References

1. Nardi AE and Perna G. Clonazepam in the treatment of psychiatric disorders: an update. Int Clin Psychopharmacol 2006; 21(3): 131–422. Rosenbaum JF. The development of clonazepam ass a psychotropic: the Massachusetts General Hospital Experience. J Clin Psychiatry 2004; 65(suppl5): 3–63. Rosenblaum JF, Moroz G, and Bowden CL. Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. Clonazepam Panic Disorder Dose-Response Study Group. J Clin Psychopharmacol 1997; 17(5): 390–4004. Susman J and Klee B. The role of high-potency benzodiazepines in the treatment of panic diosorder. Prim Care Companion J Clin Psychiatry 2005; 7(1): 5–115. Pollack MH, Otto MW, Tesar GE et al. Long-term outcome after acute treatment with alprazolam or clonazepam for panic disorder. J Clin Psychopharmacol 1993; 13(4): 257–636. Stahl SM, Mood Disorders, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 453–5107. Stahl SM, Antidepressants, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 511–6668. Stahl SM, Anxiety Disorders and Anxiolytics, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 721–729. Stahl SM, Stahl’s Illustrated Anxiety, Stress and PTSD, Cambridge University Press, New York, 201010. Stahl SM, clonazepam, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 97–10111. Stahl SM, duloxetine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 165–70

Patient FileThe Case: The man whose antipsychotic almost killed him

The Question: How closely should you monitor atypical antipsychotic augmentation in a Type 2 diabetic with treatment resistant depression?

The Dilemma: Can you rechallenge a patient with an atypical antipsychotic for his highly resistant depression when he developed hyperglycemic hyperosmotic syndrome on the medicine the last time he took it?

Pretest Self Assessment Question(answer at the end of the case) The presence of diabetes is a contraindication to treatment with atypical antipsychotics, especially high risk agents such as olanzapine or clozapine

A. True

B. False

Patient Intake 56-year-old man

Chief complaint of unremitting depression, unresponsive to treatments

Psychiatric History Prior to Diagnosis Although he has only been treated for the past 10 years, in retrospect, has always had mood fluctuations and other psychiatric comorbidities

As a child, adolescent and young adult, always a loner, few friends, chronic low grade depression

In teens and adulthood, always shy, inappropriate in social settings

Developed first major depressive episode 10 years ago after retiring as a firefighter and losing his routine, and this also occurred shortly after his third divorce

Social and Personal History Alcohol helped his social discomfort, so abused it until 1 year ago

Joined AA (Alcoholics Anonymous) and has been sober since

Abused LSD several years ago

Abused marijuana until one year ago, now only uses occasionally

Has used crack cocaine for a six month period of time approximately two years ago

“Made me feel great” and in fact possibly induced mania transiently

Married 3 times; 2 children from first marriage, one from the second, none from the third

Non smoker

Some college now retired after a long career as firefighter

Family History Mother: alcoholic

No first degree relatives with depression or bipolar disorder known

Medical History Thin, normal BP

Type II diabetes, good control on oral hypoglycemics

Medications One Year Following the First Episode of Depression Glucotrol

Glucophage

Levothyroxine

Prilosec

Lithium

Clomipramine

Psychiatric HistoryTreatment of Mood Disorder, Past 10 years Treated with SSRIs, venlafaxine, then hospitalized and received ECT

Transient improvement on ECT, relapsed on venlafaxine, tricyclic antidepressants

Rehospitalized, received ECT again, transient response again

Relapsed again despite treatment with MAO inhibitor phenelzene, and then augmentation of SSRIs with bupropion, lithium, valproate, lamotrigine, mirtazapine, stimulants, modafinil, then trials of protriptyline, and clomipramine plus lithium, all without effect

Patient Intake The patient was soft spoken, withdrawn, flat, monotone affect

Rates himself as 9 out of 10 on a 10 point scale of severity (10 worst)

Clearly suicidal; has thoughts of taking a garden hose and duct tapking it to his car exhaust to kill himself with carbon monoxide

States he does not do it because he still has some hope that he might get better and is also concerned that he does not want to hurt his children

Agrees to no harm verbally and wishes to try several treatment options and does not want to be hospitalized at the present time

Patient does not want ECT again as it causes memory problems

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation The patient clearly has had long standing social anxiety disorder with superimposed drug and alcohol abuse, the latter recently in remission

He has a recurrent depressive disorder, but unclear whether any of his hypomania was spontaneous or only cocaine-induced

Clearly is treatment-resistant

Has not tried an atypical antipsychotic

Based on just what you have been told so far about this patient’s history and recurrent episodes of depression, how would you treat him?

Refer for another neurostimulation treatment (VNS, TMS, DBS)

Treat with an atypical antipsychotic

Check therapeutic blood levels of his antidepressants to see if nonabsorption/rapid metabolism

Other

Case Outcome: First and Second Interim Followup, Weeks 1–4 The patient was given olanzapine 5 mg added to his regimen of lithium and clomipramine

He had an almost immediate response within about 3 days

Doing much better with renewed interest in life, resolution of suicidal thoughts and increased energy levels

Bought a puppy

No hypomania

About a month later, lost much of the effect, and increased olanzapine to 7.5 mg, and responded again, relapsed again in another month, increased olanzapine to 10 mg and responded again

However, got a call from the emergency room, patient presented with dehydration, confusion, obtundation and fever, with blood glucose over 600 but no ketosis or acidosis

Was diagnosed as HHS (hyperglycemic hyperosmotic syndrome), treated briefly with insulin and discharged off olanzapine

What do you think?

In retrospect, should olanzapine not have been given to this patient?

If given, should olanzapine treatment have been closely monitored with frequent blood glucose measurements?

Should diabetics avoid atypical antipsychotics?

Should a different atypical antipsychotic have been given?

Attending Physician’s Mental Notes: First and Second Interim Followup, Weeks 1 and 4 The patient, a known type II diabetic, developed a complication of atypical antipsychotic use

At the time of this evaluation, olanzapine had just been reported to be effective in treatment-resistant depression by the attending physician and colleagues, and there were no warnings yet about the risk for sudden DKA (diabetic ketoacidosis) or HHS (hyperglycemic hyperosmotic syndrome) in the literature or in FDA labels

The patient had stable glucose measurements for years, well controlled on oral hypoglycemics, the patient’s internist was aware of the treatment with olanzapine, but there was no specific monitoring of blood glucose levels in this patient following administration of olanzapine

The standard has now evolved so that warnings about acute and chronic complications of atypical antipsychotics should be given, and those risks weighed against the potential benefits of treatment

Also, some antipsychotics like olanzapine are considered higher risk for metabolic complications than other antipsychotics like ziprasidone or aripiprazole, but all agents have a class warning about metabolic complications

Case Outcome: Third Interim Followup As might be expected, discontinuation of the olanzapine led to relapse and recurrence of suicidal ideation

Now the patient feels desperate and without options

Referred for VNS which was available at the time (TMS not available then)

Received VNS and had an excellent response to it

Even experienced some hypomania on it

Because of some nausea during stimulation, the patient’s VNS stimulator was turned off for a while, and the patient relapsed, then responded again when stimulation began again

After about a year, the VNS was no longer effective and the patient fell back into a deep depression

Augmentation with quetiapine, aripiprazole and ziprasidone all ineffective once the VNS no longer worked

Felt forced to undergo ECT again, and this third set of treatments worked transiently, and fell back into deep depression despite maintenance ECT

Would you rechallenge this patient with olanzapine or prescribe a trial of clozapine?

Yes

No

Case Outcome: Third Interim Followup, Continued The patient was advised of the risks and benefits of another trial of olanzapine, and with the input of his internist and close metabolic monitoring, olanzapine was given again

The patient responded again but without any metabolic complications this time

However, the response was not sustained despite augmentation with lithium and the patient yet again relapsed into deep depression with recurrent suicidal ideation

The patient has not had therapeutic drug monitoring, or genetic testing

Considering now DBS and, despite the possible metabolic risks, clozapine

The case goes on. . . .

Case Debrief Despite life threatening complications from olanzapine, the patient was given a second olanzapine trial because the risks of his depression were thought to outweigh even the risks of olanzapine to him

Now, he may even be a candidate for clozapine, perhaps the antipsychotic with the greatest metabolic risk, even though the patient is a diabetic and has experienced HHS on olanzapine

Therapeutic decisions in cases like this can be quite difficult but risks can be justified if taken prudently to attempt to save the life of a patient like this

Two-Minute Tute: A brief lesson and psychopharmacology tutorial (tute) with relevant background material for this case – Hyperglycemic hyperosmotic syndrome

Table 1: Hyperglycemic Hyperosmotic Syndrome (HHS) Warning Signs and Symptoms to Know and to Tell the Patient Dry, parched mouth

Extreme thirst (although this may gradually disappear)

Warm, dry skin that does not sweat

High fever (over 101 degrees Fahrenheit, for example)

Sleepiness or confusion

Loss of vision, speech impairment

Hallucinations (seeing or hearing things that are not there)

Weakness on one side of the body

Blood sugar level over 600 mg/dl

Coma

Convulsions

Nausea

Weight loss

Increased heart rate with low blood pressure

Increased serum osmolality

High BUN (Blood Urea Nitrogen) and creatinine

Only mild or absent ketosis

Get to a doctor or emergency room

Rehydration with fluids

Potassium

Insulin

Death rate may be as high as 40%

Circulatory collapse (shock)

Stroke

Cerebral edema

Differs from diabetic ketoacidosis which is the combination of hyperglycemia with both ketosis and acidosis, absent from HHS

DKA (Diabetic Ketoacidosis) even more dangerous and life threatening than HHS

HHS is much more common than DKA in type II diabetes

Posttest Self Assessment Question: Answer The presence of diabetes is a contraindication to treatment with atypical antipsychotics, especially high risk agents such as olanzapine or clozapine

A. True

B. False

Answer: B

Although closer monitoring would be necessary if a patient has diabetes, it is not a contraindication to give a diabetic patient an atypical antipsychotic. There are far too many patients with diabetes to exclude them from antipsychotic treatment, and no antipsychotic is without risk. The point is to calculate a risk: benefit ratio for an individual patient, inform them, monitor them and get their consent. Taking risks can yield therapeutic rewards, but does not always turn out well.