References

1. Franke B, Neale BM, and Faraone SV. Genome-wide association studies in ADHD. Hum Genet 2009; 126(1): 13–502. Haberstick BC, Timberlake D, Hopfer CJ et al. Genetic and environmental contributions to retrospectively reported DSM-IV childhood attention deficit hyperactivity disorder. Psychol Med 2008; 38(7): 1057–663. McLoughlin G, Ronald A, Kuntsi J et al. Genetic support for the dual nature of attention deficit hyperactivity disorder: substantial genetic overlap between the inattentive and hyperactive-impulsive components. J Abnorm Child Psychol 2007; 35(6): 999–10084. Todd RD, Rasmussen ER, Neuman RJ et al. Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins. Am J Psychiatry 2001; 158(11): 1891–85. Faraone SV, Advances in the genetics and neurobiology of attention deficit hyperactivity disorder, Biol Psychiatry 2006; 60: 1025–76. Stahl SM, Stahl’s Illustrated Attention Deficit Hyperactivity Disorder, Cambridge University Press, New York, 20097. Stahl SM, Attention Deficit Hyperactivity Disorder and its Treatment, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 863–988. Stahl SM, Atomoxetine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 51–59. Stahl SM, d,l methylphenidate, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 329–3510. Stahl SM, Mixed Salts of d,l Amphetamine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 39–4411. Stahl SM, Paroxetine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 409–15

Patient FileThe Case: The doctor who couldn’t keep up with his patients

The Question: Is cogntitive dysfunction following a head injury due to traumatic brain injury or to depression?

The Psychopharm Dilemma: How can treatment improve his functioning at work?

Pretest Self Assessment Question(answer at the end of the case) Agents that enhance DA and NE in prefrontal cortex may be useful in treating executive dysfunction of a residual head injury, but not for the cognitive dysfunction of depression and anxiety.

A. True

B. False

Patient Intake 52-year-old man

Chief complaints: anxiety, depression, problems concentrating

Psychiatric History Anxiety since college, waxing and waning, bothersome but never disabling, treated with psychotherapy and no meds

Became a physician in a very stressful high-volume practice eight years ago with an increase of anxiety

Trial of nefazodone (Serzone) not helpful

Switch to sertraline (Zoloft) which caused akathisia on two consecutive doses, so discontinued it and reinstituted psychotherapy with good results

Medical History Developed angina five years ago, diagnosed as coronary artery disease and had a stent placement

Post-operatively had more anxiety, treated with fluoxetine (Prozac) 20 mg with “fabulous” results except moderate sexual dysfunction

Not obese but diagnosed with obstructive sleep apnea and restless legs syndrome, treated with CPAP (continuous positive airway pressure) and clonazepam (Klonopin) 0.5 mg at night

Head Injury Bicycle accident two years ago with flaccid right hemiparesis (later with full right sided motor recovery), prolonged loss of consciousness, seizure, ICU (intensive care unit) hospitalization and documented left prefrontal brain contusion on MRI brain scan

Neuropsychological testing documents– Average memory– Average psychomotor speed– Average reaction time– Average complex attention– Average cognitive flexibility– However, might be low for performance for that expected of a physician

Able to understand oral and visual information better than written information

Does not make errors when able to work slowly and methodically

Becomes frustrated and overwhelmed when presented information too quickly or forced to perform multitasking

Fully disabled for four months

Returns to work part-time as an internist in a well known HMO (health maintenance organization) outpatient clinic

Partially disabled for eight months, i.e., works full-time but fewer patients scheduled per day than for a normal full time physician to allow him additional time for charting and to take short breaks between appointments with every other Friday off

HMO performance standards for a full-time physician schedule 11 patients an hour, juggling no-shows, phone calls and time-consuming new patients or patient crises as necessary

Social and Personal History Married for 28 years

2 children

Non smoker, no substance of alcohol abuse

Interested in photography as a hobby

Many friends

Family History No history of depression in the family

First degree relatives with premature deaths from cardiovascular disease

Psychiatric History: Following the Head Injury Upon returning to work part-time four months after the head injury, noted to be somewhat disinhibited emotionally, with some low-grade anxiety and depression

Increased fluoxetine to 30 mg and noted side effects: falling backward, occasional myoclonus, fasciculations in the day, worsening restless legs at night

Reduced fluoxetine to 10 mg and noted periods of waxing and waning depression (maximum severity 4/10 on a 10-point scale with 10 worst; lasting a few days) followed by a near recovery for a few days

Notes slowness of problem-solving skills, difficulty reading medical journals

Over the next year after returning to work, tries to raise work productivity under increased pressure to do so

Repeat neuropsychological testing six months after brain injury shows no further improvement; still only average memory but slightly below-average complex motor speed, complex attention and cognitive flexibility

Trial of methylphenidate (Ritalin) in an attempt to improve subjective cognitive performance and work productivity back to baseline: causes activation and paranoia

Trials of a number of SSRIs, SNRIs, tricyclic antidepressants to improve mood and anxiety either did not work or were not tolerated

Referred to you for evaluation and management

Current Medications Citalopram (Celexa) 10 mg/day

Clonazepam (Klonopin) 0.5 mg/day

ACE (angiotensin converting enzyme) inhibitor for hypertension

Statin for hypercholesterolemia

Omeprazole for GERD (gastroesophageal reflex disease)

Aspirin

CPAP

From the information given, what do you think the diagnosis for this patient’s mood disorder is?

Unipolar major depression with anxiety

Bipolar spectrum disorder

Organic affective disorder

Unipolar major depression with anxiety and organic effective disorder

Bipolar spectrum disorder and organic effective disorder

Other

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation Seems to have had a good recovery so far from a potentially devastating head injury

However, recovery from head injury does appear to be incomplete

He is undoubtedly frustrated at incomplete recovery although thankful for avoiding the worst case outcome

Nevertheless, he is now nearly a year out from his head injury and it is likely that the majority of his recovery has already occurred, or at least that the pace of any further recovery is likely to be very slow and over many months

He may have some organic cognitive symptoms, but his mood disorder is likely to be linked both to his mild pre-existing mood and anxiety disorder, plus the psychosocial stressor of the head injury, requiring an adjustment in the workplace, rather than to an organic affective disorder

His disinhibition does suggest, however a mild organic component to his mood

From the information given, what do you think is the cause of his continuing low work productivity?

Secondary to anxious depression, pre-existing but currently not in remission

Subtle and now permanent organic brain syndrome

Laziness in an MD clever enough to try to exploit his head injury to work at an easier pace

Unreasonable and diabolical, profit-motivated HMO productivity demands!

All the above

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued The cognitive deficiency from his head injury is now subtle and seems only to be unmasked under situations where the limits of anyone would be exposed

He was able to handle this schedule previously, so his problems do represent a problem linked to incomplete recovery from his head injury and not likely to be due to his mild to moderate depression

Further recovery is possible, but not a good idea to over-work but to set his pace and see if he gets better over the next year

Unfortunately, business is business and his colleagues and his employer expect him to “pull his weight” and he is asked to take a pay cut in proportion to his reduced productivity

The patient is upset and his wife thinks he should consult an employment lawyer

The patient thinks this will poison the work environment for him, so refuses to do so

Given his head injury and single seizure, would you avoid treating him with bupropion?

Yes

No

Of the following choices, what would you do?

Add another antidepressant

Switch to another antidepressant

Add a mood stabilizer

Add modafinil (Provigil) or armodafinil (Nuvigil)

None of the above

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 Most likely his cognitive problems are linked to his head injury, but he is moderately depressed, so we might get lucky and improve his cognition if his depression goes into complete remission

In many ways, cognitive symptoms linked to depression might be the most treatable cognitive symptoms he could have and also the fastest to respond to effective treatment, so it is definitely worth trying

In selecting an antidepressant, best to avoid one that is either sedating or that causes sexual side effects

Although any antidepressant that improves his depressive episode sufficient for a complete remission would be able to concomitantly improve the cognitive symptoms of depression, choosing an agent with pro-dopaminergic effects might be preferable

Although immediate release formulations of bupropion have an increased incidence of seizures, controlled release formulations of bupopion do not

Thus, he was started on bupropion XL 150 mg once daily

Case Outcome: First Interim Followup, Week 4 Four weeks later “99% success”

Depression, rumination, anxiety gone; staying up later; more energy, getting more done at work (increased work load) and at home (photography hobby)

Sometimes a bit overactivated, especially with caffeine

Has to stop drinking coffee now

Has some continuing sexual dysfunction (continued his citalopram)

Notes forgetting of some phone calls with clonazepam 1.0 mg qhs, so reduces again to 0.5 mg qhs but experiences some insomnia

Switch to zolpidem (Ambien) from clonazepam for sleep

Reduced citalopram to 5 mg

Case Outcome: Second Interim Followup, Week 12 In another eight weeks, patient reports continuing sexual dysfunction and muscle twitching and headaches even on 5 mg citalopram. When he stops it on his own, immediately these side effects are gone

Citalopram discontinued

Increased bupropion XL to 300 mg

Case Outcome: Third Interim Followup, Week 28 After another four months, doing very well except for slight mood reactivity with depression and anxiety when under more stress

Sees up to 10 patients per hour, but under pressure from HMO and colleagues/partners to pull full weight and get back to 11

Gets flustered occasionally at slightly reduced workload, and too exhausted to extend work hours

Employer considering reduction of pay for full-time work with only 10/11 productivity; patient considering disability litigation

And so it goes for practicing medicine in the 21st century….

Case Debrief This patient with mild pre-existing depression and anxiety not needing psychopharmacological management, developed depression in response to a head injury that left him disabled for a while, and now appears to be headed for a robust but incomplete recovery

Treatment of residual symptoms of depression definitely improved his cognition, his frustration tolerance, and sense of well being

Take-Home Points Bupropion in sustained-release formulations is not demonstrably more pro-convulsant than any other antidepressant (1/1000), but patient should be advised and get his/her consent

It can be difficult to see the consequences of closed head injury in a high-functioning patient unless (s)he is pushed to the limits of his/her high function

Affective disorder can compound the effects of a head injury and may be the most treatable component of patients with both

Nevertheless, agents that enhance DA and NE in prefrontal cortex may be useful in the executive dysfunction of residual head injury as well as in the executive dysfunction of depression and anxiety

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?– Perhaps some intervention with his employers to ensure that they understand his limits would take some pressure off him– Trying to resolve this situation without litigation with his employer or his disability carrier would be ideal, since losing his job or prolonged litigation is likely to make his depression, and possibly even his cognition, worse– Perhaps earlier treatment of his depression with bupropion would have been helpful

Possible action item for improvement in practice– Make sure he has a support mechanism with psychotherapy for his frustrations– More active involvement of his wife may have been indicated, so getting spouse involved early in treatment could be an item for improvement

Tips and Pearls The dorsolateral prefrontal cortex is the site where problem solving and executive functioning is regulated

This is the exact area of the brain he damaged on his bicycle and is also the same area of the brain thought to be involved in the cognitive symptoms of depression

Improving the efficiency of information processing in this part of the brain, buy boosting dopamine and/or norepinephrine neurotransmission, can lead to subjective and objective improvement in executive functioning just as in ADHD

Posttest Self Assessment Question: Answer Agents that enhance DA and NE in prefrontal cortex may be useful in treating executive dysfunction of a residual head injury, but not for the cognitive dysfunction of depression and anxiety.

A. True

B. False

Answer: B. False

These agents can be useful for executive dysfunction from both of these as well as other causes.