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Microsoft word - recovery -schizophrenia - bipolar.doc

Is There a Psychopharmacology of Recovery from
Medical parallel:
treatment of complicated medical
illness such as cancer requires clinician to be good
strategist and good technician; same applies to
complicated psychiatric illness such as schizophrenia
Current challenges in treating severe mental illness:
cure unlikely for most patients;
-more medication choices than ever,
-more chances to “get it right”
-more chances to “get it wrong”;
-controversy about degree to which newer medications
can improve outcome;
-newer antipsychotic medications still have burden of side
effects different from that of older antipsychotics (eg,
newer antipsychotics have reduced neurologic burden but
increased metabolic burden)
Treatment models in schizophrenia:
phase-of-illness model
goal of keeping patient stable and avoiding relapse;
-hierarchical model,
-treatment progresses in linear fashion, from stabilizing
patient to reducing burden of treatment and/or burden of
disease to recovery (no consensus on what constitutes
recovery in schizophrenia; clinician, patient and family,
and insurance company have differing definitions)
Treatment goals in schizophrenia:
remission—concept derived from treatment of affective
disorders, in which it means patient has no symptoms; in
schizophrenia, it means symptoms may be present but do
not interfere with patient’s functioning or quality of life;
recovery—defined by President’s New Freedom
Commission on Mental Health as “process in which
people are able to live, work, learn, and participate fully
in their communities; for some individuals,
recovery is the ability to live a fulfilling and productive
life despite a disability”; ie, patient may experience
symptoms but still lead full productive life
Recovery model in schizophrenia: key assumptions
-deterioration not inevitable
- stability marks beginning, not end, of treatment;
-goals are for achieving individual’s health rather than
comparing him or her to others with persistent illness;
-specific goals chosen by patient, not family or clinician
Reasons recovery-oriented treatment realistic in
-ascendancy of neurodevelopmental model over
neurodegenerative model;
-evidence for continued improvement over and above
stabilization with newer medications;
-evidence that psychosocial interventions can reduce
persistent symptoms;
-consistency of differences of side-effect profiles across
antipsychotic treatment options
Recovery-oriented approach to medication
-patient sets goals and frustrations;
-match frustrations with target symptom that can be
treated and
-work with patient to identify priority symptom to
-advise patient not to stop medications
-Persistent positive symptoms: optimize current
medication regimen before changing medications;
-anticholinergics attenuate response to antipsychotics; -
-antidepressants delay or attenuate response to
-rule out nonpharmacologic causes of poor treatment
Cognition: news mixed; Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) study showed that
-newer antipsychotics have limited benefits on cognition,
relative to older antipsychotics;
-anticholinergic estimated to account for ≈50% of
cognitive dysfunction in patients taking anticholinergic; -
-when asked which symptoms most frustrating, most
patients say cognitive symptoms and affective symptoms
trump positive symptoms and negative symptoms;
-first consideration is not to make cognitive symptoms
-Depression: newer antipsychotics better for attenuating
comorbid depression; if depression continues, consider
whether antidepressant or psychosocial intervention better
adjunct, remembering that antidepressants can aggravate
psychosis in some patients
Adverse events and burden of treatment: theoretically,
antipsychotic response can be achieved without side
effects; difficult and requires good strategy;
extrapyramidal side effects and sedation not necessary
components of treatment;
-assess level of distress and risks of treatment modalities
New Treatment Options for Bipolar Disorder
in registration studies, in both mania and
depression, antipsychotics provide 20% benefit (on
average) over placebo; average number of medications in
patients with bipolar disorder is 5
Divalproex (Depakote): monotherapy—studies found
that “loading divalproex could be effective,” and loading
strategy used in registration studies for divalproex
extended release (ER); starting dosage 25 mg/kg per day,
rounded up to nearest 500, then increased by another 500
mg on day 3; combination therapy— in American
approach, foundational therapy is mood stabilizer (lithium
or divalproex), with atypical antipsychotic added; in
European approach, foundational therapy is antipsychotic,
with mood stabilizer added; in European trial, valproate
added to antipsychotic achieved extra benefit of 20% to
25% over antipsychotic monotherapy
Carbamazepine (Tegretol): monotherapy—benefit
≈20% over placebo; starting dosage 400 mg/day in
divided doses produced “fair bit of toxicity”; suggest that
starting with 200 mg/day and increasing by 200 mg every
other day decreases toxicity; carbamazepine lowers blood
levels of “almost everything” except maybe ziprasidone;
combination therapy
in trial of acute mania where olanzapine (Zyprexa) or
added to carbamazepine, no additional benefit seen;
in study where risperidone added to carbamazepine, 40%
decrease in risperidone blood levels, and patients on
carbamazepine had to be censored to see add-on
risperidone separate from placebo and other mood
stabilizers; carbamazepine should have no
pharmacokinetic interaction with lithium, excreted
lithium, even olanzapine, failed to show additional benefit
when added to carbamazepine
Bipolar disorder: patients symptomatic about half the
time, and depression more common than mood elevation;
Systematic Treatment Enhancement Program (STEP)
showed in depressed patients that adding antidepressant to
mood stabilizer does not add much benefit over mood
stabilizer alone, and mood stabilizer alone achieved only
≈25% response; with mood stabilizer as monotherapy
in depressed patients, perhaps adding antidepressant
later; if antidepressant does not work, try atypical
Pramipexole (Miramex): 2 trials show it may work as add-on, but only 22 patients total, and “there were some mood switches”; speaker starts with 0.125 mg at bedtime and increases every 4 days to 1.75 mg; “look out for nausea” Other add-ons: 1 trial showed 22% response rate to modafinil (Provigil), with 4.9% switch rate; gabapentin shown not to be effective as primary treatment for mania or for treatmentresistant rapid-cycling bipolar disorder, but may be useful in comorbid conditions such as anxiety or pain Lamotrigine: in trials, lamotrigine worked well in terms of response rate, but placebo worked well also; not indicated for acute bipolar depression or acute mania; may be effective in preventing recurrent depression; combination of lamotrigine and lithium may prevent depressive and manic episodes; in study, lamotrigine effective in treatment-resistant rapid cycling Topiramate Topomax): ineffective in acute mania, but patients lost weight; may be effective in treating comorbid disorders such as eating disorders, alcohol dependence, and migraine; can cause metabolic acidosis Zonisamide (Zonegran): produced weight loss in obese
people with no psychiatric disorder and in obese people
with euthymic
medicated bipolar disorder; long half life; cannot be used
by patients with sulfonamide allergy; weight loss and
tolerability adequate in one third of patients, intolerance
in onethird, and it “just doesn’t work” one-third;
metabolic acidosis can occur
Oxcarbazepine (Trileptal): “data not too encouraging”;
consider oxcarbazepine if patient has failed
carbamazepine or is too unreliable to comply with blood
testing associated with carbamazepine
Atypical antipsychotics: all seem to work in mania;
clozapine is only atypical antipsychotic not approved by
Food and Drug Administration (FDA) for use in bipolar
mania; clozapine helpful if patient unable to sleep, but
requires blood testing because of risk for agranulocytosis
Risperidone: response ≈20% compared to placebo; if
added to lithium or divalproex, additional benefit seen
Olanzapine: response rate 20% to 25%; doses in trials 10
mg/day to 20 mg/day; in head-to-head trial with
divalproex, olanzapine slightly better in efficacy, but
divalproex slightly better in tolerability;
in head-to-head trial with lithium, olanzapine slightly better in relapsing mania, but associated with more weight gain than lithium Olanzapine plus fluoxetine combination: response “so-so” with 7.5 mg of olanzapine and 40 mg of fluoxetine per day; “if you absolutely have to use an antidepressant in bipolar depression and you want to do evidence-based medicine, this is what you would do”; in head-to-head trial with lamotrigine, combination had 9% response rate vs 7% weight gain Quetiapine (Sertoquel): response rate ≈17%; must be titrated to avoid hypotension Other atypical antipsychotics: ziprasidone (Geodon) and aripiprazole (Abilify), “we know [they] work in acute mania”; aripiprazole has maintenance indication; asenapine (Saphris)—separated from placebo on primary-outcome measure but not on response rate Emerging uses for atypical antipsychotics in bipolar disorder: primary therapies—olanzapine for mania, maintenance, and, when combined with fluoxetine, depression; risperidone, ziprasidone, and asenapine for mania; quetiapine for mania and depression; aripiprazole for
mania and maintenance;
adjunctive therapies—olanzapine and risperidone
for mania; quetiapine for mania and maintenance;
clozapine for treatment resistance
Conclusions: many new agents with diverse mechanistic
efficacy and side-effect profiles in development; new
anticonvulsants as class not effective in acute mania and
have variable efficacy in bipolar disorders and comorbid
conditions; newer antipsychotics as class effective in
acute mania and show emerging efficacy in acute
depression and maintenance



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