References

1. Stahl SM, Lamotrigine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 259–652. Stahl SM, Clozapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 113–83. Stahl SM, Risperidone, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 475–814. Stahl SM, Olanzapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 387–925. Citrome L, Kantrowitz JT, Olanzapine dosing above the licensed range is more efficacious than lower doses: fact or fiction? Expert Reviews Neurother 2009; 9: 1045–586. Stahl SM, Antipsychotics, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 327–4527. Goff DC, Keefe R, Citrome L et al. Lamotrigine as add-on therapy in schizophrenia. J Clin Psychopharmacol 2007; 27: 582–98. Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation. Cur Med Chem 11: 313–26

Patient FileThe Case: The woman with depression whose Parkinson’s disease vanished

The Question: Can state dependent parkinsonism be part of major depressive disorder?

The Dilemma: How to diagnose and treat with simultaneous antidepressants and anti-parkinsonian drugs?

Pretest Self Assessment Question(answer at the end of the case) The severity of depression associated with Parkinson’s disease usually correlates with the severity of the movement disorder

A. True

B. False

Patient Intake 53-year-old female

Chief complaint: “I’m always tired”

Psychiatric History States she was well until about three years ago

Eventually felt she “needed bedrest” and finally stayed in bed for eight months!

Medical workup negative

Felt better spontaneously, went back to work, and then “relapsed” four months later

Previous trials of nortriptyline (Pamelor) and paroxetine (Paxil, Seroxat) worsened fatigue and she discontinued after a few doses

Felt somewhat better on low dose amitriptyline (Elavil) when she was staying in bed

Medical History Normal BMI, BP, blood tests

Extensive recent medical evaluation within normal limits

Social and Personal History Middle East origin, English is her second language

Emigrated to the US 20 years ago

Married for 30 years

2 children

Non smoker, non drinker, no drugs of abuse

Works in her husband’s business

Family History No psychiatric, neurologic or medical illnesses known in relatives

Current Medications Zolpidem (Ambien)

Alprazolam (Xanax)

Estrogen/progestin

Patient Intake States she doesn’t like to look at faces because she has a hard time turning to look at them

States her “feet are tired”

She always wants to stay at home

Also describes a sort of restless movements in her legs

Upon closer questioning it is clear that she is depressed with insomnia, but what is striking is her neurological examination– She sits with a stooped posture– Masked face and “reptilian stare,”– Walking with a rigid manner and much decreased arm swing bilaterally, turning “en bloc” with obvious axial rigidity about the neck– Positive Myerson’s sign– Cogwheeling bilaterally– States she has akathisia– States she has problems turning over in bed

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation Some current symptomatic relief from alprazolam for agitation, but not dramatic

Diagnosed with primary Parkinson’s disease with secondary depression and insomnia, not necessarily a major depressive episode, pending neurological evaluation

Because of the prior good response to amitriptyline, given 50–75 mg/day at night for sleep, and for its anticholinergic effects that might improve parkinsonism while she is awaiting neurological evaluation, although the dose is probably too low for robust antidepressant action

She is referred to a neurologist for evaluation

Lost to follow-up for three years

Case Outcome: Three Years Later Returned three years later with the following interim history

First neurological consultation shortly after her initial psychiatric evaluation– While awaiting her first neurological consult for a few weeks on amitriptyline, she became much more animated, with improved facial expression and less rigidity– Speech still hard to initiate at times– Remained apathetic but now was able to sleep well– Neurologist saw her shortly thereafter and diagnosed Parkinson’s disease and started levodopa/carbidopa– Not helpful– Neurologist then added a dopamine agonist– Patient began to experience “mood swings” with increased pressure of speech and was somewhat inappropriately talkative on an airplane trip and was referred to a local psychiatrist– Neurologist then discontinued the dopamine agonist and reduced the dose of levodopa/carbidopa– Patient had no more mood swings and movements seemed to be better– Neurologist referred her to a local psychiatrist for evaluation of mood swings

New psychiatrist– Patient saw the psychiatrist to whom the neurologist had referred her, and he increased amitriptyline to 150 mg at night and also started clonazepam– Parkinsonism again improved along with depression, but patient had weight gain and increased fatigue from amitriptyline so stopped it

Third psychiatrist– Then went to another psychiatrist in a nearby city who spoke her native language and was prescribed mirtazapine (Remeron) and risperidone (Risperdal) !!– Predictably worsened and patient stopped all meds, resulting in her looking more parkinsonian and more depressed

Second neurological consultation– Referred to second neurologist at a major medical center where she seemed somewhat parkinsonian– Was a nonresponder to dopaminergic treatments– A PET scan failed to confirm Parkinson’s disease– Led to a diagnosis of “atypical parkinsonism”– No antiparkinson treatment– Referral to psychiatry at that center

Fourth psychiatrist– Patient had several short term trials– Various SSRIs– Trazodone– Venlafaxine (Effexor XR)– Every drug and every combination caused some therapeutic effects for both depression and parkinsonism, but unacceptable side effects for the first few doses of each and stopped every one each time she got an early side effect

Third neurological consultation– Referred to a third neurologist at yet another major medical center who diagnosed Parkinson’s disease and depression– Tried amantadine (Symmetrel) and other dopamine agonists without positive effects, so all antiparkinson treatment stopped

Patient returns now to you, the original psychiatrist, for a re-evaluation three years after your first and only visit– Has moderate parkinsonism and moderate depression– Taking low dose amitriptyline

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

Recurrent major depression and Parkinson’s disease

Depression secondary to early Parkinson’s disease

Recurrent major depression and severe psychomotor retardation masquerading as Parkinson’s disease

Other

Of the following choices, what would you do?

Add antidepressant alone

Refer to a fourth neurologist for antiparkinsonian treatment first

Coordinate addition of antiparkinsonian treatment by a neurologist with your addition of an antidepressant

None of the above

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

SSRI (selective serotonin 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: First Followup, 3 Years Later This poor women has been running in circles between neurologists and psychiatrists, including this attending physician, without resolution of the problem

Seems like parkinsonian symptoms are curiously linked to depressive symptoms, and both seem coupled together, rising together when one gets worse and falling together when one gets better

Parkinson’s disease does not behave like this

Also, the PET scan does not confirm actual loss of dopaminergic neurons consistent with the diagnosis of Parkinson’s disease

Could this be profound psychomotor retardation that rises and falls as the patient’s depression gets worse, and better, respectively?

The way to tell is to closely track psychomotor symptoms and depressive mood status as antidepressants are given

If this formulation is correct, her so-called parkinsonian symptoms should not require direct treatment, only improvement of the depression

Her hypomanic episode clearly suggests a mood disorder as well

She thought she was an angel in first class cabin flying on an international trip and kept taking the slippers off other passengers as they slept

She herself did not sleep at all on the trip, shortly after starting a dopamine agonist, and was talkative, intrusive to sleeping passengers, and embarrassed her husband who witnessed this

Since her symptoms seem linked to dopamine, a trial of a pro-dopaminergic agent, perhaps bupropion, an effective antidepressant often well tolerated in bipolar spectrum patients, might be worth a try

Given a trial of bupropion SR 150 mg increasing to 300 mg per day

Case Outcome: Second Followup, 4 Weeks Later Bupropion causes tongue dyskinesias

Attending Physician’s Mental Notes: Second Followup, 4 Weeks Later Well, I guess this was not such a brilliant idea to try bupropion

This patient seems to be extraordinarily sensitive to dopamine actions, looking very parkinsonian when her depression is bad and her psychomotor retardation is poor, and with prodopaminergic drugs causing either hypomania or dyskinesias

Better avoid drugs with direct actions on dopamine for now

At this first followup visit, discontinued the bupropion and switched her to citalopram (Celexa)

Continued amitriptyline 50 mg at night

Continued clonazepam 0.5 mg prn

Case Outcome: 8 Weeks Later and for the Next 5 Years Amazingly, the citalopram was robustly effective for her depression over the next few months

She completely resolved her parkinsonism

She has had intermittent anxiety treatable by varying doses of supplemental clonazapam over the years but has had essentially no recurrence of depression and no signs of parkinsonism again

Case Debrief In retrospect, the patient’s parkinsonism has always fluctuated in direct proportion to the severity of her depression

The patient may indeed have some kind of presymptomatic movement disorder underlying her depression, or such severe psychomotor retardation that it looks parkinsonian even to international neurological experts at more than one major medical center, and that remits not with parkinsonian treatment but with only those antidepressants that improve her mood

Cultural and language problems can make analyzing and managing a complex case even more complicated

This case is unusual in that the severity of depression associated with Parkinson’s disease does NOT usually correlate with the severity of the movement disorder

This case is also unusual in that what now seems to be simply very severe psychomotor retardation presented as parkinsonism and led to a complicated set of failed treatments by both neurologists and psychiatrists at first

Take-Home Points Reversible parkinsonism is not Parkinson’s disease

Specialists in both neurology and psychiatry can tend to see a case through the prism of their own specialty’s perspective when a patient with neurological and psychiatric symptoms may require a dual and simultaneous perspective

This patient has more prominent parkinsonism than depression and fooled all of us that this was a primary motor disorder and not a primary mood disorder, as was ultimately shown to be the case

The patient wasted years in back and forth consultations and ineffective treatments awaiting a good outcome

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?– Should the depression have been treated more aggressively from the beginning, and while the original neurological consultation was taking place?– Should the normal PET scan have signaled that this was a mood disorder and not a primary motor disorder?– Better coordination between neurology and psychiatry may have led to the discovery of her diagnosis and her treatment much more quickly

Possible action item for improvement in practice– Learn more about Parkinson’s disease and its treatments– Do not be hesitant to treat depression in an undiagnosed motor disorder, but start treatment while motor disorder is being evaluated

Tips and Pearls Dopamine agonists and prodopaminergic agents that do not improve parkinsonism or depression, but instead cause dyskinesias and hypomania should suggest a case that is out of the ordinary

When levodopa/carbidopa is not effective and the PET scan does not confirm degeneration of striatal dopamine nerve terminals, the patient does not have Parkinson’s disease no matter how convincing the motor examination

None of the neurologists had ever seen such a convincing case of clinical parkinsonism, state dependent upon mood

Nor had any of the psychiatrists

In the end, this case turned out to have a remarkably simple therapeutic solution that was robust and long lasting

Posttest Self Assessment Question: Answer The severity of depression associated with Parkinson’s disease usually correlates with the severity of the movement disorder?

A. True

B. False

Answer: B. False