Medication Management of Early Psychosis and Ultra-High Risk States

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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

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EARLY PHASES OF SCHIZOPHRENIA
Functioning
PREMORBID
PRODROME
PSYCHOTIC
Course of Illness
ProdromeUltra-High Risk StateAt Risk Mental
State
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Prodromal or Ultra-High Risk (UHR) states

• In majority of schizophrenic patients, a
  prodromal phase is evident. Duration of prodrome
  from lt 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).

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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.

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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

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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.

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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.

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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).

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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.

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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.

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Dosing Strategies

• In 1960s and 70s, with advent of high potency
  agents, high dose strategies became popular ( gt
  2000 mg of CPZ equiv)
• Practice was to titrate doses up until acute EPS
  appeared, then anticholinergic compounds were
  added.
• Rapid neuroleptization ---gt 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).

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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 patients
  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.

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Maintenance Treatment

• Among schizophrenic patients in remission for gt 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.

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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 clinicians recommendation, better to
  work with patient and maintain therapeutic
  alliance than to alienate patient.

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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

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Side Effects of Typical Agents I
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Side Effects of Typical Agents II
Retinitis pigmentosa low avoid Mellaril
Tardive Dyskinesia
5 risk per year
Clozapine
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Adverse Effects of Atypical Agents
Other adverse events Type II diabetes Hyperlipide
mia Long-term risk of Tardive Dyskinesia has not
been ruled out.
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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.

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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.

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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.

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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)

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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.

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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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Thank you