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Question:

A 32-year-old man is admitted to the hospital after being found standing on the edge of a bridge.  He appears severely depressed and says that his life is over.  The patient is in financial ruin, and his wife recently left him and took their children.  He is crying, is unable to sleep, has no appetite, and continues to express hopelessness and suicidal thoughts.  He was taking phenelzine for depression but stopped the medication a month ago due to adverse effects.  In the hospital, the patient is given sertraline.  The next day, after calling his wife, he becomes agitated and starts to blame himself for destroying his life and family.  The patient is given olanzapine for worsening agitation during the first 3 days, after which he is noticeably calmer but unable to get out of bed.  He appears confused and does not respond to questions appropriately.  The patient is diaphoretic.  Temperature is 40.1 C (104.2 F), blood pressure is 167/97 mm Hg, and pulse is 112/min.  As staff members attempt to get him out of bed, they notice that his arms and legs are stiff and difficult to bend.  Which of the following is the most likely cause of this patient's symptoms?

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Explanation:

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Neuroleptic malignant syndrome vs serotonin syndrome

Neuroleptic malignant syndrome

Serotonin syndrome

Causative agent

  • Dopamine antagonist
  • Serotonergic agent

Course

  • Slow onset/offset (days to weeks)
  • Not dose dependent, can occur anytime
  • Rapid onset/offset (<24 hr)
  • Often associated with dose increase or additional serotonergic agent

Overlapping features

  • Autonomic dysregulation
  • Altered mental status
  • Hyperthermia
  • Autonomic dysregulation
  • Altered mental status
  • Hyperthermia

Distinct features

  • Severe, diffuse muscle rigidity
  • Hyperreflexia
  • Clonus
  • Nausea, vomiting common

This patient's presentation is consistent with neuroleptic malignant syndrome (NMS).  NMS is a rare, idiosyncratic, and potentially life-threatening complication of treatment with antipsychotics.  Although it is more commonly associated with the use of high-potency, first-generation antipsychotics (eg, haloperidol), NMS can occur with every class of antipsychotics, including second-generation drugs (eg, olanzapine).

Physical examination findings of NMS include hyperthermia, lead-pipe rigidity (eg, stiff arms and legs), mental status changes (eg, agitation), and autonomic instability (eg, hyperthermia, hypertension, tachycardia, diaphoresis).  Overlapping symptoms with serotonin syndrome (SS) are common (eg, hypertension, tachycardia, hyperthermia, altered mental status); NMS can be differentiated from SS as follows:

  • NMS is caused by dopamine antagonists, not serotonergic agents (eg, sertraline) (Choice E).  SS is typically due to a combination of serotonergic agents or a drug interaction between these medications and a monoamine oxidase inhibitor (eg, phenelzine) (Choice B).  This patient has had a sufficient 2-week washout period from phenelzine, and sertraline alone (or in combination with olanzapine) is unlikely to cause SS.
  • The onset of NMS is gradual, as seen in this patient.  In contrast, SS is characterized by abrupt onset (usually <24 hr).
  • Severe, generalized lead-pipe rigidity is the hallmark of NMS.  Neuromuscular excitability (eg, clonus, hyperreflexia) distinguishes SS.
  • Gastrointestinal symptoms (eg, vomiting, diarrhea) are usually absent in NMS but present in SS.

(Choice A)  Catatonia is a syndrome that occurs in severely ill psychiatric and medical patients, characterized by decreased motor activity, lack of responsiveness during interview, and posturing.  It is not to be confused with malignant catatonia, a specific disorder with autonomic instability (similar to NMS) but with motor symptoms that include posturing and waxy flexibility.  Catatonia would not explain this patient's hyperthermia and autonomic dysregulation.

(Choice C)  Malignant hyperthermia is a specific disorder characterized by symptoms similar to those of NMS, but it presents with the use of volatile anesthetics or succinylcholine.  Symptoms occur during or immediately after anesthetic use (not present in this patient).

Educational objective:
Neuroleptic malignant syndrome (NMS) is a potentially life-threatening condition that can occur after administration of antipsychotic medications.  Symptoms include hyperthermia, autonomic dysregulation, altered mental status, and generalized muscle rigidity.  Lead-pipe rigidity and absence of hyperreflexia can distinguish NMS from serotonin syndrome.