Medication Management of Early Psychosis and Ultra-High Risk States

1. Medication Management of Early Psychosis and Ultra-High Risk States Daniel H. Mathalon, M.D., Ph.D. Demian Rose, M.D., Ph.D. University of California, San Francisco

2. EARLY PHASES OF SCHIZOPHRENIA Functioning PREMORBID PRODROME* PSYCHOTIC Course of Illness *Prodrome=“Ultra-High Risk State”=“At Risk Mental State”

3. “Prodromal” or Ultra-High Risk (UHR) states • In majority of schizophrenic patients, a prodromal phase is evident. Duration of prodrome from < 1 year to several years (mean 1-2 yrs). • Current prospective definitions of the schizophrenia prodrome: • PACE II Criteria in Melbourne (Yung, Phillips, McGorry et al, 1998), • COPS Criteria at Yale (Miller et al, 2002), tied to SIPS interview. • These have defined the prodrome as comprising 3 syndromes: • Attenuated positive symptom state: Non-psychotic, pre-delusional unusual thought content; pre-hallucinatory perceptual abnormalities; or subthreshold disorganization of speech. • Brief intermittent psychotic state: Psychotic symptoms emerging in the recent past that are too brief to meet criteria for psychotic disorder. Symptoms present at least several minutes per day at least once per month. • Genetic risk and deterioration state: Genetic risk for psychosis (first degree relative with any psychotic disorder, affective or nonaffective; and/or patient has schizotypal personality disorder) plus a loss of social or work capacity, or both, in past month (= at least 30 point drop GAF).

4. Prodromal (UHR) Syndrome and Psychosis Risk • 22% - 54% of prodromal patients identified by these criteria convert to psychosis within 1 year. • Recent NAPLS Study: 35% conversion to psychosis by 2.5 years.

5. Prodromal States vs. Early Psychosis: A Diagnostic Challenge • Psychosis involves: • Delusions (e.g., persecutory, grandiose, ideas of reference) • Hallucinations (typically auditory) • Disorganization of thought process (tangentiality, derailment, loosening of associations, incoherence). • Can be part of presentation of first episode of • Schizophrenia (or schizophreniform disorder) • Schizoaffective disorder • Bipolar disorder - manic or depressed phase of illness. • Drug induced psychosis (especially stimulant abuse) • Other conditions…

6. Prodromal States vs. Early Psychosis: • Crossing the line: When is symptom considered psychotic and no longer prodromal? (SIPS Criteria): • Individual has psychotic symptoms now. • Believes that the hallucinations or delusion are “true”, i.e., no longer ambivalent or uncertain about the symptom (e.g., not just mind playing tricks or “possibly true”). • Symptoms are present for at least an hour each day, four days per week on average, over a 1 month period. • If severity is sufficient to be dangerous or “disorganizing” (i.e, threat to livelihood, family relationships, dignity)…then psychosis is considered present regardless of duration.

7. Treating the Prodrome: Very Few Controlled Studies • McGorry et al. (2002) • Randomized, non-blind, comparison of risperidone +psychosocial treatment vs. supportive monitoring. • Modestly significant reduction in 6-month conversion rate. • No difference by 12 months-so modest delay in psychosis onset. • McGlashan et al. (2006) • Randomized, double-blind, comparison of olanzapine vs. placebo on 12-month conversion rate. • Only statistical trend level reduction of 12-month conversion rate. • Weight gain a major problem in active treatment group. • Morrison et al. (2004) • Randomized, non-blind, comparison of CBT vs. supportive treatment (as usual) on 12-month conversion rate. • Significant reduction in 12-month conversion rate.

8. McGlashan et al, 2007, Schizophrenia Bulletin • “As a collection, these studies unquestionably support further treatment research in the prodrome, but they cannot be said to support any particular treatment strategy at the present time other than intensive follow along. Any treatment that is provided for patients meeting current criteria for the prodrome must continue to be regarded as experimental” (p. 716).

9. Psychosis Risk in UHR Patients • 65% of patients identified as prodromal by SIPS interview will not develop a psychotic disorder within 2.5 years. • Most may never develop a psychotic disorder. • Limited evidence of benefit from controlled treatment studies. • Risk/benefit ratio does not currently support treatment with anti-psychotic medication.

10. Medication Treatment Decisions in Early Psychosis • Longer duration of untreated psychosis is associated with worse clinical outcomes and worse responses to medication. • Risk/Benefit ratio supports treatment with anti-psychotic medication as soon as psychosis is present.

11. Dosing Strategies • In 1960s and 70s, with advent of high potency agents, high dose strategies became popular ( > 2000 mg of CPZ equiv) • Practice was to titrate doses up until acute EPS appeared, then anticholinergic compounds were added. • “Rapid neuroleptization” ---> More rapid recovery? • Hypothesis was not supported by data. • By late 80s, became clear from numerous dosing studies that maximum beneficial effects of neuroleptics likely to occur at doses at or below 600 mg chlorpromazine (10-15 mg haloperidol). • Recent studies suggest effectiveness of very low doses in first episode patients (5 mg haloperidol, see Zipursky et al).

12. Anti-psychotic Treatment of Early Psychosis • Low-doses work well for most patients • Higher doses in acute phase sometimes used for “chemical restraint. True anti-psychotic effect does not require high dose. • Takes between 2 to 4 weeks to show an initial response and 6 months or longer to show full or optimal response. • Higher doses are associated with side effects (e.g., Parkinsonism, dystonic reactions, sedation) that can adversely affect the patient’s attitude toward medications and his/her longer-term adherence to medication treatment. • Avoid use of multiple anti-psychotics, either in rapid succession, or in combination. • Give each medication a sufficient trial before moving to another. • No evidence that combining different anti-psychotics is any safer or more effective than using higher doses of a single agent. • Same dopamine D2 receptors are being acted upon by all current anti-psychotic medication.

13. Maintenance Treatment • Among schizophrenic patients in remission for > 1 year, 75% will relapse within 12-18 months after discontinuation of antipsychotic. • Benefit of maintenance treatment (many studies) • Lower doses possible, but will increase relapse rate • Superior to intermittent treatment • D/C once stable, then restart at earliest sign of relapse. • Objective was to limit acute and long-term adverse effects • Relapse rate was two-fold greater than maintenance over 1 yr. • Despite maintenance, 15-20% of patients will relapse in any given year.

14. Anti-Psychotic Treatment of Early Psychosis: How long to treat? • Patients recovering from a first psychotic episode are often unconvinced about their need to remain on anti-psychotic medication once symptoms have abated. • Recommend that patients remain on medication for at least 6 months to 1 year before considering taper. • Educate patient and family to watch for return of symptoms. • Patient should continue regular appointments to monitor for symptoms. • Patients with residual psychotic symptoms should remain on medication. • Studies have shown strategy of episodic treatment of psychotic episodes or exacerbations followed by medication taper to lead to more frequent relapses and hospitalizations. • Ultimately, if patient wishes to stop medication despite clinician’s recommendation, better to work with patient and maintain therapeutic alliance than to alienate patient.

15. Risks of Treatment with Anti-Psychotic Medication • Anti-psychotics are not benign medications. • Risks are considerable. • Typical vs. “Atypical” Agents- • Typical agents • E.g. Haldol, Prolixin, Trilafon, Thorazine • Atypical Agents- • Clozapine • Olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole

16. Side Effects of Typical Agents I

17. Side Effects of Typical Agents II Retinitis pigmentosa low avoid Mellaril Tardive Dyskinesia 5% risk per year Clozapine

18. Adverse Effects of Atypical Agents Other adverse events: Type II diabetes Hyperlipidemia Long-term risk of Tardive Dyskinesia has not been ruled out.

19. CATIE STUDY (Lieberman et al, 2006) • Patients are no more likely to tolerate and remain on an atypical antipsychotic than a typical antipsychotic. • Significant weight gain, hyperlipidemia, type-II diabetes are major concerns. • Clinical benefit of atypicals is questionable, particularly in light of their cost.

20. Non-psychotic symptom domains in UHR and Early Psychosis Patients • Depression: • Consider anti-depressants (SSRI, SNRI) • Careful history to rule out prior manic or hypomanic episodes before starting anti-depressant. • If history of mania or hypomania is clearly present, start a mood stabilizer before adding anti-depressant. • First line mood stabilizers in non-psychotic patients include lithium, valproate, carbamazepine, lamotrigine. • In psychotic patient, anti-psychotic medication also provides mood stabilization to protect against anti-depressant induced mania. • In adolescents, pay special attention to suicidal ideation and suicide risk during treatment with anti-depressants.

21. Non-psychotic symptom domains in UHR and Early Psychosis Patients • Anxiety: • Consider using anti-depressants (SSRI, SNRI) for longer term management of anxiety disorder. • Consider using benzodiazepines for immediate relief of anxiety symptoms. • Insomnia: • Treat with benzodiazepines, antihistamines, or trazodone. • Acute insomnia can trigger mania in patients with underlying bipolar disorder, so protection of sleep is important.

22. Non-psychotic symptom domains in UHR and Early Psychosis Patients • Attention Deficits: • Can be seen in schizophrenia prodrome. • Use of stimulants that enhance dopamine transmission (methylphenidate, dextroamphetamine) may pose a risk of potentiating a psychosis in prodromal individuals. • No evidence for this -- still just a theoretical risk. • Alternative non-stimulant treatments may be better choice if ADD is a concern: • Wellbutrin (buproprion) or Strattera (atomoxetine)

23. Enlist the Patient and Family as Partners in Medication Decisions • Explain risks/benefits. • Educate them about potential side effects. • Explain DUP data. • Emphasize that trial can be stopped if patient cannot tolerate medication or if it does not seem to help. • Better to know what patient is actually taking rather than creating the perception that the clinician expects treatment compliance or would disapprove of non-compliance.

24. Conclusions • Ultra-high risk (prodromal) states vs. early psychosis: • A diagnostic challenge • A critical distinction for medication treatment decisions • Different risk-benefit ratios when considering medications in psychotic vs. pre-psychotic conditions. • UHR patients • Routine use of anti-psychotics is premature and is not recommended. • Based on current research, risks of these medications outweigh their potential benefits. • Supportive psychotherapy, education of patient and family, forging a strong therapeutic alliance, are all mainstays of treatment. • Early Psychosis • Treat with anti-psychotic medication as soon as possible to improve treatment response and clinical outcome. • Use low doses and give each dose time to work. • Supportive psychotherapy, education of patient and family, forging a strong therapeutic alliance, are all mainstays of treatment, and facilitate adherence. • May take 6 months to a year to find a regimen that works and that a patient can tolerate. • In Both Groups: • Treat depression, anxiety, insomnia, with appropriate medications and psychotherapy.

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