Chief Complaint: “I want to see my lawyer.”SUBJECTIVE:HPI: AG is a 32 year old female brought to the state hospital by the police for her first admission. She had created a disturbance at a local fast-food restaurant, the police were called, and she was brought to the hospital on an order of protective custody. The patient exhibits numerous delusions, including believing that people sneak into her room at night and place a thousand worms inside her body, she is being raped by passing men on the street, her ideas have been given to a Cuban communist who is pretending to be her, her feet were cut off and were reattached after they were sent back from Central America, eggs were taken from her body, she used to have transmitters in her backbone, and snakes were in her stomach. She also demonstrates some grandiose ideations, including believing she used to be a surgeon, she owns gold, she owns the fast-food restaurant, and she has great wealth. She also has rambling speech.

Past Psych History: Denies any prior hospitalizationsFamily Psych History: claims her family is not really her family and she is not sure who is her familyPMH: Gallbladder surgery 2 months ago, no documentation of broken hip, no documentation of rapeSH: + tobacco (2 ppd), denies drug or alcohol use; divorced, lives in an apartment aloneMeds: UnknownAll: Penicillin - rashROS: Reports occasional GI upset, complains that worms are inside her stomach

OBJECTIVE:MSE: Appearance: wf of Hispanic ethnicity, morbidly obese, modestly dressed w/some disarray. Hair unwashedSpeech: clear, constant, pressured, rambling, flight of ideas, hyperverbalMood: euphoric, marked grandiosityAffect: mood-congruentThought process: illogical, delusional, grandioseThought content: no auditory/visual hallucinations, no suicidal/homicidal ideation, marked delusions with paranoid ideation prominent Memory: immediate, recent, and remote are fairConcentration: adequateIntellectual function: averageJudgment: markedly impairedInsight: markedly impaired

PE: VS: BP 140/85, P 80, RR 17, T 37.1, Wt 97 kg, Ht 5’3”, BMI: 37.9 (Obesity class II), CrCl 91 mL/min; Skin: scratches on both hands; Remainder wnl

Labs: Neutrophils 66%, Lymphocytes 24%, Monocytes 8%, GGT 38, Total cholesterol 208, Phosphate 5.1, remainder wnl. Urine pregnancy negative

Complete Problem List: Schizophrenia, paranoid type, Obesity

Problem 1: Schizophrenia, paranoid typeAssessment:The patient endorses at least 3 of the 5 characteristic symptoms of schizophrenia (criterion A from DSM-IV-TR), including delusions, disorganized speech, and grossly disorganized behavior. Based on the information provided in the HPI and the MSE, it is difficult to discern if the patient has any negative symptoms (affective flattening, avolition, anhedonia, etc). The patient was disarrayed with unwashed hair, indicating she may have some impairment in self-care. It is difficult to discern if she has demonstrated impairments in other areas of function, such as work or interpersonal relationships. There is no information provided regarding duration of symptoms in this patient. In order to warrant a diagnosis of schizophrenia, the patient must have continuous signs of disturbance for at least 6 months with at least 1 month of symptoms (less if patient is treated). Although we have no information regarding duration of symptoms, the patient does have characteristic symptoms of schizophrenia and would warrant a diagnosis of schizophrenia. Since the patient has prominent delusions, particularly persecutory and grandiose delusions, she would further be classified as having paranoid type schizophrenia. While any antipsychotic could be used to treat the patient, it is preferred to use a second generation antipsychotic for initial treatment (TMAP Schizophrenia algorithm, accessible at http://www.dshs.state.tx.us/mhprograms/disclaimer.shtm), excluding clozapine which is reserved for treatment resistant cases. Options within the atypical antipsychotic class include risperidone, quetiapine, olanzapine, aripiprazole, ziprasidone, paliperidone, and the recently approved, but not yet available, iloperidone. There is no clinical evidence demonstrating that any atypical agent is more efficacious than another atypical agent. As such, the adverse effect profile should be taken into account, particularly for this obese female. The propensity for weight gain in the recommended and available atypical antipsychotics is as follows: olanzapine > quetiapine > risperidone = paliperidone > ziprasidone ~= aripiprazole. The patient’s unknown employment status and unknown insurance status should also be considered.

It is important to note that this patient’s primary symptoms are delusions, and delusions are the last symptom of schizophrenia to resolve, if they do resolve. The possibility of these delusions being fixed delusions and unresponsive to medications should always be considered. If the delusions do resolve with the use of medication, it may take from 4 to 12 weeks to resolve.

Plan:Goals of therapy: Resolution of target symptoms – ultimate goal is remission of symptoms; Minimize adverse effects from medications; Improved quality of life

Non-pharmacological plan:Educate patient about schizophrenia and medications. Stress

importance of adherence with medication regimen. Review the onset of effect of medication since efficacy is not seen for many weeks and patient should be aware to not discontinue medication believing it is ineffective

Pharmacological plan: Any of the followingRisperidone 1 mg BID, titrate up daily by 1-2 mg/day. MDD per PI: 16

mg/day, usual dose range 2-8 mg/day. Aripiprazole 10 mg qAM, titrate up q2weeks to response. MDD per PI:

30 mg/day, clinical trials have used up to 45 mg/dayQuetiapine 25 mg BID x 1 day, 50-75 mg BID x 2 days, 150-200 mg BID,

continue to titrate to response. MDD per PI: 800 mg/day, clinical trials have used up to 1600 mg/day

Olanzapine 10 mg qday (preferentially HS), titrate up by 5 mg/d weekly to response. MDD per PI: 20 mg/day, clinical trials have used up to 60 mg/day. No evidence showing increased efficacy >20 mg/day in treatment naïve pts. May be greater efficacy with high dose in treatment refractory patients.

Ziprasidone 20 mg BID with food (full meal), titrate up no more frequently than 2 day intervals. MDD per PI: 100 mg BID

Paliperidone 6 mg qday, titrate up no more frequently than 5 day intervals. MDD per PI: 12 mg

*Notes for facilitatorsAny atypical antipsychotic agent, except for clozapine, would be

appropriate for initial treatment for this patient. Alternatively, a typical agent could be used, provided that the students provide rationale for choosing a typical agent over an atypical agent. The only absolutely wrong answer is clozapine.

All recommended Max Daily Doses for atypical antipsychotic agents are per package insert recommendations and based on doses for FDA approvals. All agents have been used clinically in higher than recommended doses and higher than recommended doses may be required in order to stabilize patients.

Specific medication notes: Risperidone: doses > 6 mg/day confers greater D2 binding and functions

similarly to a typical agent. Higher doses are associated with a greater risk of development of EPS and elevated prolactinPaliperidone: the active metabolite of risperidone (9-hydroxyrisperidone). No evidence exists indicating that this medication has any greater efficacy than risperidone. There are no fewer adverse effects, should not be used in patients with severe GI issues (IBS, strictures, etc) because of the extended release OROS formulation and must be dose adjusted in patients with renal dysfunction. This could play a role in patients with active hepatic disease as it does not undergo extensive hepatic metabolism. Of note, risperidone is available generically while paliperidone is not.Quetiapine: has recently become available as an XR formulation.

Pharmacokinetic studies indicate that the pharmacokinetics are not highly different between the two formulations. Quetiapine IR can be dosed once daily if tolerated by the patient. There is no difference in efficacy or adverse effects between the two formulations. The only difference is price (XR being more expensive).Aripiprazole: essential that titration is done slowly. Approximately 33% of patients experience akathisia, and this percentage is increased by 2x if you include those patients who experience anxiety. Low initial doses and slow titrations help to minimize risk of development of akathisia. Should not be used in combination with typical antipsychotic agents or atypical agents with tight D2 biding (e.g. risperidone) because of the novel pharmacokinetics of a partial D2 agonism/antagonismOlanzapine: may cause substantial weight gain in relatively short periods of time. Have been reports of weight gain >30 lbs in 1-2 months with use of olanzapine. Caution should be taken using this medication in this already obese female. Also of note: if benzodiazepines are used to manage agitation/aggression initially in the patient, care should be taken with combining lorazepam with olanzapine. Olanzapine IM and lorazepam IM should not be used within 1 hour of each other as the combination has been shown to result in severe hypotension leading to cases of coma and death. Although there are no specified recommendations regarding combining one

oral agent with one IM agent or both oral agents combined, caution should be used and it may be best to separate doses by a minimum of 1 hour. Also important to note patient’s smoking status. Depending on reference, smoking may decrease olanzapine serum concentrations anywhere from 60-90%. This is a function of the aromatic hydrocarbons in cigarette smoke, not a function of nicotine, so this only plays a role if the patient is smoking, not if the patient is receiving NRT. Although there are no recommendations regarding dose adjustments in smokers, this should be kept in mind if the patient is receiving NRT while inpatient (when she is discharged if she begins smoking again, will have decreased olanzapine levels, potentially resulting in readmission). This should also be kept in mind in the event that she is stabilized on a dose outpatient & decides to quit smoking (quitting smoking will result in an increase in serum olanzapine levels – may need to decrease dose if patient decides to quit).

Patient may also require an immediate acting agent for management of agitation/aggression. Olanzapine, ziprasidone, and aripiprazole are available in IM injections, which may help to alleviate this. Other options include short-term benzodiazepine use (generally lorazepam as it is available both PO and IM). Other considerations that may be brought up include use of orally-disintegrating agents, including Risperdal M-tabs, Zyprexa Zydis, and Abilify DiscMelts. It is important to note that there are no pharmacokinetic differences between ODTs and regular tablets. There is no faster onset of action with ODTs as compared with tablets. While patients have reported a subjective faster onset of action with ODTs, this is a placebo effect. The greatest advantage for ODTs is to facilitate adherence with medications initially and is of use in patients who have difficulty swallowing tablets.

If long-term adherence is a concern, risperidone is available as a long-acting injection (Risperdal Consta) given IM q2weeks. If consideration is given to starting patient on Consta injections for long-term adherence, patient should be stabilized on oral dose first prior to conversion. Oral risperidone supplementation is required for the first three weeks after the first Consta shot as it takes 3 weeks for the microspheres in the IM injection to release the drug.

Monitoring:Efficacy: resolution of symptoms/delusions, may monitor with regular assessments with BPRS(For all atypical agents): Baseline: BMI, FPG/HbA1c, fasting lipids, EPS evaluation, TD assessmentOngoing: BMI monthly for 6 months then quarterlyFPG/HbA1c yearly if no diabetes risk or weight gainFPG/HbA1c at 4 months then yearly if diabetes risk or weight gainFasting lipids every 2 years if lipid levels are at goalFasting lipids every 6 months if LDL > 130Assess for symptoms of elevated prolactin (galactorrhea, amenorrhea, etc) yearly If symptoms of elevated prolactin, prolactin level yearly EPS evaluation weekly after initiation and dose increases, continue x 2 weeks after last dose increase TD assessment every 12 months Vision questionnaire yearly and ocular evaluation q2years

For specific atypical agents:Ziprasidone: baseline EKG, follow-up EKGs indicated if patient has symptoms of QTc prolongation (e.g. syncope)Quetiapine: although not specified in PI, baseline & follow-up EKGs could beconsidered. Clinically QTc prolongation has been reported in greater incidence with quetiapine, particularly high dose quetiapine, than has been reported with ziprasidone. Monitor for hypotension & syncope.Risperidone: assess for symptoms of elevated prolactin quarterly during the first year of treatment

Problem 2: ObesityAssessment:Patient is classified as category II obesity per NHBLI criteria. Requires education regarding weight loss, appropriate dietary changes, and regular exercise.

Sample Presenter Questions

1. Briefly describe the 5 Axis systemAxis I: clinical disorders (psychiatric diagnoses)Axis II: personality disorders and mental retardationAxis III: general medical conditionsAxis IV: psychosocial and environmental problemsAxis V: Global assessment of functioning (0-100 scoring)

2. According to DSM-IV, what are the diagnostic criteria for schizophrenia?

a. At least two of the following characteristics, each present for at least one monthDelusionsHallucinationsDisorganized speech(e.g. frequent derailment or incoherence)Grossly disorganized or catatonic behaviorNegative symptoms (i.e affective flattening, alogia, or avolition)

b. Social/occupational dysfunctionc. Any of above symptoms lasting at least six monthsd. Schizoaffective disorder and Mood disorder exclusione. Illness not due substance/general medical conditionf. Illness not due to autism or a pervasive development disorder

3. What does a global assessment of functioning score of 32 mean?Some impairment in reality testing or communication OR major impairment in several areas (such as work or school, family relations, judgment, thinking or mood).

4. What are the classes of antipsychotics?Typicals (conventional, dopamine antagonists): haloperidol, fluphenazine, thiothixene, chlorpromazine, trifluperazine and thioridazineAtypicals (second generation, serotonin-dopamine antagonists):clozapine, risperidone, olanzapine, quitiapine, ziprassidone, aripriprazole, and paliperidone

5. What are some general side effects of typical antipsychotics?Extrapyrimidal symptoms, sedation, anticolnergic and cardiovascular effects

6. What are some general features that distinguish atypical from typical antipsychotics?

Decreased incidence of EPS and tardive dsykinesia (TD)Lack of effect on serum prolactinGreater efficacy for refractory schizophreniaGreater activity against negative symptoms

7. What is the mechanism of action of antipsychotics?Postsynaptic blockade of D2 and serotonin 5-HT2A receptor sitesFour dopamine tracts involved: (blockade leads to)

Mesolimbic: reduction of positive symptomsMesocortical: reduction of negative symptomsNigrostriatal: extrapyramidal symptoms (EPS)Tuberonfundibular: hyperprolactinemia

8. In general, what adverse effects are associated with antipsychotics?SedationEPSAnticholinergic effectsOrthostasisSeizuresProlactin elevationWeight gain

9. What are extrapyramidal symptomsThey are neurological complications of caused by neuroleptic blockade of the D2 receptors in the basal ganglia and include: acute dystonic reactions; akathisia; pseudo-parkinsonism; and tardive dyskinesia

10. In what order would you expect the EPS to present?Early onset:Acute dystonia (90% within 3 days)Akathisia (approx 5 days onwards) Pseudoparkinsonism (8 days onwards)Late onset:Tardive dyskinesia (tardive dystonia and tardive akathisia): may present after 100days or years of treatment

11. Define/describe dystoniaBrief or proloned muscle contractures (usually of the head, neck, and tongue, oculogyric crisis, spasm of the jaw) occurring within a few hours or days. Laryngeal dystonias are the most serious and are potentially fatal.

12. Describe/define akathisiaThis is a syndrome consisting of subjective feelings of restlessness or the urge to move, and an objective motor component expressed as semipurposeful movement most often involving the lower extremities. It is chacreacteized by pacing, rocking, and inability to sit or stand in one place for extended periods of time. Observed in up to 50% of patients treated with typical and ranges from 5% to 15% in patients treated with atypical. Can produce dysphoria and possibly aggressive or suicidal behavior. Patients pacing around and unable to sit should be assessed for this.

13. Describe/define pseudo-parkinsonismThis is characterized by resting tremor, rigidity and bradykinesia. The symptoms are virtually indistinguishable from Parkinson’s Disease. It occurs after a few weeks or more of therapy. Akinesia’s should be differentiated from primary depression and blunted affect.

14. What is tardive dyskinesia?Involuntary movements, especially of the lower face (tongue thrusting, repetitive chewing, jaw swinging, and/or facial grimacing) but can include involuntary movements of the neck and trunk or flexion of the ankles.

15. How do you treat TD?If patient is on typical antipsychotic switch to Clozapine or other atypical. Other agents that have been used with minimal success include diazepam, clonazepam, valproate, propranolol, clonidine, and vitamin E.

16. How would you monitor this patient for TD?With the Dyskinesia Identification System Condensed User Scale (DISCUS) orAbnormal Involuntary Movement Scale (AIMS)at the beginning of treatment and then quarterly.Because it is believed that the risk of TD is much less with atypicals, this is only done every 6-12 months in patients on these. Quarterly is the

recommendation for the typicals. AIMS is the most commonly administered and is very easy to use.

17. Describe AIMS.Interactive and observational examination of involuntary movementsFacial and Oral movements - muscles of facial expression, lips/perioral area, jaw, and tongueExtremity movements – upper (arms, wrists, hands, fingers) and lower (legs, knees, ankles, toes) Trunk movements – neck, shoulders, and hipsGlobal judgments – severity of abnormal movements, incapacitation due to abnormal movements, and patient’s awareness of abnormal movementsDental Status – current problems with teeth/dentures, does pt wear denturesHigher scores indicate greater severity of impairment

18. What are the risk factors for EPS?Younger age (<35); IM route of administration, male gender, previous dystonic reaction.

19. How will I treat acute dystonia?Benztropine 2mg IM/IV or diphenhydramine 50mg – 100mg IM/IV, resolution within 30 minutes. If no response in 30 minutes, repeat. If no response after 2 trials, give lorazepam 1mg to 2mg IM/IV. If symptoms return, decrease dose, switch to a lower potency neuroleptic or switch to AAP

20. How do I treat Pseudo-Parkinsonism?In mild cases, immediate intervention may not be required if the movement disorder is not bothersome to the patientFor troublesome cases, the antipsychotic can be reduced to the lowest effective dose or switch to a low potency antipsychotic or an AAP.If above does not resolve parkinsonian symptoms, add antiparkinsonian agents: benztropine 0.5 to 2mg po bid and/or diphenhydramine 25-50mg po bid or amantadine 100mg po bid or tid

21. How long should anticholinergic therapy be?They should be stopped after 14days if asymptomatic because of the potential to increase the risk if tardive dyskinesia

22. How do I treat akathisia?Akathisia is less responsive to treatment than are antipsychotic-induced parkinsonism and dystonia. First step is to lower dose. If symptoms persist then following is attemptedIf no EPS: first choice is propranolol 10mg to 30mg tid (max 120mg daily). Second option is lorazepam 1mg pot idIf other EPS is present: benztropine 2mg po bid

23. What lab tests will be required to monitor therapy with olanzapine?

Flasting blood glucose; cholesterol; specifically TGs and weight

24. How long does it take for olanzapine to work?The full effect may take several months. If patient has not responded to a therapeutic dose by week 8-12, move on to the next drug.

25. What are the major (serious) side effects of clozapine?Clozapine has five blackbox warnings from the FDA: agranulocytosis, seizures, myocarditis, increased mortality in elderly patients with dementia-related psychosis, and other adverse cardiovascular (hypotension) and respiratory effects.Agranulocytosis (1% of patients): requires baseline and weekly complete blood count (CBC) and granulocyte count during early therapy initiation. Frequency of tests decrease with time.May also cause sialorrhea, or hypersalivation (incidence ranges from 31% to 80%). Most often worst at night, and may lead to social withdrawal, choking, or aspiration pneumonia.

26. Do atypical antipsychotics have any effect on the hypothalamic-pituitary system?

Risperidone is the only one really thought to potentially increase prolactin levels. Olanzapine temporarily increase prolactin.

27. Which of the atypical agents is most likely to cause weight gain?Clozapine>olanzapine>quitiapine=risperidone>aripriprazole=ziprasidone

28. What is the mechanism of weight gain with the atypical agents?The mechanism of antipsychotic-induced weight gain is unclear, but antagonism of histamine H1 and serotonin 5-HT2C receptors has been implicated. A genetic predisposition exists for weight gain; a mutation

in the 5-HT2C receptor gene may increase the risk for weight gain from atypical.

29. Somnolence seems to be a common occurrence with atypicals. Tell me about this side effect?

Somnolence is very common with olanzapine, clozapine and quetiapine. It occurs in dose-related fashion. Less commonly it may occur with risperidone.

30. Describe the Neuroleptic Malignant Syndrome (NMS)NMS is rare but potentially lethal adverse effect of antipsychotic therapy. The risk seems to be lower for atypical than for typical.NMS can occur hours to months after the initial drug exposure, and the mortality rate is reported to be high as 20%. Incidence is between 0.02% and 3.23% of patients taking typical antipsychotic drugs. Cardinal features: muscular rigidity, hyperthermia, autonomic dysfunction, and altered consciousness.NMS is self-limiting and usually lasts 2 to 14 days after the oral antipsychotic is discontinued or longer after discontinuation of depot injections.

31. Describe the mechanism by which antipsychotics can cause seizures

Antipsychotic drugs can lower seizure threshold. Seizures are most common with low- potency typical antipsychotics (chlorpromazine and thioridazine) and clozapine.

32. What is the available evidence for appropriateness or inappropriateness of antipsychotic use in pregnancy?

Use of antipsychotics during the first trimester should be minimized or avoided if possible, especially between weeks 6 and 10. If necessary during this period, high potency typical antipsychotics (e.g. haloperidol, fluphenazine, loxapine, trifluperazine) may be safer.

33. How are you going to monitor patient response to medication?CGI – Clinical Global Impression: a three-item scale commonly used in studies on schizophrenia that enables clinicians to quantify severity of illness and overall clinical improvement. The items are: severity of illness; global improvement and efficacy index. A seven-point scoring system is usually used with low scores indicating decreased severity and/or greater recovery

BPRS – Brief Psychiatric Ratings Scale: an 18-item scale measuring positive symptoms, general psychopathology and affective (“negative”) symptoms. The original scale has sixteen items, but a revised eighteen-item scale is commonly used. Scores can range from 0-126. Each item is rated on a seven-point scale, with high scores indicating more severe symptoms

PANSS – Positive and Negative Symptoms Scale: a 30-item scale with 16 general psychopathology symptom items, seven positive-symptom items, and seven negative symptom items. Also completed by the physician, each item is scored on the same seven point severity scale as the PANSS, resulting in a range of possible scores from 30 to 210SANS – Scale for the Assessment of Negative Symptoms: a global rating of the following negative symptoms: alogia (impoverished thinking), affective blunting, avolition-apathy, anhedonia-asociality and attention impairment. Assessments are made on a six-point scale (0=not at all to 5=severe). Higher scores indicate more symptoms

34. How long would you treat this patient for?Schizophrenia is typically a life-long disease characterized by multiple relapses. Long term maintenance therapy is recommended. In the absence of continuing prophylaxis up to 75% of patients will relapse with an acute psychotic episode within 6-24 months.

35. How likely is it that this patient will experience complete resolution of her

symptoms on treatment?With treatment, approximately 30% of patients achieve a partial but good response to treatment, 30% a partial but inadequate response with the remainder experiencing chronic deterioration. Approximately 10% of patients experience continuous psychotic symptoms.

36. What is the prevalence of schizophrenia?Between 0.5-1% of the adult US population.

37. Is this a typical age of onset for schizophrenia?Yes. Median age of onset for women is late twenties and for men is early to mid-twenties. It rarely presents before adolescence or after the age of 40 years.

38. What are ‘positive’ and ‘negative’ symptoms?Positive symptoms include delusions, hallucinations, disorganized thought, bizarre behavior and insomnia. Negative symptoms include social withdrawal, poverty of speech (alogia) and inability to experience pleasure (anhedonia).

39. What symptoms of schizophrenia does this patient manifest?Delusions, paranoid ideations, grandiose ideations, disorganized speech.

40. How would you confirm a diagnosis of schizophrenia?There are no lab tests to diagnose or assess the severity of schizophrenia. To confirm the diagnosis the patient must have two or more symptoms (delusions; hallucinations; disorganized speech; grossly disorganized or catatonic behavior negative symptoms) for at least one month, with some of the symptoms persisting for up to 6 months.

41. What differential diagnoses did you consider?Patient may have another psychotic disorder including the possibility of a psychotic disorder due to a general medical condition or a drug-induced psychosis. A toxicology screen should be performed. A diagnosis of schizophrenia (vs. schizophreniform disorder etc) may typically only be made after exclusion of other diagnoses over time.

42. Risperidone recently got a ‘black box’ warning from the FDA. What for?

It has been associated with increased mortality in elderly patients treated for dementia-related psychosis. These primarily appear to be cardiovascular in nature. It is not approved for this indication.

43. Risperidone recently got a ‘black box’ warning from the FDA. Is this a class effect?

All of the atypical agents have received the same warning. Based on analysis of 17 placebo-controlled trials (modal duration 10 weeks) there was a 1.6 to 1.7-fold increase in risk of death vs. placebo-treated patients (i.e. a death-rate of 4.5% vs 2.6%).

Sample Non-Presenter Questions

What is the mechanism of action of the second-generation antipsychotics?They act primarily by inhibition of dopamine D2 and serotonin 5-HT2a receptors. They also (variably) inhibit dopamine D1 and D4, histamine H 1, serotonin 5-HT2 c, cholinergic and α 1-adrenergic receptors.

Aripiprazole: high affinity for D2 (partial agonist), D3, 5-HT1A (partial agonist), 5-HT2A (antagonist); moderate affinity for D4, 5-HT2C, 5-HT7, alpha-1, histamine-1; moderate affinity for serotonin reuptake

Olanzapine: selective monoaminergic antagonist with high affinity for 5-HT2A/C, 5-HT6, D1, D2, D3, D4, histamine-1, and adrenergic alpha-1; antagonist with moderate affinity for 5-HT3, muscarinic M1-5; also weakly binds to GABA-a, BZD, and beta-adrenergic receptors

Paliperidone: D2 antagonist with 5-HT2a activity; some alpha-1, alpha-2, and histamine-1 antagonism; no affinity for cholinergic muscarinic or beta receptors

Quetiapine: antagonist at 5-HT1a, 5-HT2, D1, D2, histamine-1, alpha-1 & 2; no affinity for muscarinic or BZD receptors

Risperidone: selective monoaminergic antagonist with high affinity for 5-HT2, D2, alpha-1/alpha-2 adrenergic, and histamine-1 receptors; low-to-moderate affinity 5-HT1A/C/D; weak affinity for D1; no affinity for muscarinic or beta receptors

Ziprasidone: high affinity for D2 (antagonist), D3, 5-HT2a (antagonist), 5-HT1a (agonist), 5-HT1d (antagonist), and alpha-1; also inhibits synaptic re-uptake of serotonin and norepinephrine; no affinity for other receptor sites

Can you name other drugs in this therapeutic class?Clozapine (Clozaril®), Olanzapine (Zyprexa®), Risperidone (Risperdal®), Ziprasidone (Geodon®), Aripiprazole (Abilify®), Quetiapine (Seroquel®/Seroquel XR), Paliperidone (Invega®)

What would a month of treatment with this agent cost?See table. The atypical agents are generally far more expensive than the typical agents.

Are generics available for these agents?Of the atypical antipsychotics risperidone and clozapine are available as generics

What are the most common side-effects of the antipsychotic agents?ADRs of these agents can be split into antihistaminic (sedation), antidopaminergic (EPS and hyperprolactinemia); anticholinergic (dry mouth, blurred vision, constipation, urinary retention, sinus tachycardia, cognition and memory effects);

and anti-adrenergic effects (reflex tachycardia and orthostasis). These include drowsiness, dizziness, anxiety, constipation and nausea. Generally, the atypical antipsychotics are more tolerable than the typical antipsychotics and have a lower propensity (with the exception of risperidone) to cause EPS. Risperidone at a dose of >6mg qd has a similar risk of EPS as haloperidol. The risk of metabolic side-effects such as weight gain, glucose dysregulation and dyslipidemia appears to be greater with the atypical agents.

Freedman, R. NEJM. 10/30/2003.

Are there any significant drug-drug interactions between the medications you have prescribed?Answer will depend on the medications prescribed. If the students elect to prescribe lorazepam or another benzodiazepine in addition to an antipsychotic then an increase in sedation may be noted. The students could also be asked about significant interactions between the agent they have prescribed and other medications in general Alcohol should typically be avoided with all of these agents.

How would you counsel a patient about how to take this medication?Note: Counseling this patient about her medication would most likely be deferred until she is stabilized. The usual advice should be given with regard to storage, missed doses, pregnancy, taking other new prescription/nonprescription medications, taking as prescribed and the avoidance of alcohol. Warn patient of the possibility of drowsiness, dizziness, anxiety, constipation and nausea. Patient should be alerted with regard to orthostatic hypotension and the management of same. Patient will need to be examined at 6-12 month intervals for the development of movement disorders and periodically for weight gain and development of hyperglycemia.

How effective is this antipsychotic agent?Overall, antipsychotics have only a moderate effect in the management of schizophrenia (mean effect size =0.25).When compared to the typical antipsychotics, the atypical agents appear to be as effective in the treating the positive symptoms, and more effective in treating the negative symptoms of schizophrenia. It is argued that in clinical practice they are more effective in the management of positive symptoms due to a lower propensity to be discontinued because of poor tolerance / adverse effects.

Do any of the AAPs need to be dose-adjusted in renal or hepatic failure?Aripiprazole - noOlanzapine – noPaliperidone- hepatic no, renal yesQuetiapine – hepatic yes, renal noRisperidone - reduce dose in both renal and hepatic dysfunctionZiprasidone - hepatic yes, renal no

Max dose informationAripiprazole – 30mg QD; though not shown to be more effective than doses of 10-15mg QD; if solution used – match tablet dose on a mg-mg basis to a max of 25 mg dose of oral solution Olanzapine – 20 mg QDPaliperidone – 12 mg QDQuetiapine – 800mg daily in divided doses Risperidone - 16mg daily, though EPS/ADRs worsen at doses >8mg daily; maximal efficacy seen with doses 4-8mg dailyZiprasidone - 80mg BID

Are there any OTC or alternative therapies which are effective in the treatment of schizophrenia?Short answer – NO!! There is some evidence of the use of gingko biloba in addition to AP, but patients should be cautioned to avoid the use of herbals/OTC’s without MD/pharmacist supervision.

Approximate Cost of Drug Treatment Drug /Strength (mg) Price (30 tabs/caps) Comments

Olanzapine (Zyprexa) 2.5 209.73 Zydis 10mg #30 $395.20

*Usual daily dose 10-20mg i.e. $360-$720/month

Olanzapine (Zyprexa) 5 240.61Olanzapine (Zyprexa) 7.5 311.51Olanzapine (Zyprexa) 10 359.74Olanzapine (Zyprexa) 15 558.33

Risperidone (Risperdal) 1 127.24 M-Tab 2mg #28 $211.72Consta 50mg #1 $567.99*Usual daily dose 4-6mg i.e. $330-$500/month

Risperidone (Risperdal) 2 207.29Risperidone (Risperdal) 3 242.58Risperidone (Risperdal) 4 324.08

Aripiprazole (Abilify)2 377.76*Usual daily dose 15mg i.e. $350/month

Aripiprazole (Abilify)5 346.41Aripiprazole (Abilify)10 353.38Aripiprazole (Abilify)15 353.38Aripiprazole (Abilify) 20 487.78Aripiprazole (Abilify) 30 487.78

Ziprasidone (Geodon) 20 163.41*Usual daily dose 160mg i.e. $360/month

Ziprasidone (Geodon) 40 163.41Ziprasidone (Geodon) 60 174.05Ziprasidone (Geodon) 80 177.50

Quetiapine (Seroquel) 25 #60 131.62*Usual daily dose 600-800mg i.e. $550-660/month

Quetiapine (Seroquel) 50 #60 221.94Quetiapine (Seroquel) 100 #60 222.21Quetiapine (Seroquel) 200 #60 414.67Quetiapine (Seroquel) 300 #60 542.12Quetiapine (Seroquel) 400 #60 663.35

Paliperidone (Invega) 3 366.53 *Usual daily dose is 6mg i.e.$400/monthPaliperidone (Invega) 6 366.53

Paliperidone (Invega) 9 548.47

Note: Older antipsychotic agents are significantly less expensive. Alternative dosage forms are typically more expensive than oral tablets (injectables, oral solutions).