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, Lamotrigine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 259–665. Stahl SM, Bupropion, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 57–626. Stahl SM, Modafinil, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 359–637. 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): 97–1088. 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: 1243–519. Angst J. (2007) The bipolar spectrum. British Journal of Psychiatry 190; 189–9110. 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 60; 261–9.11. 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): 543–5212. 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): 77–8813. 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): 307–1514. 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): 39–4215. 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): 25–3216. 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): 207–1617. Savitz J, van der Merwe L and Ramesar R. Dysthymic and anxiety-related personality trait in bipolar illness. J Affect Disord 2008; 109(3): 305–1118. 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 FileThe Case: The anxious woman who was more afraid of her anxiety medications than of anything else

The Question: Is medication phobia part of this patient’s anxiety disorder?

The Dilemma: How do you treat a patient who has intolerable side effects with every medication?

Pretest Self Assessment Question(answer at the end of the case) Which of the following is available as a liquid formulation?

A. Citalopram (Celexa)

B. Duloxetine (Cymbalta)

C. Escitalopram (Lexapro)

D. Fluvoxamine (Luvox)

Patient Intake 33-year-old woman with a chief complaint of “extreme anxiety”

Psychiatric History The patient was well until about age 20 when, as an undergraduate in college, she developed a major depressive episode (perhaps related to seasonal depression)

She responded to paroxetine (Paxil, Seroxat) and continued treatment with it for two years

After stopping medication, she had at least two emergency room visits for panic attacks but received no treatment

Over the next seven years she received no treatment despite experiencing a great deal of generalized anxiety and feeling tense and overwhelmed

Because of relapse of her depression in the last two years she started again on various SSRIs

Restarted paroxetine but unlike the first time she took it, could not tolerate it after 2 weeks and discontinued it– Had fatigue and blurred vision

Trial of sertraline (Zoloft)– Had worsening anxiety and discontinued it after a week– Started CBT

Trial of fluoxetine (Prozac)– First dose caused a panic attack and discontinued it– Continued CBT

Trial of venlafaxine (Effexor XR)– Vomited on the first dose and discontinued it– Continued CBT

Trial of fluvoxamine (Luvox)– Made her tired and stopped after 3 days– Continued CBT

Trial of duloxetine (Cymbalta)– Racing pulse and palpitations after first dose and discontinued it– Continued CBT

Trial of escitalopram (Lexapro)– Insomnia and agitation and stopped after 3 days

Social and Personal History Single, no children

Non smoker

No drug or alcohol abuse

College graduate

Unemployed, supported by wealthy parents

Medical History Mitral valve prolapse

BP normal

BMI normal

Normal fasting glucose and lipids

Family History Father: posttraumatic stress disorder (PTSD) and depression

Maternal grandparents: alcoholism and anxiety

Paternal grandparents: bipolar disorder; grandmother received electroconvulsive therapy (ECT)

Current Medication Lorazepam 0.5 mg, up to 1.0 mg/day

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation Patient seems very upset and apprehensive

Afraid attending physician is going to prescribe something else

For the last few years she has not been able to function fully independently, to maintain significant relationships, or to maintain steady and fulfilling employment

The patient is well-informed and well-read but seems to irrationally overvalue the side effects of medications– In particular, she anticipates catastrophic consequences such as death in the middle of the night, problems from serotonin syndrome, and some of the other most dire potential consequences of psychotropic drugs

She both readily acknowledges the excessive nature of these fears and yet still has some degree of belief in them and certainly experiences subjective fear about them– However, she always has activating side effects, electric shock sensations, headaches, tremors on the inside but not on the outside, hair on her head standing on end, no matter what medication she takes lately– Does not understand why these problems were not present with these medications in the past nor why she tolerates and, in fact improves on lorazepam (Ativan)

She also recognizes that her chronic anxiety is interfering with her life and keeping her from being employed, having relationships, and again becoming independent

She is therefore highly motivated to find a plan to reduce her symptoms and allow her to resume a normal life with the high level of functioning that she has enjoyed in the past

She displays a broad affect but a somewhat depressed mood, almost becoming tearful at times while discussing her history

She is able to respond to humor and paradox and is not currently suicidal

With just the information you have now, what do you think is her diagnosis?

Hysteria

Hypochondriasis

GAD

Medication phobia

Panic disorder

Recurrent major depressive disorder with anxious features

Bipolar II or bipolar NOS being activated by SSRIs/SNRIs, as suggested by her family history

Psychological conflicts and dependency issues about separation individuation from parents and gaining full independence

Other

Considering this patient’s history, symptoms, and fear of side effects, would you recommend another trial of a serotonergic antidepressant?

Yes

No

In addition to trials of 6 SSRIs/SNRIs, and CBT for several months, only lorazepam is giving any relief. Which of the following strategies would you be most likely to suggest to this patient?

Discontinue medication treatment and begin cognitive behavioral therapy (CBT) and/or psychotherapy with a new therapist

Maintain current benzodiazepine dose and add new CBT and/or psychotherapy

Increase dose of benzodiazepine

Increase dose of benzodiazepine and add new CBT and/or psychotherapy

Switch to a serotonergic antidepressant

Switch to a serotonergic antidepressant and add new CBT and/or psychotherapy

Add a serotonergic antidepressant

Add both a serotonergic antidepressant and CBT and/or psychotherapy

Get plasma drug levels on the next serotonergic antidepressant you try

Attending Physican’s Mental Notes: Initial Psychiatric Evaluation, Continued She clearly needs some form of treatment beyond her current low-dose benzodiazepine in order to resume her normal life and withstand the associated psychosocial stressors without experiencing symptoms of anxiety and depression from a recurrent anxious depression

She now has superimposed some legitimate side effects but also seems to exaggerate them

Does not appear to be conscious exaggeration

Although her side effects overlap with possible hypomanic activating symptoms in some cases, they are much more consistent with anxiety than with substance-induced hypomania from an SSRI

Although it seems that some of these side effects may reflect self-fulfilling prophecies, and “all in her head” they are nonetheless real to her and require management

Although CBT and/or psychotherapy are well-established treatment methods for all of her symptoms, including particularly her phobic symptoms, they are not working here after several months

It is important to rule out abnormal drug metabolism from a genetic predisposition and unusual cytochrome P450 drug metabolizing system

She can get genotyping or simply a therapeutic drug level on a normal dose of any SSRI/SNRI

Blood sent for CY450 2D6, 2C9, 2C19 genotyping

Agrees to try very low dose venlafaxine again

Case Outcome: First Interim Followup, 3 Weeks Predictably, had side effects (nausea) on venlafaxine XR

Was able to take for one week at 37.5 mg/day and had barely detectable plasma drug levels

Genotyping comes back with no evidence of being a poor metabolizer

Thus, abnormally high drug levels due to abnormal drug metabolism cannot explain her side effects

Showed results to patient and told her that she might very well respond with the same side effects to placebo

Asked if she would be willing to try a behavioral desensitization approach

Continuing medication treatment may also be helpful and in fact exposure to medications may be important to overcome her phobia of them

A useful strategy may be a behavioral desensitization approach involving extremely slow dose titration of a serotonergic antidepressant

Alternatively, she will have to opt for non medication options– Continuing CBT– Considering rTMS over the right hemisphere (for anxiety) and over the left hemisphere (for depression)

Could consider chronic higher dose benzodiazepine treatment

Escitalopram is selected, as it is generally considered one of the better tolerated selective serotonin reuptake inhibitors

Escitalopram is also available as a liquid, which allows extra flexibility when developing a slow titration schedule

The patient is instructed to dilute 10 mg liquid escitalopram in 100 ml of fruit juice and then, using an eye dropper, drink 1 ml and dispose of the rest; this can be done daily for 1–3 days

She can then increase by 1 ml or so every day as she feels comfortable

This gives her complete control over the pace of dosing and allows her to defer a dose or back off the dosing if desired

She should slowly and steadily increase her escitalopram concentration over one or two months, until she is on a full 10 mg/day dose

In the meantime she should continue to take lorazepam, both to reduce her symptoms and as a rescue medication for her escitalopram

Once escitalopram has been up-titrated, her dose of lorazepam may also be reevaluated and may need to be increased to allow for full symptom control and return to normal functioning

Case Outcome: Second and Subsequent Interim Followup Visits, Over the Next 6 Months Slowly but surely, with some pauses in dose increases and some transient side effects, the escitalopram was increased to 10 mg/day while continuing lorazepam

She eventually relaxed, was reassured, and her symptoms abated

Whether this was pharmacologically mediated or was de facto CBT as well as systematic desensitization to medication is not clear

Referred for psychotherapy to deal with adult development issues

Case Debrief A patient with pre existing anxiety disorder and a major depressive episode, developed a recurrent anxious depression and developed a phobia to her medications because she had become sensitized to side effects to them

Systematic desensitization was successful in getting her to a therapeutic level of drug that was tolerated and she responded

She was likely avoiding dealing with various adult development issues over many years by concentrating on her drugs and side effects

Take-Home Points Many factors can significantly impair adherence, including real or feared side effects; clinicians must do their best to address what factors they can

This may include using unusual titration schedules, emphasizing behavioral treatments over medication treatments, considering alternative treatments, and other strategies

Posttest Self Assessment Question: Answer Which of the following is available as a liquid formulation?

A. Citalopram

B. Duloxetine

C. Escitalopram

D. Fluvoxamine

Answer: C