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Unexpected improvement

Current Psychiatry. 2011 August;10(08):55-61
August 1, 2011|Current Psychiatry
Ricardo Millán-González, MD
Author and Disclosure Information

Ricardo Millán-González, MD
Dr. Millán-González is a Professor of Psychiatry and Psychosomatic Medicine at the University of Costa Rica, San José
Carlos Loizaga-Arnaiz, MD
Dr. Loizaga-Arnaiz is a Psychiatrist at the Padre Menni Clinic, Pamplona, Spain
Fabricio Zúñiga-Montes, MD
Dr. Zúñiga-Montes is a Psychiatrist at the Padre Menni Clinic, Pamplona, Spain

For 30 years, Ms. U, age 53, has experienced treatment-resistant schizophrenia. After she is treated for a neurologic disorder, her psychotic symptoms improve markedly. What could be the cause?

An assessment 18 months after starting riluzole describes a Positive and Negative Syndrome Scale (PANSS) score of 9 for positive symptoms, 11 for negative, 35 for the general psychopathology, and -2 for the composite (Table 1). Laboratory tests are normal except for a mild normocytic, normochromic anemia. MRI shows no detectable lesions or changes in comparison with previous images.

Table 1

Ms. U’s clinical course

PANSS scoreTreatmentMental status
Before starting riluzole
No PANSS reportedClozapine, 600 mg/d; lithium, 1200 mg/d; haloperidol, 6 mg/dPersistent auditory hallucinations. Persistent hallucinatory behavior. Paranoid delirious ideas. Negativism, mutism, and liability reactive to her psychosis state. Poor and flattened affect. Lack of disease awareness. Progressive social isolation. Loss of self care
After starting riluzole
Positive subscale: 9 (below 5th percentile)
Negative subscale: 11 (between 5th-25th percentile)
General psychopathology subscale: 35 (between 5th-25th percentile)
Composite score: -2 (between 25th-50th percentiles)		Riluzole, 50 mg every 12 hours; risperidone, 1 mg/d; methotrimeprazine, 10 mg/d; venlafaxine, 75 mg/d; trazodone, 100 mg/d; lithium, 600 mg/dRe-establishes relationships with family because she no longer experiences paranoid delusions. Behavioral improvement. Allows physical proximity to nursing and medical personnel. Attention to physical appearance. Participates in social and recreational activities outside the hospital. Absence of auditory hallucinations. Affective improvement with appropriate responses. Realistic anxiety and fear about ALS diagnosis
ALS: amyotrophic lateral sclerosis; PANSS: Positive and Negative Syndrome Scale

The authors’ observations

We present a patient with schizophrenia and a continuous pattern of relapses, functional and social impairment, and partial remission of her psychosis despite the use of multiple typical and atypical antipsychotics at therapeutic doses. Ms. U received treatment with clozapine at therapeutic doses for >6 months without sustained improvement. After beginning riluzole, a glutamate pathway antagonist, and with no other changes to her medication regimen, Ms. U experienced substantial improvement in her mental status. This was evidenced by a significant decline in her paranoid delusions, disappearance of auditory hallucinations, and substantial improvement on her social performance.

Clinical Point

After beginning riluzole and with no other changes in her medication regimen, Ms. U experienced improvement in her mental status

This fact is consistent with previous observations where modulation of the glutamate pathway has been associated with improvement in depression and anxiety levels in different populations. This case report provides further evidence to the possibility that blocking this receptor is a promising approach to psychotic disorders.

Riluzole for psychiatric illness

Currently, there are 11 clinical trials investigating riluzole for psychiatric disorders, including OCD, depression, bipolar disorder, schizophrenia, and Tourette’s syndrome.11 Consistent with the altered glutamatergic neurotransmission implicated in mood and anxiety disorders, preliminary evidence suggests riluzole can effectively treat OCD, bipolar depression, unipolar depression, and comorbid OCD and depression (Table 2). Some investigators consider the glutamatergic pathway an essential target for future antidepressants and mood-stabilizing agents.12

Other drugs such as memantine, acamprosate, and lamotrigine act on this same pathway and therefore have a role in treating psychiatric and neurologic conditions. In the case of lamotrigine, the drug inhibits glutamate release through inhibition of voltage-dependent sodium and calcium channels13 and postsynaptic AMPA receptors14 and has been shown to effectively treat generalized epilepsies,15 bipolar depression,13,16 and depression and mood swings associated with Huntington’s disease.17

Clinical Point

Drugs such as memantine, acamprosate, and lamotrigine act on the glutamatergic pathway

Acamprosate’s attenuation of hyperglutamatergic states through NMDA antagonism and metabotropic glutamate receptors and reduction of intracellular calcium release—therefore balancing the glutamatergic and GABAergic systems and conferring neuroprotective properties—has been effective in patients with alcohol use disorders.18,19

Memantine and amantadine act through NMDA antagonism and by modulating dopaminergic transmission and may have clinical roles beyond dementia treatment.

Table 2

Evidence of efficacy of riluzole for OCD and depression

StudyDisorderFindings
Pittenger et al, 2006aOCDBrain imaging reveals elevated glutamate levels in OCD patients; agents that reduce glutamate hyperactivity may be effective
Coric et al, 2005bOCDAmong 13 patients with OCD who received riluzole, 54% demonstrated >35% reduction in Y-BOCS scores and 39% were considered treatment responders
Zarate et al, 2005cBipolar depressionIn an 8-week add-on study of riluzole in combination with lithium of 14 patients with bipolar depression, riluzole showed efficacy as measured by MADRS score and was well tolerated
Singh et al, 2004dBipolar depressionCase report of a patient with bipolar II disorder and depression who had a good response to riluzole when lamotrigine was discontinued because of a maculopapular erythematic rash
Zarate et al, 2004eUnipolar depressionIn a 6-week, open-label trial, 19 treatment-resistant depressed patients received riluzole; significant improvement measured by MADRS, CGI-S, and HAM-A were noted at weeks 3 through 6
Coric et al, 2003fComorbid OCD and major depressive disorderCase report of a patient with symptomatic OCD and depression who did not respond to appropriate pharmacotherapy, including augmentation strategies; adding riluzole significantly attenuated both obsessions and depressive symptoms
CGI-S: Clinical Global Impressions-Severity; HAM-A: Hamilton Anxiety Rating Scale; MADRS: Montgomery-Åsberg Depression Rating Scale; OCD: obsessive-compulsive disorder; Y-BOCS: Yale-Brown Obsessive Compulsive Scale Source:
a. Pittenger C, Krystal JH, Coric V. Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder. Neurotherapeutics. 2006;3(1):69-81.
b. Coric V, Taskiran S, Pittenger C, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005;58(5):424-428.
c. Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57(4):430-432.
d. Singh J, Zarate CA, Krystal AD. Case report: successful riluzole augmentation therapy in treatment-resistant bipolar depression following the development of rash with lamotrigine. Psychopharmacology. 2004;173(1-2):227-228.
e. Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161(1):171-174.
f. Coric V, Milanovic S, Wasylink S, et al. Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Psychopharmacology. 2003;167(2):219-220.

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