References

1. Stahl SM, Mood Disorders, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 453–5102. Stahl SM, Antidepressants, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 511–6663. Stahl SM, Mirtazapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 347–514. Stahl SM, Venlafaxine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 579–845. Trivedi MH, Rush AJ, Wisniewski SR et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28–406. Rush AJ, Trivedi MH, Wisniewski SR et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354(12): 1231–427. Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905–178. Warden D, Rush AJ, Trivedi MH et al. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep 2007; 9(6): 449–599. Judd LL, Akiskal HS, Maser JD et al. Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord 1998; 50(2–3): 97–10810. Kendler, KS, Thornton, LM, Gardner, CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. Am J Psychiatry 2000; 157: 1243–51

Lightning RoundThe Case: The psychotic arsonist who burned his house and tried to burn himself

The Question: How to keep an uncooperative 48-year-old psychotic man with menacing behavior under behavioral control

The Dilemma: What can you do after you think you have blocked every dopamine receptor and cannot give clozapine?

Pretest Self Assessment Question(answer at the end of the case) Which of the following is a reasonable approach to treatment resistant sychosis when clozapine is not an option?

A. Augment depot risperidone (Consta) with aripiprazole (Abilify)

B. Dose olanzapine (Zyprexa) >40 mg/day

C. Dose olanzapine to attain plasma drug levels between 5–75 ng/ml

D. Dose olanzapine to attain plasma drug levels >120 ng/ml but lower than 700–800 ng/ml which are associated with QTc prolongation

E. Use olanzapine with risperidone

F. Augment with lamotrigine (Lamictal)

G. Augment with high dose benzodiazepines

H. Use nonpharmacologic interventions

Patient Intake 48-year-old man diagnosed with paranoid schizophrenia and alcohol dependence (now in a controlled environment) with a 23-year history of alcohol abuse and relapse, and a 16-year history of psychotic illness

Referred by his treating psychiatrist for expert psychopharmacological consultation because the patient continues to have symptoms despite heroic treatment with antipsychotics

Multiple prior psychiatric hospitalizations with history of poor compliance

Predominant symptoms are persecutory ideation, ideas of reference, auditory hallucinations, and disorganized thinking with history of suicide attempts

History of thrombocytopenia, considered a contraindication for clozapine by medical consultants

History of alcohol and marijuana abuse

At least one first degree relative with a psychotic illness

Current hospitalization resulted from an incident in which the patient believed that his family was being abused via the internet and thus he needed to burn down his house to stop it, which he did, plus dousing himself with gasoline intending to commit suicide but was unable to successfully light himself on fire

Arrested and convicted of the acts but found not criminally responsible by reason of insanity and admitted to a forensic facility

Psychiatric History Patient continues to have irritability, low frustration tolerance and bizarre, violent, and sexual delusions

Has persecutory delusions that the CIA is after him, has labile and inappropriate affect, pacing, laughing to himself

He believes the staff have glued braces on his arms and legs

Has threatened to strangle staff and has grabbed a female staff member

Believes that local police raped his family and are projecting images onto the outside of a glass building of him and his wife having sex

Treatment History Many previous antipsychotics given with unclear efficacy, unclear compliance, but had a dystonic reaction to haloperidol previously

Seems to have responded to a combination of aripiprazole 30 mg plus quetiapine (Seroquel) 200 mg qhs prior to this hospitalization when he was compliant for a short period of time

During this hospitalization, has been partially responsive to depot risperidone 37.5 mg every 2 weeks, so the dose was increased to 75 mg every 2 weeks with further improvement of symptoms but not adequate remission

Now on depot risperidone 50 mg every 2 weeks plus aripiprazole 30 mg with continuing inadequate control

Of the following choices, what would you do?

Increase the risperidone dose

Increase the aripiprazole dose

Stop the aripiprazole

Add a second antipsychotic

Add lamotrigine

Add benzodiazepine

Case Outcome: First Interim Followup Recommended increase of depot risperidone to 37.5 mg every week, as it is theoretically possible that further blockade of dopamine D2 receptors could be helpful

Recommended discontinuation of aripiprazole because this can interfere with risperidone actions, since aripiprazole has a higher affinity at the D2 receptor than risperidone, but is only a partial agonist, thus potentially mitigating the therapeutic actions of risperidone

This was done, but after 1 month, was ineffective

Recommended augmentation with lamotrigine, also ineffective

Although quetiapine was helpful in the past, for some reason the patient is refusing this at the present time

Of the following choices, what would you do?

Switch to another antipsychotic

Add another antipsychotic to depot risperidone

Give prn injections of haloperidol (lorazepam, diphenhydramine)

Give a daily benzodiazepine

Case Outcome: Second Interim Followup Added olanzapine 5 mg daily, going up 5 to 10 mg per week to 40 mg/day

Behavior necessitates use of concomitant haloperidol, lorazepam, diphenhydramine prn IM or olanzapine IM prn

Patient not sedated, nor orthostatic, with olanzapine plasma drug level 46 ng/ml, so cautiously increased dose of olanzapine to 30 mg twice a day

Plasma olanzapine level 94 (target range supposedly 5–75 ng/ml for routine cases; 125 ng/ml for refractory cases, avoiding levels seen in overdose with QTc prolongation such as 700–800 ng/ml)

EKG normal, with QTc 384

Increased olanzapine transiently to 30 mg three times daily, but patient became sedated

Lowered dose of olanzapine to 30 mg twice daily, and augmented with clonazepam titrating up to 2 mg twice daily

Patient now under relative control without needing prn injections and not sedated

Patient is gaining weight and lipids are elevated

Case Debrief It appears as though this patient does have an improved response to eye-popping doses of two antipsychotics

Almost no written documentation in the literature for treating cases at these doses

The dilemma is whether to risk the danger to the staff and to the patient by treating with ineffective but evidence-based doses, or to risk medical complications of heroic (or desperate) off-label use

A treatment committee with a patient advocate reluctantly approved this treatment approach, with quarterly reviews and the patient and family agree to this extraordinary treatment approach in writing

Posttest Self Assessment Question: Answer Which of the following is a reasonable approach to treatment resistant psychosis when clozapine is not an option?

A. Augment depot risperidone with aripiprazole

– Aripiprazole can interfere with risperidone actions so is not a totally rational combination

B. Dose olanzapine >40 mg/day

– Almost no published data on this approach, but some anecdotal experience in institutional settings in extremely unusual and well selected cases

C. Dose olanzapine to attain plasma drug levels between 5–75 ng/ml

– These are standard levels for standard doses, and probably will be inadequate for this case

D. Dose olanzapine to attain plasma drug levels >120 ng/ml but lower than 700–800 ng/ml which are associated with QTc prolongation

– Many are uncomfortable with this approach, and almost no published data on this approach, but these are the plasma levels associated with olanzapine treatment above 40 mg/day and might be helpful in extremely unusual cases

E. Use olanzapine with risperidone

– Generally better to give one drug at a high dose rather than two drugs at regular doses and this is also very expensive in practice, with almost no experience to guide long term use, yet some anecdoates from heroic cases suggest it may be occasionally justified

F. Augment with lamotrigine

– This is fairly standard

G. Augment with high dose benzodiazepines

– Although this can be helpful, one has to think twice in an alcoholic patient; however, in an institutional setting without access to alcohol, it may be a viable if reluctant option

H. Use nonpharmacologic interventions

– This is obvious, but seclusion, restraint, isolation or disciplinary housing are not long term options and often are instituted after an assault, and may not prevent assaults to others or self harm

Answer: B, D, E, F, G and H