References

1. Stahl SM, Psychosis and Schizophrenia, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 247–3262. Stahl SM, Antipsychotic Agents, in Stahl’s Essential Psychopharmacology, Cambridge University Press, New York, 2008, pp 327–4523. Roffman Jl, Weiss AP, Deckersback T et al. Interactive effects of COMT Val108/158Met and MTHFR C677T on executive function in schizophrenia. Am J Med Genetics part B (Neuropsychiatric Genetics) 2008; 147B: 990–54. Coyle JT, Glutamate and schizophrenia: beyond the dopamine hypothesis. Cellular and Mol Neurobiol 2006; 26: 365–845. Stahl SM, Methylated spirits: epigenetic hypotheses of psychiatric disorders. CNS Spectrums 2010; 15: 220–306. deKoning MB, Bloemen OJN, va Amelsvoort TAMH et al. Early intervention in patients at ultra high risk of psychosis: benefits and risks. Acta Psychiatrica Scand 2009; 119: 426–427. Stahl SM, Prophylactic antipsychotics: do they keep you from catching schizophrenia? J Clin Psychiat 2004; 65: 1445–68. McGorry PD, Nelson B, Amminger GP et al. Intervention in individuals at ultra high risk for psychosis: a review and future directions. J Clin Psychiatry 2009; 70: 1206–129. Cornblatt BA, Lencz T, Smith CW et al. Can antidepressants be used to treat the schizophrenia prodrome? Results of a prospective-naturalistic treatment study of adolescents. J Clin Psychiatry 2007; 68: 546–5710. McGlashan TH, Zipursky RB, Perkins D et al. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry 2006; 163: 790–911. Seidman LJ, Guiliano AJ, Meyer EC et al. Neuropsychology of the prodrome to psychosis in the NAPLS consortium. Arch Gen Psychiatr 2010; 67: 578–8812. Lencz T, Smith CW, McLaughlin D et al. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biol Psychiatr 2006; 59: 863–7113. Howes OK, Montgomery AJ, Asselin MC et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiat 2009; 66: 13–2014. Amminger GP, Shafer, MR, Papageorgiou K, et al. Long chain omega-3 fatty acids for indicated prevention of psychotic disorders. Arch Gen Psychiat 2010; 67: 146–54

Patient FileThe Case: The young cancer survivor with panic

The Question: Why is this patient resistant to medication treatments?

The Dilemma: How aggressive should psychopharmacological treatment be in terms of dosing and duration of drug treatment for panic?

Pretest Self Assessment Question(answer at the end of the case) Which of the following is true regarding dosing of duloxetine (Cymbalta) for depression?

A. Efficacy is dose-dependent, with greater response typically seen above 60 mg/day

B. There is no evidence of increased efficacy above 60 mg/day, though some patients may benefit from it

C. The maximum dose is 60 mg/day due to a significant increase in side effects at higher doses

Patient Intake 30-year-old man with a chief complaint of anxiety and depression

Psychiatric History Onset of panic attacks was approximately nine years ago

He has also suffered from moderate depression for several years

He has been treated with every selective serotonin reuptake inhibitor (SSRI) and several different benzodiazepines without good response

Some medications, specifically sertraline and paroxetine, seemed to worsen his sweating and fatigue

He has never taken venlafaxine XR, desvenlafaxine, buspirone, or chlordiazepoxide

Three years ago, he was diagnosed with non-Hodgkin’s lymphoma, which complicated treatment of his anxiety disorder

Specifically, there was confusion regarding the side effects of psychotropic medications, the recurrence of his tumor, and the side effects of chemotherapy, so anxiety treatment was suspended

He is now in complete remission from his cancer and is assumed cured; he stopped chemotherapy two years ago

His anxiety and depression, however, have continued unabated

Social and Personal History Single, never married, no children

Non smoker

No drug or alcohol abuse

College educated

Works in software but feels under employed

Medical History Status post non-Hodgkin’s lymphoma, treated and presumably cured 2 years ago

BP normal

BMI normal

Other lab tests normal

Family History Father: depression and panic disorder

Paternal grandfather: committed suicide

Aunt: anxiety disorder

Current medications Duloxetine 60 mg in the morning

Clonazepam 2 mg in the morning

Patient Intake He has six to seven panic attacks a day, including some night panic

His attacks are characterized by sweating and a “toxic feeling,” and they make it difficult for him to interact with people

He feels that duloxetine has helped his mood, but not his panic attacks, and that clonazepam has helped his daytime panic attacks

However, he feels some resurgence of his depression in the evenings, and he continues to experience multiple panic attacks each day

He is distressed and concerned about his symptoms, and he feels that they are preventing him from living a “normal life,” having social relationships, and pursuing fulfilling employment

Considering this patient’s partial response, which of the following medication adjustments would you most likely make?

None, maintain his current medications

Increase the doses of his current medications

Switch duloxetine to a different antidepressant

Switch clonazepam to a different anxiolytic

Switch both duloxetine and clonazepam to a different treatment regimen

Attending Physician’s Mental Notes, Initial Psychiatric Evaluation Although the patient continues to have several panic attacks a day, he has experienced some reduction in his anxiety since starting clonazepam

Similarly, although he has residual depressive symptoms, he has experienced improvement while on duloxetine

Considering his history of nonresponse with other medications, it may be more prudent to increase the dose of one or both medications than to switch

Which of the following dose adjustments would you most likely make for this patient?

Increase duloxetine dose only

Increase clonazepam dose only

Increase duloxetine dose, then increase clonazepam dose

Increase clonazepam dose, then increase duloxetine dose

Increase duloxetine and clonazepam doses simultaneously

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued Although 60 mg/day is the usual dose for duloxetine when treating depression and anxiety, it is frequently prescribed at doses up to 120 mg/day

Studies have not generally demonstrated increased efficacy beyond 60 mg/day; however, in relapse prevention studies in depression, a significant percentage of patients who relapsed on 60 mg/day responded and remitted when the dose was increased to 120 mg/day

For clonazepam, the usual dose in panic disorder is 0.5 to 2 mg/day; the maximum recommended dose is 4 mg/day

It is usually preferable to use the lowest possible effective dose of benzodiazepines because the risk of dependence may increase with higher doses

Thus, the decision is made to increase the dose of duloxetine up to 120 mg/day

Duloxetine is increased to 60 mg in the morning and 30 mg at night

Case Outcome: First and Second Interim Followup, Weeks 2 and 4 After two weeks, the patient reports no improvement; the dose is thus increased to 60 mg twice per day

After another two weeks, he reports that his mood is improved and that on most days he does not feel increasing depressed as the evening approaches

However, he has not experienced any reduction in his panic attacks, and he continues to be disabled by them

Asked whether he would be willing to try cognitive behavioral therapy for his panic attacks since they have been so resistant to medications, but he wants to try higher doses of clonazepam first

Because the patient’s panic has not improved adequately, the dose of clonazepam is increased by adding a 4 p.m. dose of 1 mg

Case Outcome: Third Interim Followup, Week 8 The patient experiences partial improvement at this dose; the dose is thus increased to 2 mg twice per day

Case Outcome: Fourth Interim Followup, Week 12 The patient experiences only one panic attack a week and thus is advised to continue clozazepam at 2 mg twice a day

Case Outcome: Fifth Interim Followup, Week 16 The patient experiences only one panic attack a week and thus is advised to continue clozazepam at 2 mg twice a day

How long would you continue this regimen, which includes high-dose benzodiazepine therapy?

Until his symptoms are suppressed

For one year following remission of his symptoms

Indefinitely

Attending Physician’s Mental Notes: Fifth Interim Followup, 16 Weeks Although it is somewhat controversial to give a young person long-term, high-dose benzodiazepine therapy, there are unique considerations in this case that justify it

First, the patient has just conquered cancer, but despite this triumph he is having serious residual disability from ongoing depression and anxiety

Thus, the risk of creating additional dependence with benzodiazepine exposure may be trivial compared to the upside of helping him get his life back together now that he is healthy

To maximize the chances of a successful outcome, it may be best to continue his treatment for one year after his symptoms are completely suppressed

If successful, one could consider at that point a slow taper of some of his medication to see if he could be maintained in the long run with lower doses

During the next year he will be encouraged to reconsider trying CBT since there is evidence that CBT may be more effective in keeping panic attacks in remission after stopping this therapy than after stopping benzodiazepine treatment

If he wants to have symptom-free remission without medications, his best bet might be to try CBT

Some argue that CBT is not as beneficial when giving benzodiazepines or when symptoms are in remission, so a good time to consider this is if he experiences breakthrough symptoms on his current medications, to initiate CBT rather than raise the dose of clonazepam further

Case Debrief This patient had prominent panic disorder with secondary depression, and was not very responsive to treatment with moderate doses of SSRIs, SNRIs or benzodiazepines and never had CBT

After surviving a bout with non-Hodgkin’s lymphoma, wanted to get life on track and become better controlled in terms of panic attacks

Prudent, stepwise increase of duloxetine and clonazepam doses to the top of their therapeutic ranges but not in heroic doses was successful in suppressing most panic attacks and improving depression

Take-Home Points When using benzodiazepines to treat anxiety disorders, it is generally advisable to use the lowest possible effective dose for the shortest possible period of time (benzodiazepine sparing strategy) because the risk of dependence increases with dose and duration

In particular, it is somewhat controversial to use long-term, high-dose benzodiazepine therapy

Nonetheless, there may be some patients for whom such treatment is warranted

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?– Higher doses of clonazepam would probably have been effective if given earlier, including during his convalescence from treatment for non-Hodgkin’s lymphoma– CBT could have been effective if given earlier

Possible action item for improvement in practice– Provide more written information about dosing of psychotropic drugs and about CBT for panic disorder to patients

Tips and Pearls Duloxetine is not specifically approved for treating panic disorder, but like other SSRIs and SNRIs, there are data suggesting that all agents in this class are effective not only for major depression and generalized anxiety disorder, but also for panic disorder and other anxiety disorders

The duloxetine may have contributed to therapeutic actions in this patient’s panic disorder, with a delayed onset of action

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

Table 1: Benzodiazepines in Panic Disorder Alprazolam and clonazepam best studied

Rapid onset of action

Can be used short term to boost efficacy of SSRIs/SNRIs, and also to block some of the anxiogenic actions of SSRIs/SNRIs, and then often can be tapered without loss of efficacy a few months later

Alprazolam dosing in panic is 0.5 mg three or four times a day and can be increased 1 mg/day until a maximum dose of 10 mg is reached

Alprazolam is dosed about twice that of clonazepam

Thus, clonazepam dose is 0.5 mg twice a day, increasing by 0.5 mg per day until a maximum usually of 4–5 mg/day for panic

Treatment for over 4 months may require slow taper to avoid withdrawal effects

Generally benzodiazepines should not be given to substance abusers or to those who continually escalate their dose without supervision

Posttest Self Assessment Question: Answer Which of the following is true regarding dosing of duloxetine for depression?

A. Efficacy is dose-dependent, with greater response typically seen above 60 mg/day

B. There is no evidence of increased efficacy above 60 mg/day, though some patients may benefit from it

C. The maximum dose is 60 mg/day due to a significant increase in side effects at higher doses

Answer: B