Depression With an Uncommon Cause

[[{"type":"media","view_mode":"media_crop","fid":"30809","attributes":{"alt":"Barbara Schildkrout, MD","class":"media-image","id":"media_crop_870489515140","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3234","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","title":" ","typeof":"foaf:Image"}}]]This case is adapted from a report in The New England Journal of Medicine.¹

In 1999, The New England Journal of Medicine (NEJM) published the case of a 65-year-old woman with Parkinson disease (PD). She was unnamed in the report. I will call her Ms P.

Ms P had no psychiatric history; in particular, she had no history of depression. Yet, photographs in the NEJM article show her crying, with emotional pain contorting her facial expression.

In response to being asked why she was crying, Ms P is reported to have said, “I’m falling down in my head, I no longer wish to live, to see anything, hear anything, feel anything . . .”

And was she feeling pain? “No, I’m fed up with life, I’ve had enough . . . I don’t want to live anymore, I’m disgusted with life. . . . Everything is useless, always feeling worthless, I’m scared in the world.”

A bit later, “I’m tired. I want to hide in a corner. . . . I’m crying over myself, of course. . . . I’m hopeless, why am I bothering you? . . .”

A psychiatrist can recognize in this presentation the hallmarks of major depression: tearfulness, depressive affect and mood, unmistakable emotional distress, withdrawal and lack of interest in life, a sense of utter exhaustion, feelings of hopelessness and worthlessness, and thoughts of death. Nonetheless, Ms P did not meet DSM criteria for MDD because her symptoms lasted for less than 10 minutes.

Depression is common in PD, but Ms P’s depression had an uncommon cause. Ms P’s “transient acute depression” was an unexpected consequence of high-frequency, deep brain stimulation (DBS) to her left substantia nigra. The intended purpose was treatment for the motor symptoms of her PD.

Ms P had had PD for 30 years. Before the DBS, she had had a moderate resting tremor but severe rigidity and akinesia. She had been taking 900 mg of levodopa, 2.5 mg of pergolide, and 3 to 5 mg of lorazepam daily. However, the levodopa had induced “disabling dyskinesias.”

The NEJM report was from the 10th postoperative day. Ms P had had electrodes surgically implanted into the subthalamic region of her brain, one on each side. (Each electrode had 4 contact points along its length so that the optimal location for stimulation could be decided after implantation.) Using their standard protocol, the team was testing activation from different contact points to see which combinations led to the most effective treatment for Ms P’s motor symptoms.

Within 5 seconds of activating contact 0 on the left, the patient was transformed. She “leaned her head to the right” and, in full consciousness, became acutely and profoundly depressed. After the stimulation was turned off, the patient’s depression abated within 90 seconds. This was followed by about 5 minutes of mild euphoria and silliness: “. . . she laughed and joked with the examiner, playfully pulling his tie.” Ms P remembered the entire experience.

With the patient’s permission, the researchers twice repeated stimulation of contact 0 and demonstrated that the patient’s depression was turned on and off each time. Sham stimulation led to no change in Ms P’s mental state.

Thankfully, Ms P derived outstanding benefit with no psychiatric adverse effects from stimulation of a combination of contacts (including contact 1 on the left, which was only 2 mm from contact 0). One month postoperative, Ms P was able to discontinue all of her medications.

As psychiatrists, we are used to thinking about depression from many different perspectives. We know the existential questions that depression raises. Most of us have read Mourning and Melancholia by Sigmund Freud. We are familiar with dynamic formulations, pharmacological approaches, cognitive-behavioral treatments, the effectiveness of ECT, and the evolving DSM diagnostic criteria for depression.

But this 1999 report of an acute, transient, reversible depression prompts us to think in a different way about depression. Ms P had no history of a mental disorder. For her, there was no psychodynamic driver. Even when one speculates about the possibility of her medical disease as substrate, immediately the fact that Ms P had 30 years of PD without depression argues back. If tempted to make the gut-level case that having electrodes sunk into one’s brain would be distressing, we are faced with the fact that no depressive symptoms resulted from identical electrical stimulation delivered just 2 mm higher in Ms P’s brain.

We are left with a remarkable situation. Neural stimulation that, according to the authors, likely affected only 1 mm³ of neural tissue, nonetheless led to a constellation of mental status features seen in severe depression. So it seems most likely that in Ms P’s case, the electrical stimulation in some way affected a neural circuitry that is involved in depression.

All human behavior has a basis in the brain. That the symptoms of depression were elicited by electrical stimulation to one tiny area in this patient’s brain should not lead us to infer that there is a “depression center.” But we might reasonably conclude that there is a complex neural network that links mood, affect, cognition, sense of self and time, and so on. We might reasonably conclude that this network is influenced by genetic endowment as well as by experience (including disease).

The authors concluded, “. . . the depression probably resulted from the stimulation of afferent, efferent, or passing fibers within the substantia nigra [a subthalamic structure] or from the inhibition of these fibers . . .”

Investigations into the neural underpinnings of depression are moving forward. Dr Helen Mayberg’s DBS treatments for depression are based on hypotheses about a neural circuitry of depression.

In 2008, the FDA approved the use of rTMS (repetitive transcranial magnetic stimulation) for the treatment of depression in patients who had failed to respond to pharmacological approaches. rTMS delivers unilateral neurostimulation, targeted to prefrontal brain structures.

Probably the most influential effort in this area has been the change in research funding policy, announced by the NIMH in 2013. The awarding of research funding now favors use of the Research Domain Criteria (RDoC) over DSM diagnostic categories (including MDD). RDoC marks a major conceptual shift in that it reorganizes the way we categorize our observations, parsing behaviors and mental status find-ings into groupings that are believed to correspond more directly with underlying biological processes. RDoC promises to facilitate exploration of the underlying neural, genetic, cellular, molecular, and physiologic bases of the various component features of what we call major depression.

We are the fortunate recipients of the chance observations that were reported in the NEJM in 1999. Hopefully, that remarkable report and ensuing work on the neurology of depression will prepare us to understand and embrace future discoveries.

This article was originally posted on 1/7/2015 and has since been updated.

Disclosures:

Dr Schildkrout is Assistant Professor of Psychiatry, Part-time, Harvard Medical School, Beth Israel Deaconess Medical Center in Boston. She is the author of two books: Unmasking Psychological Symptoms: How Therapists Can Learn to Recognize the Psychological Presentation of Medical Disorders and Masquerading Symptoms: Uncovering Physical Illnesses That Present as Psychological Problems. Her Web site is www.bschildkrout.com.

References:

1. Bejjani BP, Damier P, Arnulf I, et al. Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med. 1999;340:1476-1480.