References

1. Bora E, Yucel M, Fornito A et al. Major psychoses with mixed psychotic and mood symptoms: are mixed psychoses associated with different neurobiological markers? Acta Psychiatr Scand 2008; 118: 172–872. Maier W Do schizoaffective disorders exist at all? Acta Psychiatr Scand 2006; 13: 369–713. Maier W. Common risk genes for affective and schizophrenic psychoses. Eur Arch Psychiatry Clin Neurosci 2008; 258 (suppl 2): 37–404. Vollmer-Larsen A, Jacobsen TB, Hemmingsen R et al. Schizaffective disorder – the reliability of its clinical diagnostic use. Acta Psychiatr Scand 2006; 113: 402–75. Robinson DG, Woerner MG, McMeniman M et al. Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 2004; 161: 473–96. Azorin JM, Long term treatment of mood disorders in schizophrenia, Acta Psychiatr Scand 1995; 91 suppl 388: 20–37. Hafner H, Maurer K, Trendler G et al. Schizophrenia and depression: challenging the paradigm of two separate diseases – a controlled study of schizophrenia. depression and healthy controls. Schiz Res 2005; 77: 11–248. Lake CR, The validity of schizophrenia vs bipolar disorder. Psychiatric Annals 2010; 40: 77–879. Laursen TM, Labouriau R, Licht RW et al. Family history of psychiatric illness as a risk factor for schizoaffective disorder: a Danish register based cohort study. Arch Gen Psychiat 2005; 62: 841–810. Maier W, Zobel A, Wagner M, Schizophrenia and bipolar disorder: differences and overlaps. Current Opinion in Psychiatry 2006; 19: 165–7011. Stahl SM, Psychosis and Schizophrenia, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 247–32612. Stahl SM, Antipsychotic Agents, in Stahl’s Essential Psychopharmacology, Cambridge University Press, New York, 2008, pp 327–45213. Stahl SM, Clozapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 113–814. Stahl SM, Lamotrigine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 171–5

Patient FileLightning RoundThe Case: The scary man with only partial symptom control on clozapine

The Question: How to manage breakthough positive symptoms as well as chronic negative symptoms in a 48-year-old psychotic patient with history of homicide and suicide attempts?

The Dilemma: What do you do when even clozapine does not work adequately?

Pretest Self Assessment Question(answer at the end of the case) What are potential evidence-based treatment strategies for psychotic patients with inadequate responses to clozapine?

A. Maintain plasma clozapine levels between 200–300 ng/ml

B. Raise clozapine dose up to 900 mg/day

C. Maintain plasma clozapine levels between 400–600 ng/ml

D. Augment with lamotrigine

E. Augment with a second antipsychotic

Patient Intake 48-year-old man diagnosed with schizophrenia, disorganized type, has a 31-year history of psychotic illness

Referred by his treating psychiatrist for consideration of augmentation of clozapine with another agent because he continues to have breakthough symptoms of threatening behavior to himself and to others with a history of acting upon these threats

Hospitalized in a forensic unit with hallucinations, ideas of reference, bizarre behavior, severe psychomotor agitation and self destructive behavior, including numerous suicide attempts in the past such as swallowing razor blades and jumping from a motorcycle; also elopement from psychiatric facilities and assault on others, including murdering his friend by hammering him in the head because he thought he was a vampire

Found mentally incompetent to stand trial and now resides in a forensic facility

Psychiatric History After partial and inadequate responses to many antipsychotics, clozapine (Clozaril) treatment (300 mg twice a day, with plasma concentrations in the presumed optimal range of 400–600 ng/ml) has improved many positive symptoms, but the patient continues to have prominent negative symptoms as well as denial of illness and denial of the murder of his friend

Upon provocation he rapidly develops threatening behavior to himself and others

Higher doses of clozapine may have more efficacy but also more side effects including seizures

There is little guidance for what to do when clozapine at adequate doses is not sufficiently efficacious

Patient is also taking fluvoxamine (Luvox, Favrin) 25 mg twice a day for depressive symptoms, a medication that can itself raise clozapine levels by blocking CYP450 1A2 which partially metabolizes clozapine

Of the following choices, what would you do?

Switch to another antipsychotic

Increase clozapine dose to attain plasma concentrations > 600 ng/ml

Augment with lamotrigine (Lamictal)

Augment with risperidone (Risperdal)

Augment with a benzodiazepine

Increase fluvoxamine dose

Leave well enough alone

Case Outcome Patient was too dangerous to himself and others to do nothing, yet high clozapine doses were deemed too dangerous for him

Lamotrigine was given, titrating up to 200 mg twice a day over a few months, but no improvement was seen after 3 months and several acting out episodes in the interim required restraint

Lithium was considered as a potential adjunct for self injurious and suicidal behavior, but clozapine is also useful for suicidal behavior, and a more rapid and robust plan was needed to prevent assaults on other patients and staff

Augmentation with a second antipsychotic was considered, including intramuscular acute dosing of haloperidol (Haldol), olanzapine (Zyprexa) or ziprasidone (Geodon, Zeldox), but this was not practical for long term treatment

He was instead given oral risperidone, the one antipsychotic best studied in combination with clozapine, but with mixed results in the literature

With a step-wise increase to 3 mg/day of risperidone augmenting clozapine 300 mg twice a day, the patient experienced only rare break through symptoms, and was not as provocable

Case Debrief It appears as though this patient has a very malignant psychotic illness associated with violent and dangerous behaviors

The patient’s symptoms were only partially controlled by clozapine, but prior antipsychotics were even less effective

Not clear what therapeutic role fluvoxamine is playing here nor whether it needs to be continued long term

Lamotrigine augmentation failed but risperidone augmentation was successful

This suggests that, for this patient, despite supposedly fully therapeutic doses of clozapine, D2 dopamine receptors are not fully saturated and that additional D2 antagonism by risperidone was therapeutic

If the patient relapses on current treatment regimen, his response to risperidone augmentation suggests that he might be a candidate either for an even higher dose of risperidone or even a dose increase of clozapine

Also, amisulpride (not available in the US) augmentation of clozapine has been studied with some good results reported

Posttest Self Assessment Question: Answer What are potential evidence-based treatment strategies for psychotic patients with inadequate responses to clozapine?

A. Maintain plasma clozapine levels between 200–300 ng/ml

– This is clearly not the way to go because this is considered subtherapeutic

B. Raise clozapine dose up to 900 mg/day

– Not a first choice, since will likely result only in more side effects and not necessarily more therapeutic effects

C. Maintain plasma clozapine levels between 400–600 ng/ml

– This is already being done, so seems like a necessary but not sufficient answer

D. Augment with lamotrigine

– – This is reasonable and has some evidence to support it

E. Augment with a second antipsychotic

– This might also be reasonable, if expensive and with potentially additive side effects. Risperidone might be the best choice but other agents in this class could be rationally considered

Answer: C, D and E