Role of Norepinephrine in Schizophrenia: An Old-fashioned but New Story from Emergency Medicine

| July 1, 2020

Dear Editor:

A number of hypotheses have been put forth regarding the etiology of schizophrenia, including dopamine hypothesis and glutamate hypothesis.1 However, a lesser known theory is that elevated norepinephrinergic signaling plays a causative role in schizophrenia.2 We treated a patient with septic shock schizophrenia who developed delusions and hallucinations following continuous norepinephrine infusion. This phenomenon provides additional evidence supporting the theory that norepinephrine plays an important role in the pathophysiology of schizophrenia.

Case report. A 71-year-old female patient with schizophrenia was transferred to our hospital for treatment of pyrexia and hypotension. She had a 40-year history of chronic paranoid schizophrenia, which had been successfully treated with quetiapine of 400mg/day for the past eight years prior to this admission. Her initial vital signs included a temperature of 39.6°C, blood pressure (BP) of 54/30mmHg, heart rate of 128 beats/min, respiratory rate of 24 breaths/min, and oxygen saturation of 90 percent while breathing ambient air. Her abdomen was distended without rebound tenderness. Abdominal computed tomography revealed marked dilatation of large intestine without mechanical obstruction, suggesting megacolon. Aggressive fluid resuscitation was initiated, and blood cultures obtained. Intravenous meropenem was initiated, based on suspicion of possible bacterial translocation from dilated colon. The blood culture revealed Escherichia coli within 24 hours. She was diagnosed as having septic shock due to megacolon. According to treatment guidelines for septic shock,3 the patient was administered norepinephrine 0.03µg/kg/min, which was increased to 0.2µg/kg/min, to maintain blood pressure. However, the patient became irritable  and developed symptoms of psychosis, including delusion and hallucination. Norepinephrine was discontinued, and dopamine was initiated at 5µg/kg/min and increased to 8 to 10µg/kg/min, which successfully maintained her systolic BP at 90 to 110mmHg and improved her psychotic symptoms. The patient then developed tachycardia (>110 beats/min), resulting in the decision to discontinue the dopamine and rechallenge the patient with norepinephrine. Upon reinititation of norepinephrine, the patient began screaming loudly and re-exhibiting signs of psychosis (delusion, hallucination). Norepinephrine was once again discontinued and dopamine restarted to maintain her BP. By Day 10 in the hospital, the patient was successfully weaned off the dopamine infusion, with no exacerbation of psychosis.

Discussion. It was interesting to observe in this patient that norepinephrine, not dopamine, appeared to cause symptoms of delusion and hallucination in this patient. Moreover, rechallenging the patient with norepinephrine resulted in a return of the psychotic symptoms. In this case, the Adverse Drug Reaction Probability Scale4 score was 5, which indicates “probable” causality between norepinephrine and psychosis. Our observations are consistent with results from a study in the late 1980s in which patients with schizophrenia who had relapsed were observed to have significantly higher cerebrospinal fluid norepinephrine levels than patients who did not relapse.5 Researchers have hypothesized that elevated norepinephrine signaling might play a prominent role in the development of the paranoid subtype of schizophrenia, and, subsequently, that blocking norepinephrine signaling might suppress the associated symptoms.6 A correlation between cerebrospinal fluid norepinephrine levels and severity of psychosis in patients with drug-free schizophrenia has been shown.7 Norepinephrinergic receptors are found on nerve fibers that originate from the locus coeruleus and project to many parts of the forebrain, including the cortex, cerebellum, amygdala, hippocampus, basal ganglia, thalamus, and hypothalamus.8 Norepinephrine signaling plays a role in a broad range of brain functions, such as arousal, stress response, and memory consolidation; thus, it seems possible that dysfunction in norepinephrine signaling could result in psychosis in some patients.

Circulating monoamines are prevented from entering the brain; however, high circulating concentrations of monoamines can open the blood–brain barrier. Once the barrier is open, systemically administered monoamines can enter the brain parenchyma and induce pronounced changes in neurotransmissions.9 Thus, a continuous infusion of norepinephrine or dopamine to maintain BP could open the blood–brain barrier and result in abnormal neurotransmissions in the brain of someone with schizophrenia.

Limitations. Several confounding factors, including delirium, septicemia, and schizophrenia itself, could present causal inference in this case, limiting our conclusions. 

Conclusion. We observed a strong association between norepinephrine administration and psychosis in our patient with schizophrenia, who had been successfully treated with quetiapine for eight years prior to presentation. Quetiapine binds to a broad range of receptors, including adrenergic receptors. We believe that norepinephrine could be implicated in the pathophysiology of some patients with schizophrenia. Additional research investigating the potential role that norepinephrine antagonism could play in ameliorating the symptoms of schizophrenia is warranted.

References

  1. Stahl SM. Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate. CNS Spectr. 2018;23(3):187–191.
  2. Fitzgerald PJ. Is elevated norepinephrine an etiological factor in some cases of schizophrenia? Psychiatry Res. 2014;215(3):497–504.
  3. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637.
  4. Naranjo CA, Busto U, Sellers EM. Difficulties in assessing adverse drug reactions in clinical trials. Prog Neuropsychopharmacol Biol Psychiatry. 1982;6(4-6):651–657.
  5. van Kammen DP, Peters J, van Kammen WB, et al. CSF norepinephrine in schizophrenia is elevated prior to relapse after haloperidol withdrawal. Biol Psychiatry. 1989;26(2):176–188.
  6. Vensson TH. Alpha-adrenoceptor modulation hypothesis of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(7):1145–1158.
  7. van Kammen DP, Peters J, Yao J, et al. Norepinephrine in acute exacerbations of chronic schizophrenia. Negative symptoms revisited. Arch Gen Psychiatry. 1990;47(2):
    161–168.
  8. Salgado H, Treviño M, Atzori M. Layer- and area-specific actions of norepinephrine on cortical synaptic transmission. Brain Res. 2016;1641(Pt B):163–176.
  9. Hardebo JE, Owman C. Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface. Ann Neurol. 1980;8(1):1–31.

With regards,

Takahiko Nagamine, MD, PhD

Sunlight Brain Research Center in Yamaguchi, Japan.

Funding/financial disclosures. The author has no conflict of interest relevant to the content of this letter. No funding was received for the preparation of this letter.

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Category: Current Issue, Letters to the Editor, Psychiatry, Schizophrenia

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