Evidence-Based Reviews

First psychotic episode—a window of opportunity: Seize the moment to build a therapeutic alliance

Current Psychiatry. 2003 April;2(4):50-67

References

1. Norman RM, Malla AK. Duration of untreated psychosis: a critical examination of the concept and its importance. Psychol Med 2001;31:381-400.

2. Cornblatt B, Lencz T, Obuchowski M. The schizophrenia prodrome: treatment and high-risk perspectives. Schizophr Res 2002;54(1-2):177-86.

3. McGorry PD, Yung AR, Phillips LJ, et al. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry 2002;59(10):921-8.

4. Heinssen RK, Perkins DO, Appelbaum PS, et al. Informed consent in early psychosis research: National Institute of Mental Health workshop, November 15, 2000. Schizophr Bull 2001;27(4):571-83.

5. Miller TJ, McGlashan TH, Rosen JL, et al. Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiatry 2002;159(5):863-5.

6. Young LT, Bakish D, Beaulieu S. The neurobiology of treatment response to antidepressants and mood stabilizing medications. J Psychiatry Neurosci 2002;27(4):260-5.

7. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999;56(3):241-7.

8. Tauscher J, Kapur S. Choosing the right dose of antipsychotics in schizophrenia: lessons from neuroimaging studies. CNS Drugs 2001;15:671-8.

9. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999;56(3):241-7.

10. Miller R, Mason SE. Diagnosis schizophrenia. A comprehensive resource, New York: Columbia University Press, 2002.

11. Lewis S, Tarrier N, Haddock G, et al. Randomised controlled trial of cognitivebehavioural therapy in early schizophrenia: acute-phase outcomes. Br J Psychiatry Suppl 2002;43:S91-7.

12. Turkington D, Kingdon D, Turner T. Effectiveness of a brief cognitive-behavioural therapy intervention in the treatment of schizophrenia. Br J Psychiatry 2002;180:523-7.

13. Cormac I, Jones C, Campbell C. Cognitive behaviour therapy for schizophrenia. Cochrane Database Syst Rev 2002;(1):CD000524.-

14. Smith GN, Flynn SW, Kopala LC, et al. A comprehensive method of assessing routine CT scans in schizophrenia. Acta Psychiatr Scand 1997;96:395-401.

15. Leucht S, Pitschel-Walz G, Abraham D, et al. Efficacy and extrapyramidal sideeffects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res 1999;35(1):51-68.

16. Keefe RS, Silva SG, Perkins DO, Lieberman JA. The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: A review and meta-analysis. Schizophr Bull 1999;25(2):201-22.

17. Dolder CR, Lacro JP, Dunn LB, Jeste DV. Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry 2002;159(1):103-8.

18. Vieweg WVR, Adler RA, Fernandez A. Weight control and antipsychotics: How to tip the scale away from diabetes and heart disease. Current Psychiatry 2002;1(5):10-19.

19. Compton MT, Miller AH. Sexual side effects associated with conventional and atypical antipsychotics. Psychopharmacol Bull 2001;35:89-108.

20. Stahl SM. Antipsychotic polypharmacy: squandering precious resources? J Clin Psychiatry 2002;63(2):93-4.

21. Casey DE, Daniel DG, Wassef AA, Tracy KA, Wozniak P, Sommerville KW. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology 2003;28(1):182-92.

22. Calabrese JR, Shelton MD, Rapport DJ, Kimmel SE. Bipolar disorders and the effectiveness of novel anticonvulsants. J Clin Psychiatry. 2002;63(Suppl 3):5-9.

23. Kampman O, Laippala P, Vaananen J, et al. Indicators of medication compliance in first-episode psychosis. Psychiatry Res 2002;110:39-48.

24. Overall JE, Gorham DR. Brief psychiatric rating scale. Psychol Rep 1962;10:799-812.

25. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 1970(suppl);212:11-19.

26. Guy W (ed). ECDEU assessment manual for psychopharmacology. Publication ABM 76-338. Washington, DC: U.S. Department of Health, Education, and Welfare, 1976;534-7.

27. Bosveld-van Haandel LJ, Slooff CJ, van den Bosch RJ. Reasoning about the optimal duration of prophylactic antipsychotic medication in schizophrenia: evidence and arguments. Acta Psychiatr Scand 2001;103(5):335-46.

Consider the patient’s risk for side effects when choosing an atypical antipsychotic, as each drug has strengths and weaknesses. For example, it may be reasonable to consider:

risperidone, ziprasidone, or aripiprazole—rather than olanzapine or quetiapine—for patients at high risk for weight gain or with a family history of diabetes
avoiding risperidone for patients with an early indication of sensitivity to EPS or prolactin-related side effects
an agent that can be loaded rapidly, such as olanzapine or aripiprazole—rather than an agent that requires titration, such as quetiapine—for a patient presenting with severe agitation.

Clozapine—because of its side effect potential—is generally reserved for patients who have not responded to at least two antipsychotic trials of at least 4 to 6 weeks duration and have a steady-state clozapine level >350 ng/dl.

Acute agitation. Short-acting IM formulations can be used effectively for acute agitation and impulsivity or for patients who refuse oral antipsychotics. Until recently, only first-generation antipsychotics such as haloperidol and fluphenazine were available in IM formulations. Injectable ziprasidone mesylate is now available for acute agitation and has been found to be as safe and effective as haloperidol. Lorazepam may be used to treat agitation or as an adjunct to a patient’s antipsychotic agent.

Adjunctive therapies

When antipsychotic monotherapy is inadequate, adjunctive medications may be considered:

to treat catatonia, obsessive-compulsive disorder, or depression
to resolve agitation or mania more quickly
to control agitation or anxiety while an antipsychotic dosage is being titrated
when side effects emerge or residual symptoms remain despite adequate dosage and duration of antipsychotic treatment.

Deciding if and when to add another drug depends on the nature and severity of target symptoms, the degree and time course of response, and whether side effects appear. If you use adjunctive therapies during acute stabilization, attempt to taper and discontinue them after the patient’s symptoms have improved. Avoid combining antipsychotics, as no clinical data support the effectiveness and safety of this practice.²⁰

Benzodiazepines are often used adjunctively for agitation, anxiety, or temporary insomnia in patients with schizophrenia. Common dosages are:

for agitation or anxiety, lorazepam, 0.5 to 2 mg bid or tid, or clonazepam, 0.5 mg bid to 2 mg tid
for insomnia, lorazepam or clonazepam, 1 to 2 mg at bedtime, or zolpidem, 5 to 10 mg at bedtime.

Benzodiazepines also are effective for catatonia, which may be misdiagnosed as negative symptoms or depression when it presents as marked psychomotor retardation, staring, selective mutism, negativism, mild posturing, or stereotypies. If undiagnosed, catatonia may worsen during antipsychotic titration. Symptoms usually respond to high-dose lorazepam, 1 mg bid or tid, with increases up to a maximum dosage of 12 mg/d.

Mood stabilizers are often used adjunctively to treat acute agitation and disinhibition²¹ or as add-on agents for residual psychotic or affective symptoms. Recommended dosages and blood levels, as tolerated, are:

valproic acid, starting at 10 to 20 mg/kg bid, with a target serum level of 60 to 120 μg/ml. A once-daily, extended-release formulation may improve compliance.
lithium, starting at 300 mg bid to tid, aiming for a serum level of 0.8 to 1.2 mEq/L.

Manic symptoms in a schizoaffective presentation may require one or even two mood stabilizers.

Lamotrigine may be the treatment of choice for depressed patients with schizoaffective disorder, bipolar type.²² However, it must be started at 25 mg/d and titrated extremely slowly—by 25 mg every other week, up to a target 200 to 400 mg/d—to avoid the risk of potentially fatal Stevens-Johnson syndrome.

Gabapentin, 300 mg tid to 1,500 mg tid, may help treat anxiety—particularly in patients with comorbid substance abuse, in whom benzodiazepines should be used sparingly after stabilization.

Table 3

SYMPTOM-BASED DRUG TREATMENT OF FIRST-EPISODE SCHIZOPHRENIA

Target symptom	Medication choices	Dosage range	Comments
Agitation	Atypical antipsychotic Mood stabilizer Benzodiazepine ECT	Depends on level of agitation and individual agent	Ziprasidone IM may be useful for acute agitation
Psychosis	Atypical antipsychotic ECT	=50% of dosage used for multiple episode patients	Start low/go slow, monitor side effects
Catatonia	Lorazepam ECT	1 mg/d bid to4 mg/d tid	Use sedation, symptom resolution as threshold
Negative symptoms	Atypical antipsychotic Glycine, cycloserine may help	Dictated by positive symptom response	Effect on functioning, quality of life unclear
Cognitive symptoms	Atypical antipsychotic	Same as above for negative symptoms	Same as above
Insomnia	Lorazepam Zolpidem Trazodone Mirtazapine	1 to 2 mg HS 5 to 10 mg HS 50 to 200 mg HS 7.5 to 15 mg HS	Short-term treatment preferred
Depression, obsessive-compulsive symptoms, anxiety/panic	SSRI, SNDRI, NDRI, SARI, NASA	As per individual agent Possible interference with	antipsychotic blood levels*
Parkinsonism	Benztropine Trihexyphenidyl	0.5 to 2 mg/d 1 to 15 mg/d	Possible effect of decreased cognition
Akathisia	Propranolol	20 to 160 mg/d	Monitor blood pressure
Weight gain	Ziprasidone Aripiprazole	Dictated by positive symptom response	Prevention more effective than remediation
Non-adherence	Olanzapine oral disintegrating tablets Risperidone liquid Risperidone microspheres	5 to 20 mg/d 1 to 4 mg/d IM injections every 2 weeks	Dissolves instantly Can be mixed with water, coffee, orange juice, or low-fat milk Not yet available
* Fluoxetine and paroxetine increase risperidone levels by CYP-P450 2D6 inhibition; fluvoxamine increases clozapine and olanzapine levels by CYP-P450 1A2 inhibition; fluvoxamine and nefazodone increase quetiapine and may increase ziprasidone levels by CYP-P450 3A4 inhibition; all three CYP-P450 inhibitors may increase aripiprazole levels, but the extent is not known.
ECT: electroconvulsive therapy; SSRI: selective serotonin reuptake inhibitor; SNDRI: serotonin-norepinephrine-dopamine reuptake inhibitor; NDRI: norepinephrinedopamine reuptake inhibitor; SARI: serotonin antagonist and reuptake inhibitor; NASA: norepinephrine-antagonist and serotonin antagonist.