidone and LFT abnormalities, mostly transient, have been reported to be more frequent with clozapine than haloperidol.

20. GENITOURINARY SYSTEM Urinary hesitancy and retention is reported with low-potency FGAs and with clozapine. Urinary incontinence among the SGAs ( due to alpha-blockade ), it appears to be particularly problematic with clozapine . The incidence has been reported to be as high as 44%, and it may be persistent in 25% of patients. Risperidone produces at least as much sexual dysfunction as FGAs, other SGAs, which have weak effects on prolactin or are “prolactin-sparing,” produce less sexual dysfunction.

21. HEMATOLOGIC SYSTEM Agranulocytosis reportedly occurs in 0.01% of patients receiving FGAs, and more frequently with chlorpromazine and thioridazine. The onset is usually within the first 8 weeks of therapy. In SGA’s Clozapine has 0.8% risk of developing Agranulocytosis in 1 year treatment. In 18 months treatment the risk is 0.91%. Agranulocytosis with clozapine significantly limits the clinical utility of this agent. Increasing age and female gender are associated with greater risk.

22. DERMATOLOGIC SYSTEM Allergic reactions are rare and usually occur within 8 weeks of initiating therapy. Both SGAs and FGAs cause photo sensitivity. Erythema and severe sun burns can occur. MISCELLANEOUS ADVERSE EFFECTS Sialorrhea - which may occur in up to 54% of patients taking clozapine.

23. USE IN PREGNANCY AND LACTATION Epidemiologic studies show a slightly increased risk of birth defects with low-potency FGAs. Haloperidol is the best studied of all antipsychotics, and no relationship between its use and teratogenicity has been found, But is found excreted greatly through breast milk. 30mg/day for 6 days – 5ng/ml of haloperidol concentration in breast milk. In SGA’s - use of clozapine in pregnancy is not recommended. The weight gain associated with olanzapine and clozapine and potential risk of gestational diabetes should be considered in drug selection. Antipsychotics appear in breast milk with milk : plasma ratios of 0.5 to 1. However, 1 week after delivery, clozapine milk concentrations have been found to be as much as 279% of serum concentrations. Its use during breast-feeding is not recommended.

24. DRUG INTERACTIONS Excess sedation - antipsychotics are used concomitantly with other medications that have sedative side effects (e.g., mood stabilizers, hypnotics, alcohol, antidepressants, anxiolytics, or antihistamines). Antipsychotics used with other medications with antimuscarinic effects (e.g., antihistamines, antidepressants, or antiparkinsonism agents) may result in urinary retention, constipation, blurred vision, or other anticholinergic side effects. Orthostatic hypotension - Antipsychotic is used with other medications that cause orthostasis (e.g., antidepressants with α-blockade, antihypertensive agents, or diuretics). patients are more likely to experience akathisia and other extrapyramidal side effects if metoclopramide is used concomitantly with antipsychotics. A potentially more dangerous interaction may occur when medications that slow myocardial conduction( e.g.,quinidine , procainamide, or tricyclic antidepressants), and thus prolong the QTc interval, are used in combination with antipsychotics that significantly prolong the QTc interval, such as ziprasidone, thioridazine, or mesoridazine .

25. If a CYP 3A4 inhibitor (e.g., cimetidine, ketoconazole, nefazodone, grapefruit juice, or erythromycin) is added to quetiapine, increased side effects ( e.g.,sedation or orthostasis) may occur. If an enzyme inducer such as carbamazepine or St.John’s wort is added to quetiapine, then decreased antipsychotic effects may occur. inhibitors of CYP 1A2 have the greatest potential for causing interactions with olanzapine.109 Examples include cimetidine, fluvoxamine, and fluoroquinolone antibiotics (e.g., ciprofloxacin). fluvoxamine has been reported to increase clozapine serum concentrations by an average of two to three fold and up to five fold. ( risk of seizures ). Mean clozapine serum concentrations are reported to be 32% lower in smokers compared with nonsmokers . Carbamazepine may also induce clozapine metabolism and lead to lower serum concentrations.

26. PHARMACOECONOMIC CONSIDERATIONS Outcomes and related economics of treating patients with the SGAs compared with the traditional, largely generic FGAs were examined. Although medication costs are higher with SGA’s than with FGA’s, studies with various SGA’s have fairly consistently shown total mental health costs to be no higher or even lower with SGA’s. Some studies have shown clozapine to result in lower overall mental health care costs, while others have shown no difference in costs compared to FGAs. Clozapine decreases suicidality more than comparator antipsychotics, and it is more effective in treatment-resistant schizophrenia. Of greater debate is whether differences in cost-effectiveness exist among the SGAs.

27. Atypical antipsychotics may have advantages in four areas, 1. Tolerability and compliance appears to be better , in particular with less likelihood of inducing the extrapyramidal effects and hyperprolactinaemia ( although its common with risperidone and amisulpride ) . 2. Greater efficacy against the negative symptoms of schizophrenia, which are particularly debilitating in chronic illness. 3. Clozapine ( but not any other newer atypicals ) is more effective than classical agents in treatment - resistant schizophrenia. 4. Although medication costs are higher with SGA’s than with FGA’s, studies with various SGA’s have fairly consistently shown total mental health costs to be no higher or even lower with SGA’s.

28. In a meta-analysis the effect sizes of olanzapine, risperidone, amisulpride , and clozapine were respectively 0.21, 0.25, 0.29, and 0.49 times greater than those of first generation neuroleptic drugs. An independent cross-sectional survey, in schizophrenic outpatients clinically stabilized on a neuroleptic drug for a period of 6 months showed that quality-of-life not differ significantly in patients taking typical neuroleptic drugs and novel ones. Adverse effects have been studied in people with mental retardation treated with atypical neuroleptic drugs, typical neuroleptic drugs or no drugs. The patients taking atypical neuroleptic drugs did not have different overall adverse events from those taking no medications, and both had significantly fewer overall adverse effects than those taking typical neuroleptic drugs.

29. ATYPICAL DRUGS VERSUS HALOPERIDOL In a randomized double-blind trial in inpatients with chronic schizophrenia, clozapine, olanzapine, and risperidone, but not haloperidol, produced statistically significant improvements in total scores on the Positive and Negative Syndrome Scale after 14 weeks. There was a significant fall in the Extrapyramidal Symptom Rating Score with the three atypical drugs at the end of the study and no change with haloperidol. One patient developed agranulocytosis, two had hypertensive episodes, and four had seizures while taking clozapine.

30. CLOZAPINE VERSUS TYPICAL NEUROLEPTIC DRUGS A meta-analysis of randomized controlled comparisons of clozapine with typical neuroleptic drugs shows, Clozapine was more effective in reducing symptoms in patients with both treatment-resistant and non-resistant schizophrenia. In a subset of 13 trials hematological problems tended to be more frequent in patients taking clozapine; hypersalivation was also more frequent, as were fever and sedation. Extrapyramidal symptoms were more frequent in the patients treated with typical neuroleptic drugs. There was no difference between the two groups in weight gain, hypotension or dizziness, or seizures.

31. CLOZAPINE VERSUS HALOPERIDOL Clozapine and haloperidol have been compared in 75 schizophrenic outpatients. Long-term clozapine was associated with significant improvements in social and occupational functioning, but not in overall quality of life. There were no significant differences between the two groups in adverse effects from previous neuroleptic drug treatment, and dizziness, Salivation and nausea were significantly more common in patients treated with clozapine. In contrast, dry mouth was significantly more common with haloperidol. Patients who completed the double blind study entered a 1-year open clozapine study. Over the course of that year, there was a small reduction in adverse effects, apart from hypersalivation, which increased significantly. Clozapine responders were rated as less severely ill, had fewer negative symptoms, and had fewer extrapyramidal adverse effects at baseline compared with haloperidol.

32. REFERENCES MEYLERS’S SIDE EFFECTS OF PSYCHIATRIC DRUGS. COMPREHENSIVE PHARMACY REVIEW 7 TH EDITION. PHARMACOTHERAPY A PATHOPHYSIOLOGICAL APPROACH – JOSEPH T DIPIRO. MICROMEDEX. STAHL’s ESSENTIAL PSYCHOPHARMACOLOGY.