References

1. Lisi AJ. Management of Operation Iraqi Freedom and Operation Enduring Freedom veterans in a Veterans Health Administration chiropractic clinic: a case series. J Rehab Res Dev 2010; 47(1): 1–62. Amin MM, Parisi JA, Gold MS et al. War-related illness symptoms among Operation Iraqi Freedom/Operation Enduring Freedom Returnees. Mil Med 2010; 175(3): 155–73. Shaw WS, Means-Christensen AJ, Slater MA et al. Psychiatric disorders and risk of transition to chronicity in men with first onset low back pain. Pain Med 2010; Epub ahead of print4. Cyders MA, Burris JL, and Carlson CR. Disaggregating the relationship between posttraumatic stress disorder symptom clusters and chronic orofacial pain: implications for the prediction of health outcomes with PTSD symptom clusters. Ann Behav Med 2010; Epub ahead of print5. Asmundson G, Wright K, McCreary D et al. Post-traumatic stress disorder symptoms in united nations peacekeepers: an examination of factor structure in peacekeepers with and without chronic pain. Cogn Behav Ther 2003; 32(1): 26–376. Geisser ME, Roth RS, Bachman JE et al. The relationship between symptoms of post-traumatic stress disorder and pain, affective disturbance and disability among patients with accident and non-accident related pain. Pain 1996; 66(2–3): 207–147. Roth RS, Geisser ME, and Bates R. The relation of post-traumatic stress symptoms to depression and pain in patients with accident-related chronic pain. J Pain 2008; 9(7): 588–968. Sharp TJ and Harvey AG. Chronic pain and posttraumatic stress disorder: mutual maintenance. Clin Psychol Rev 2001; 21(6): 857–779. Beckham JC, Crawford AL, Feldman ME et al. Chronic posttraumatic stress disorder and chronic pain in Vietnam combat veterans. J Psychosom Res 1997; 43(4): 379–8910. de Leeuw R, Schmidt J, and Carlson C. Traumatic stressors and post-traumatic stress disorder symptoms in headache patients. Headache 2005; 45(10): 1365–7411. Afari N, Harder LH, Madra NJ et al. PTSD, combat injury, and headache in veterans returning from Iraq/Afghanistan. Headache 2009; 49(9): 1267–7612. Stahl SM, Mood Disorders, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 453–51013. Stahl SM, Antidepressants, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 511–66614. Stahl SM, Anxiety Disorders and Anxiolytics, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 721–7215. Stahl SM, Stahl’s Illustrated Anxiety, Stress and PTSD, Cambridge University Press, New York, 201016. Stahl SM, Quetiapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 459–6417. Stahl SM, Valproate, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 569–7418. Stahl SM, Topiramate, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 535–919. Stahl SM, Venlafaxine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 579–58420. Stahl SM, Bupropion, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 57–6221. Stahl SM, Clonazepam, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 97–10122. Silberstein SD, Marmura MJ, Stahl SM (Ed), Cyclobenzapine, in Essential Neuropharmacology: The Prescriber’s Guide, Cambridge University Press, New York, 2010, pp 78–80

Patient FileThe Case: The young man everybody was afraid to treat

The Question: How can you be confident about the safety of combining antihypertensive medications for serious hypertension with psychotropic drugs for serious depression in a patient with a positive urine screen for amphetamine?

The Dilemma: Which antidepressants can you use?

Pretest Self Assessment Question(answer at the end of the case) Hypertension is a contraindication for treatment with either lithium or with MAO inhibitors.

A. True

B. False

Patient Intake 24-year-old male

Chief complaint: crippling depression

Psychiatric History Onset of depression age 13 in 8th grade

Given fluoxetine with good short-term results

Discontinued it after it stopped working perhaps two years later

Began cutting himself, thoughts of self-loathing and self-hatred

Deteriorated into major depressive episode at age 17; hospitalized

Diagnosed as bipolar II for unclear reasons and given lithium

Did well in college for two years, but then progressive worsening of depression past four years

Recently failed college and relocated to home, unable to study or work

Treatment over past four years: drugs, doses and duration of medications unclear but best responses reportedly to lithium and mixed amphetamine salts

Not clear he ever had a diagnosis of ADHD so reasons for giving mixed amphetamine salts similarly unclear

Poorly documented, marginal responses to aripiprazole (Abilify), venlafaxineXR (Effexor XR), lamotrigine (Lamictal), bupropionSR (Wellbutrin SR) and sertraline (Zoloft), perhaps in part because of compliance issues

“Some drugs don’t work; others that work only do so for a period of time” – however, experiences very few side effects

Most recently tried ziprasidone (Geodon, Zeldox) 40 mg with no therapeutic effects and no side effects, so discontinued it

No manic episodes

“Mood swings” characterized by being “enthusiastic,” happy, seeing things clearly and being somewhat better than well

Five such episodes lasting about a day but never as long as four days

Has also had many more frequent mood fluctuations, particularly recently, from normal to suicidal over a period of hours

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation Currently, sleeping 12–14 hours several times a week

Unbelievable tiredness, all the time, lacking motivation with severely depressed mood and thoughts of death

Denies active suicidal ideation in the past few weeks yet rates himself 10/10 in severity on a 10-point scale (10 worst)

Parents are concerned as they have never seen him this depressed before and think he might kill himself even though he denies this

Medical History Developed hypertension, noted 4 years ago

Workup from different renal specialists, diagnosed with “primary hypertension”

Variable and slightly elevated creatinine and proteinuria

BP controlled adequately and stable, but requires four meds from four different antihypertensive classes to keep BP<150/90

Social and Personal History Non smoker, denies substance or alcohol abuse

Few friends or outside interests

Completed two years of college in another state, then dropped out because of depression

Trying to go part time to a local community college nearly his parents’ home where he is now living

Family History Grandmother: depression

No first degree relatives with early onset hypertension

Current Medications Lamotrigine 200 mg/day

Trazodone 200 mg qhs prn, usually 4x weeklyFor hypertension:Metoprolol (beta blocker)Isradipine (calcium channel blocker)Olmesartin (angiotensin II)Medoxomil (diuretic)

From the information given, what do you think his diagnosis is?

Recurrent major depression

Bipolar II disorder

Bipolar NOS

Other

Further Investigation: Is there anything else you would especially like to know about this patient?

What about details concerning the diagnosis of bipolar II disorder in the past and about his cutting behaviors?– No behaviors elicited from patient or his parents of unequivocal hypomania– Patient has experienced mood swings, not reaching the criteria of bipolar disorder I or II– Patient is very vague and seems ashamed of prior cutting behaviors, none in the past five years– He explains it as wanting to destroy himself then, but without the courage to kill himself, and not that it makes him feel alive or takes away the psychic pain of his depression

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued Certainly his depression is recurrent, and no episodes of mania ever, but it is unknown why he was diagnosed as bipolar II in the past

He might be bipolar II but there is no unequivocal hypomanic episode that the patient relates or that is documented in any available medical records

Might be best to defer the diagnosis of bipolar spectrum for now and have a provisional diagnosis of recurrent unipolar depression while being vigilant to the possibility of bipolar II disorder, mixed episodes, or bipolar disorder NOS, as well as possible induction of hypomanic, mixed or rapid cycling states by antidepressants

His rare but definite cutting behaviors are of concern but he denies them currently

Nothing in the current evaluation that suggests definite borderline personality disorder, but perhaps this is the reason that prior examiners thought he might be bipolar

Also, no first degree relatives with bipolar disorder

Nevertheless, cases like this can respond to medications used in bipolar disorder, such as lithium and lamotrigine and atypical antipsychotics

Given his hypertension and slightly elevated creatinine, would you avoid re-treating him now with lithium despite his good response in the past?

Yes

No

Of the following choices, which would you utilize at this point?

Add antipsychotic

Add antidepressant

Add anticonvulsant mood stabilizer

Add lithium

Add antipsychotic plus antidepressant

Add mood stabilizer plus antidepressant

None of the above

If you would give a mood stabilizer/anticonvulsant, which would you add?

Lithium

Divalproex

Lamotrigine

Carbamazepine

Oxcarbazepine

Topiramate

Levetiracetam

Zonisamide

Gabapentin/pregabalin

I would not add a mood stabilizer/anticonvulsant

If you would give an antipsychotic, which would you add?

Clozapine

Risperidone

Paliperidone

Olanzapine

Quetiapine

Ziprasidone

Aripiprazole

Asenapine

Iloperidone

Lurasidone

Conventional antipsychotic

Depot antipsychotic

I would not add an antipsychotic

Given his hypertension and slightly elevated creatinine,would you avoid treating him with high doses (225–375 mg/day) of venlafaxine?

Yes

No

Given his hypertension and slightly elevated creatinine would you treat him with a MAOI?

Yes

No

If you would give an antidepressant, which would you add?

SSRI (serotonin selective reuptake inhibitor)

SNRI (serotonin norepinephrine reuptake inhibitor)

NDRI (bupropion; norepinephrine dopamine reuptake inhibitor)

NRI (norepinephrine reuptake inhibitor)

Mirtazapine

Trazodone

Tricyclic antidepressant

MAO inhibitor

I would not give an antidepressant

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued This is a complicated case, given his hypertension and antihypertensive medications

His hypertension expert physician managing the case is not pleased with the prospect of starting lithium, but agrees this may be justified under the circumstances of the patient’s severe and potentially life threatening depression, with a history of having responded to it before

Restarted lithium 300 mg bid (nephrologist agrees; lithium level 0.3)

Patient does not want to take anything that could make him sedated as he is already sleeping too much

Restarted ziprasidone 60 mg twice a day with food

Lamotrigine and trazodone continued

Case Outcome: First Interim Followup, Week 4 Patient lives in another city, and flies back for an appointment by himself in 4 weeks, without his parents

On the waiting list of a new psychiatrist in his home city, unable to get in to see him yet

No antidepressant response in past 4 weeks

Lithium increased to 900 mg/day (level 0.6)

No response in 4 weeks to 60 mg twice a day so Ziprasidone increased to 160 mg/day

Case Outcome: Second Interim Followup, Week 8 Phone appointment

Still awaiting appointment with psychiatrist

A “bit of a response” noticeable at 8 weeks

Rates himself 9/10 on a 10-point scale of severity (10 worst)

Started transdermal selegiline 6 mg/day

Case Outcome: Third Interim Followup, Week 12 Phone appointment

Saw new psychiatrist, who is unwilling to treat him because of his hypertension, concomitant antihypertensive medications, and unease about prescribing especially the MAO inhibitor, but also the lithium

Still rates himself 9/10 on a 10 point scale (10 worst)

Increased selegilene to 9 mg/day

Case Outcome: Fourth Interim Followup, Week 16 Phone appointment

Now rates himself 4/10

Several psychiatrists have refused to treat him

Increased selegilene to 12 mg.day

Case Outcome: Fifth Interim Followup, Week 20 Patient flies in for a face-to-face appointment by himself

Parents on the phone from their home during the appointment

Now rates himself 2–3/10; last time this well was 4 years ago

Still has bad days, “dragged down”

Still looking for a psychiatrist

Attending physician now begins to search with him for contacts with another psychiatrist in the patient’s city

Case Outcome: Sixth Interim Followup, Week 24 Phone appointment

The situation makes him feel both desperate that he will not find psychiatric care and not entirely trusting that the medication choices are the best ones since there is so much turmoil among nephrologists and psychiatrists about how to treat him

Since the last appointment, he has become concerned both about taking meds and about running out, so on his own cuts doses of lithium and ziprasidone in half, continuing lamotrigine and transdermal selegiline at full doses

Attending physician thus calls in his prescriptions to a local pharmacy in his town, and recommends increase in lithium and ziprasidone back to full dose since he had responded so well to this combination with his other medications

The search for a local psychiatrist continues

The family’s primary care physician is also not comfortable managing the patient’s medications

Case Outcome: Seventh Interim Followup, Week 28 On his own, patient decreased transdermal selegiline by half and keeps lithium and ziprasidone at half dose to hoard medications fearing he will run out because he cannot find a doctor

Severe relapse occurred; parents take him to emergency room; BP normal but urine positive for amphetamine; ER physicians refuse to give him any antidepressants, think he is a drug abuser

Found a young psychiatrist who trained with the attending physician and who now lives in the patient’s city willing to prescribe these meds with some continuing supervision by the attending physician but she is concerned about the safety of this combination and now concerned about the patient’s stimulant abuse which he adamantly denies, but neither the parents, the new psychiatrist or the emergency room personnel believe that he did not ingest stimulants

Given his positive urine test for amphetamine and his denial of abuse, is this yet another reason for you to be hesitant to take him on as a psychopharmacology management case?

Yes

No

Case Outcome: Seventh Interim Followup, Week 28, Continued Phone consult with new psychiatrist: reminded her that selegiline metabolized to methamphetamine and recommended increase of doses of all meds back to levels where he responded

Positive urine drug screen was from selegiline, not abused stimulants

Patient continues on transdermal selegiline, ziprasidone, lithium, lamotrigine and trazodone

The saga continues . . .

Case Debrief A complex case of a young man who developed both serious hypertension requiring four antihypertensives from four classes of drugs, plus serious depression unresponsive to standard therapy and requiring heroic psychopharmacological intervention

Many psychiatrists and internists alike are uncomfortable managing a case like this

Nevertheless, it is possible to have one’s cake and eat it too: namely, control of both hypertension and depression, although with numerous medications

Take-Home Points Hypertension is not a contraindication for lithium or for MAO inhibitors

Use ziprasidone at reasonable doses (120–160 mg/day with food in most cases) or not at all

MAO inhibitors remain a viable treatment option

MAO inhibitors by themselves more likely to cause HYPOtension (especially orthostatic) than HYPERtension (unless given with sympathomimetic amines or reuptake inhibitors)

Difficult cases may justify aggressive treatments

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?– Took too long to find a local psychiatrist willing to manage the case– This led to a sense of desperation and lack of confidence, compromising therapeutic alliance and leading to medication nonadherence and relapse– The distance of the patient from the original treating physician also interfered with getting psychotherapy established, which could have been helpful in getting patient to adjust to dropping out of college and to his disappointment and anger that depression was interfering with his getting on with his life

Possible action item for improvement in practice– Being more proactive in finding contacts in cities where referred patients live so that local experts can manage the case when referred back– Should have told the patient or parents about the urine drug screen for patients taking selegiline and this might have avoided some conflict and tension– Should have told the patient or parents about how to extend the use of the transdermal patches (see below) or considered a switch to a less expensive MAOI

Tips and Pearls Note that both selegiline and another MAO inhibitor, tranylcypromine, itself an amphetamine, can show up as positive urine drug screens for stimulants

Although not approved for use this way, note that each transdermal patch of selegiline actually contains more than 3 days of drug; if patient’s skin is not irritated by prolonged administration in a single site, and the adhesive continues to work, costs of this expensive treatment option can be reduced by two or three days use of each patch instead of one

Also, can switch to another MAOI that is much less expensive

Modern psychopharmacologists should not be afraid to administer MAOIs for selected cases

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

– Tips on how to use MAOIs

– see also Case 1 Two-Minute Tute p 8

Table 1: Currently approved MAO inhibitors Table 2: MAO inhibitors with amphetamine actions or amphetamines with MAO inhibitions? Table 3: MAO Enzymes Table 4: Suggested tyramine dietary modifications for MAO inhibitors^* Table 5: Potentially dangerous hypertensive combos: agents when combined with MAOIs that can cause hypertension (theoretically via adrenergic stimulation) Table 6: Potentially lethal combos: agents when combined with MAOIs that can cause hyperthermia/serotonin syndrome (theoretically via SERT inhibition) Table 7: Tyramine content of cheese Table 8: Tyramine content of commercial chain pizza Table 9: Tyramine content of wine Posttest Self Assessment Question: Answer Hypertension is a contraindication for lithium and MAO inhibitors.

A. True

B. False

– Although many internists and psychiatrists are uncomfortable with this combination, and it has to be used with caution and extensive monitoring by experts, the combination is not contraindicated and can in fact treat both depression and hypertension successfully as in this case

Answer: B