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, Mood stabilizers, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 667–7204. Stahl SM, Quetiapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 459–645. Stahl SM, Paroxetine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 409–156. 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): 97–1087. 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: 1243–518. Angst J. The Bipolar Spectrum. British Journal of Psychiatry 2007; 190: 189–1919. Judd LL, Akiskal HS, Schettler PJ et al. A prospective investigation of the natural history of the long term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60: 261–26910. Merikangas KR, Akiskal HS, Angst J et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the national Comorbidity Survey replication. Arch Gen Psychiatry 2007; 64(5): 543–5211. Benazzi F and Akiskal HS. How best to identify bipolar-related subtype among major depressive patients without spontaneous hypomania: superiority of age at onset. J Affect Disord 2008; 107(1–3): 77–8812. Ng B, Camacho A, Lara DR et al. A case series on the hypothesized connection between dementia and bipolar spectrum disorders: bipolar type VI? J Affect Disord 2008; 107(1–3): 307–1513. Akiskal HS and Benazzi F. Continuous distribution of atypical depressive symptoms between major depressive and bipolar II disorder: dose-response relationship with bipolar family history. Psychopathology 2008; 41(1): 39–4214. Vázquez GH, Kahn C, Schiavo CE et al. Bipolar disorders and affective temperaments: a national family study testing the “endophenotype” and “subaffective” theses using the TEMPS-A Buenos Aires. J Affect Disord 2008; 108(1–2): 25–3215. Oedegaard KJ, Neckelmann D, Benazzi F et al. Dissociative experiences differentiate bipolar-II from unipolar depressed patients: the mediating role of cyclothymia and the Type A behavior speed and impatience subscale. J Affect Disord 2008; 108(3): 207–1616. Savitz J, van der Merwe L and Ramesar R. Dysthymic and anxiety-related personality trait in bipolar illness. J Affect Disord 2008; 109(3): 305–1117. Correa R, Akiskal H, Gilmer W et al. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J Affect Disord 2010; 127(1–3): 10–8

Patient FileLightning RoundThe Case: The psychotic sex offender with grandiosity and mania

The Question: How to stabilize an assaultive patient with deviant sexual fantasies not responsive to standard doses of antipsychotics and mood stabilizers?

The Dilemma: Should heroic doses of quetiapine be tried when standard doses give only a partial response?

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

A. Dose olanzapine (Zyprexa) >40 mg/day to attain plasma drug levels >120 ng/ml but lower than 700–800 ng/ml which are associated with QTc prolongation

B. Dose quetiapine (Seroquel) up to 1200 mg/day

C. Dose quetiapine up to 1800 mg/day

D. Use olanzapine plus quetiapine

E. Use risperidone (Risperdal) with quetiapine

F. Augment with lamotrigine (Lamictal)

G. Augment with high dose benzodiazepines

H. Use nonpharmacologic interventions

Patient Intake 33-year-old man diagnosed with schizoaffective disorder, bipolar type, polysubstance abuse in remission in a controlled environment and antisocial personality disorder

Diagnosed as conduct disorder prior to age 18 with criminal activity, then after age 18 as a psychotic and mood disorder for the past 15 years, with intermittent assaultive behavior, grandiose and grossly disorganized thinking and behavior

Truancy, fighting, abuse of alcohol, methamphetamine and other drugs, continuing minor criminal activity

Dropped out of college age at 21 when drinking heavily and initially diagnosed as bipolar disorder and treated with lithium and carbamazepine (Tegretol); also later diagnosed as schizoaffective

Developed deviant sexual fantasies involving coerced sexual activity with adult women linked to grandiose delusions associated with hypersexuality in the context of mania but also without empathy or remorse

Then became intoxicated and joined a group in a park which raped and sodomized a woman; following arrest his charges were reduced to assault with a deadly weapon

Was convicted of this charge, sentenced to state prison, but required psychiatric treatment so that at the time of parole he was declared to be a mentally disordered offender and hospitalized in a forensic facility

Psychiatric History Despite treatment with standard doses of multiple different antipsychotics, continues to exhibit signs and symptoms of irritability, hostility towards women, loosening of associations, persecutory ideation, grandiose ideation, and auditory and visual hallucinations

Patient has low frustration tolerance and bizarre, violent, and sexual delusions, plus rape fantasies with the belief that by excessively washing his hands he can cleanse himself of sexually deviant thoughts

Continues to make verbal threats and engages in overt physical confrontations with staff and other patients and also exposes himself to other patients

He also has a low grade and intermittent leucopenia that medical consultants have not diagnosed but are reluctant to approve the patient for clozapine treatment

Treatment History Inadequate responses to standard doses of risperidone, haloperidol and olanzapine, plus lithium, carbamazepine, lamotrigine and valproate (Depakote)

Currently taking quetiapine 400 mg twice a day plus topiramate (Topamax) 200 mg twice a day

Of the following choices, what would you do?

Increase the quetiapine dose

Add a second antipsychotic

Add a benzodiazepine

Stop the topiramate

Case Outcome: First Interim Followup, Week 8 Recommended increasing the dose of quetiapine by 100 mg/wk to 1200 mg/day

No response in 8 weeks but tolerating it well

Some weight gain, little sedation

Is obese and has dyslipidemia

Of the following choices, what would you do?

Keep increasing the quetiapine dose

Add a second antipsychotic

Add a benzodiazepine

Stop the topiramate

Case Outcome: Second Interim Followup, Week 14 Recommended increase the dose of quetiapine by 100 mg/wk to 1400 mg/day

No response in 6 weeks; still tolerating it well

Recommended increasing the dose to 1800 mg/day

At 1800 mg/day, patient did remarkably well

Decline in auditory hallucinations, improvement in irritability, no further violent sexual fantasies and excessive handwashing declined

Case Debrief It appears as though this patient has some sort of mixed psychotic and mood disorder. During development, the patient showed signs of conduct disorder and later antisocial personality disorder without regard for his victims

He may also have a sexual disorder or paraphilia, as well as having conscious criminal intent, refusing to show remorse for his victims, and also refusing to pursue conditional outpatient treatment as he does not believe he should be required to participate in a criminal sex offender treatment program, this despite continuing to expose himself

It is not clear whether antipsychotic treatments can target all of his behavioral symptoms, and thus whether his treatment resistance is due to comorbid personality and sexual disorders or to treatment resistant psychosis

Nevertheless, given the severity of his condition, and few other options since many antipsychotics have failed, the cautious step-wise increase of quetiapine doses to heroic levels seems to have been empirically effective

Whether he is failing to absorb the drug, or is having therapeutic effects from actions of quetiapine other than blocking D2 dopamine receptors is not clear

Whether he could benefit from more standard doses of clozapine is not clear, but an intermittent and undiagnosed leucopenia makes medical consultants hesitant to approve him for clozapine treatment

There is almost no written documentation in the literature for treating cases at these doses of quetiapine, with the literature that does exist suggesting that 1200 mg/day is no more effective than 600 mg/day

The dilemma is whether to risk the danger to the staff and to the patient by treating with ineffective but evidence based doses of quetiapine, 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 agreed to this plan

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

A. Dose olanzapine >40 mg/day to attain plasma drug levels >120 ng/ml but lower than 700–800 ng/ml which are associated with QTc prolongation

– This appears to be a prudent choice with cautious monitoring

B. Dose quetiapine up to 1200 md/day

– Data suggest that this dose may have more side effects but not be more effective than 600 mg/day; however, anecdotes suggest that some patients respond to such high doses

C. Dose quetiapine up to 1800 mg/day

– Almost no significant experience with this dose, and only in institutional settings with extraordinary cases and extraordinary monitoring; like this case, some anecdotes suggest that only doses this high help some patients

D. Use olanzapine plus quetiapine

Antipsychotic polypharmacy is not well studied but may be justified when all monotherapies fail

E. Use risperidone with quetiapine

– Antipsychotic polypharmacy is not well studied but may be justified when all monotherapies fail

F. Augment with lamotrigine

– This is a standard recommendation with a bit of data to support it

G. Augment with high dose benzodiazepines

– Can help some patients but improvement may be proportional to sedation

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: All of the above in selected cases under unusual circumstances only.