Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-26T07:27:39.190Z Has data issue: false hasContentIssue false
  • English
  • Français

Modafinil: A Candidate for Pharmacotherapy of Negative Symptoms in Schizophrenia

Published online by Cambridge University Press:  28 November 2007

John H. Peloian  and
Joseph M. Pierre
John H. Peloian
Affiliation:
Department of Psychiatry, VA Greater Los Angeles Healthcare System; Email: jpeloian@ucla.edu
Joseph M. Pierre
Affiliation:
Department of Psychiatry, VA Greater Los Angeles Healthcare System Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at the University of California, Los Angeles, USA; Email: joseph.pierre2@va.gov
Get access Rights & Permissions [Opens in a new window]

Extract

ABSTRACT

Background: Although historically neglected in clinical research, negative symptoms of schizophrenia are now considered distinct targets of pharmacotherapy. While second-generation antipsychotic treatments were heralded as having a greater therapeutic impact on negative symptoms than their conventional antipsychotic counterparts, the size of this effect is modest. Adjunctive medications such as antidepressants offer limited efficacy, while stimulants have a poor risk–benefit profile. More recently, promising results have been demonstrated with pro-glutamatergic agents such as glycine or D-cycloserine, although a larger trial found no advantage with either agent compared with placebo. Modafinil, a novel wakefulness-promoting agent, is an intriguing candidate for adjunctive pharmacotherapy to treat negative symptoms in schizophrenia. We explored this therapeutic potential through a placebo-controlled trial of patients with prominent negative symptoms. Methods: We randomly assigned patients with schizophrenia or schizoaffective disorder to treatment with either modafinil or placebo for 8 weeks. Double-blind assessments of clinical symptoms and neurocognition were administered at baseline and every 2 weeks thereafter. Results: Twenty subjects were enrolled (N = 10 modafinil, N = 10 placebo). There were no significant differences between modafinil and placebo for changes in negative symptom ratings, the primary study endpoint. However, modafinil treatment was associated with a greater rate and degree of global improvement at study endpoint compared with placebo. No significant worsening of psychopathology was observed and modafinil was well-tolerated. Interpretation: Although no effect on negative symptoms was found, adjunctive therapy with modafinil may result in global improvements in patients with schizophrenia who have prominent negative symptoms. These findings support additional research into a potential role for modafinil in the treatment of negative symptoms in schizophrenia.

Keywords

cognitiondeficit syndromemodafinilnegative symptomsschizophrenia.
Type
Research Article
Information
Progress in Neurotherapeutics and Neuropsychopharmacology , Volume 3 , Issue 1 , January 2008 , pp. 259 - 274
Copyright
© 2008 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Amador, X.F., Kirkpatrick, B., Buchanan, R.W., Carpenter, W.T., Marcinko, L., et al. (1999). Stability of the diagnosis of deficit syndrome in schizophrenia. American Journal of Psychiatry, 156, 637–639.Google Scholar
Andreasen, N.C. (1982). Negative symptoms in schizophrenia. Archives of General Psychiatry, 39, 784–788.Google Scholar
Arndt, S., Andreasen, N.C., Flaum, M., Miller, D., & Nopoulos, P. (1995). A longitudinal study of symptom dimensions in schizophrenia: prediction and pattern of change. Archives of General Psychiatry, 52, 352–360.Google Scholar
Army Individual Test Battery (1994). Manual of Directions and Scoring. Washington, DC: War Department, Adjutant General's Office.
Bark, N., Revheim, N., Huq, F., Khalderov, V., Ganz, Z.W., & Medalia, A. (2003). The impact of cognitive remediation on psychiatric symptoms of schizophrenia. Schizophrenia Research, 63, 229–235.Google Scholar
Beusterien, D.M., Rogers, A.E., Walsleben, J.A., Emsellem, H.A., Reblando, J.A., Wang, L., et al. (1999). Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep, 22, 757–765.Google Scholar
Breier, A., Buchanan, R.W., Kirkpatrick, B., Davis, O.R., Irish, D., Summerfelt, A., et al. (1994). Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. American Journal of Psychiatry, 151, 20–26.Google Scholar
Buchanan, R.W., Strauss, M.E., Kirkpatrick, B., Holstein, C., Breier, A., & Carpenter, W.T. Jr. (1994). Neuropsychological impairments in deficit vs nondeficitforms of schizophrenia. Archives of General Psychiatry, 51, 804–811.Google Scholar
Buchanan, R.W., Breier, A., Kirkpatrick, B., Ball, P., & Carpenter, W.T. Jr. (1998). Positive and negative symptom response to clozapine in schizophrenia patients with or without the deficit syndrome. American Journal of Psychiatry, 155, 751–760.Google Scholar
Buchanan, R.W., Javitt, D.C., Marder, S.R., Schooler, N.R., Gold, J.M., McMahon, R.P., et al. (2007). The cognitive and negative symptoms in schizophrenia trial (CONSIST): The efficacy of glutamatergic agents for negative symptoms and cognitive impairments. American Journal of Psychiatry, 10, 1593–1602.Google Scholar
Bustillo, J.R., Lauriello, J.R., Horan, W.P., & Keith, S.J. (2001). The psychosocial treatment of schizophrenia: an update. American Journal of Psychiatry, 158, 163–175.Google Scholar
Carpenter, W.T. (1995). Serotonin–dopamine antagonists and treatment of negative symptoms. Journal of Clinical Psychopharmacology, 15, 30S–35S.Google Scholar
Carpenter, W.T., Heinrichs, D.W., & Alphs, L.D. (1985). Treatment of negative symptoms. Schizophrenia Bulletin, 11, 440–452.Google Scholar
Coyle, J.T. (2006). Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Molecular Neurobiology, 26, 365–384.Google Scholar
Damian, M.S., Gerlach, A., Schmidt, F., Lehmann, E., & Reichmann, H. (2001). Modafinil for excessive daytime sleepiness in myotonic dystrophy. Neurology, 56, 794–796.Google Scholar
Davis, K.L., Kahn, R.S., Ko, G., & Davidson, M. (1991). Dopamine in schizophrenia: a review and reconceptualization. American Journal of Psychiatry, 148, 1474–1486.Google Scholar
DeBattista, C., Doghramji, K., Menza, M.A., Rosenthal, M.H., & Fieve, R.R. (2003). Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. Journal of Clinical Psychiatry, 64, 1057–1064.Google Scholar
Delis, D.C., Dramer, J.H., Kaplan, E., et al. (1987). The California Verbal Learning Test (manual). San Antonio, TX: The Psychological Corporation.
de Saint Hilaire, Z., Orosco, M., & Rouch, C. (2001). Variation in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport, 12, 3533–3537.Google Scholar
Erhart, S.M., Marder, S.R., & Carpenter, W.T. (2006). Treatment of schizophrenia negative symptoms: future prospects. Schizophrenia Bulletin, 32, 234–237.Google Scholar
Evins, A.E., Amico, E., Posever, T.A., Posever, T.A., Toker, R., & Goff, D.C. (2002). D-cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia. Schizophrenia Research, 56, 19–23.Google Scholar
Fava, M., Thase, M.E., & DeBattista, C. (2005). A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. Journal of Clinical Psychiatry, 66, 85–93.Google Scholar
Fenton, W.S., & McGlashan, T.H. (1991). Natural history of schizophrenia subtypes: positive and negative symptoms and long-term course. Archives of General psychiatry, 48, 978–986.Google Scholar
Ferraro, L., Antonelli, T., O'Connor, W.T., Tanganelli, S., Rambert, F., & Fuxe, K. (1997). The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus. Neuroreport, 8, 2883–2887.Google Scholar
Ferraro, L., Antonelli, T., Tanganelli, S., O'Connor, W.T., Perez de la Mora, M., Mendez-Franco, J., et al. (1999). The Vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade. Neuropsychopharmacology, 4, 346–356.Google Scholar
First, M.B., Spitzer, R.L., Gibbon, M., & Williams, J.B.W. (1996). Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (Version 2.0). New York, NY: Biometrics Research, New York State Psychiatric Institute.
Frye, M.A., Grunze, H., Suppes, T., McElroy, S.L., Keck, P.E. Jr., Walden, J., et al. (2007). A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. American Journal of Psychiatry, 164, 1242–1249.Google Scholar
Goff, D.C., & Evins, A.E. (1998). Negative symptoms in schizophrenia: neurobiological model and treatment response. Harvard Review of Psychiatry, 6, 59–77.Google Scholar
Goff, D.C., Tsai, G., Levitt, J., Amico, E., Manoach, D., Schoenfeld, D.A., et al. (1999). A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Archives of General Psychiatry, 56, 21–27.Google Scholar
Greenwood, K.E., Landau, S., & Wykes, T. (2005). Negative symptoms and specific cognitive impairments as combined targets for improved functional outcome within cognitive remediation therapy. Schizophrenia Bulletin, 31, 910–921.Google Scholar
Heresco-Levy, U., Javitt, D.C., Ermilov, M., Mordel, C., Silipo, G., & Lichtenstein, M. (1999). Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Archives of General Psychiatry, 56, 21–27.Google Scholar
Heresco-Levy, U., Ermilov, M., Shimoni, J., Shapira, B., Silipo, G., & Javitt, D.C. (2002). Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. American Journal of Psychiatry, 159, 480–482.Google Scholar
Horan, W.P., Kring, A.M., & Blanchard, J.J. (2006). Anhedonia in schizophrenia: a review of assessment strategies. Schizophrenia Bulletin, 32, 259–273.Google Scholar
Javitt, D.C., Zylberman, I., Zukin, S.R., Heresco-Levy, U., & Lindenmayer, J.P. (1994). Amelioration of negative symptoms in schizophrenia by glycine. American Journal of Psychiatry, 151, 1234–1236.Google Scholar
Kirkpatrick, B., Buchanan, R.W., Mckenney, P.D., Alphs, L.D., & Carpenter, W.T. (1989). The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Research, 30, 119–124.Google Scholar
Kirkpatrick, B., Buchanan, R.W., Ross, D.E., & Carpenter, W.T. Jr. (2001). A separate disease within the syndrome of schizophrenia. Archives of General Psychiatry, 58, 165–171.Google Scholar
Kirkpatrick, B., Fenton, W.S., Carpenter, W.T., & Marder, S.R. (2006). The NIMH-MATRICS consensus statement on negative symptoms. Schizophrenia Bulletin, 32, 214–219.Google Scholar
Kopelowicz, A., Zarate, R., Tripodis, K., Gonzalez, V., & Mintz, J. (2000). Differential efficacy of olanzapine for deficit and nondeficit negative symptoms in schizophrenia. American Journal of Psychiatry, 157, 987–993.Google Scholar
Laughren, T., & Levin, R. (2006). Food and drug administration perspective on negative symptoms in schizophrenia as a target for a drug treatment claim. Schizophrenia Bulletin, 32, 220–222.Google Scholar
Lehman, A.F. (1988). A quality of life interview for the chronically mentally ill (QOLI). Evaluation and Program Planning, 11, 51–62.Google Scholar
Leucht, S., Pitschel-Walz, G., Abraham, D., & Kissling, W. (1999). Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo: a meta-analysis of randomized controlled trials. Schizophrenia Research, 35, 51–68.Google Scholar
Makela, E.H., Miller, K., & Cutlip, W.D. (2003). Three case reports of modafinil use in treating sedation induced by antipsychotic medications. Journal of Clinical Psychiatry, 61, 378–381.Google Scholar
Mariani, J.J., & Hart, C.L. (2005). Psychosis associated with modafinil and shift work. American Journal of Psychiatry, 10, 1983.Google Scholar
Menza, M.A., Kaufman, K.R., & Castellanos, A. (2000). Modafinil augmentation of antidepressant treatment in depression. Journal of Clinical Psychiatry, 61, 378–381.Google Scholar
Milev, P., Ho, B.C., Arndt, S., & Andreasen, N.C. (2005). Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry, 162 (2005), 495–506.Google Scholar
Mizenberg, M.J., & Carter, C.S. (2007). Modafinil: A review of neurochemical actions and effects on cognition. Neuropsychopharmacology (in press).Google Scholar
Möller, H.J. (2004). Non-neuroleptic approaches to treating negative symptoms in schizophrenia. European Archives of Psychiatry and Clinical Neuroscience, 254, 108–116.Google Scholar
Morein-Zamir, S., Turner, D., & Shakian, B.J. (2007). A review of the effects of modafinil on cognition in schizophrenia. Schizophrenia Bulletin (in press).Google Scholar
Murillo-Rodriguez, E., Haro, R., Palomero-Rivero, M., Millan-Aldaco, D., & Drucker-Colin, R. (2007). Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats. Behavioural Brain Research, 176, 353–357.Google Scholar
Narendran, R., Young, C.M., Valenti, A.M., Nickolova, M.K., & Pristach, C.A. (2002). Is psychosis exacerbated by modafinil? Archives of General Psychiatry, 59, 292–293.Google Scholar
Nasr, S., Wendt, B., & Steiner, K. (2006). Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice. Journal of Affective Disorders, 95, 111–114.Google Scholar
Nuechterlein, K.H., Edell, W.S., Norris, M., & Dawson, M.E. (1986). Attentional vulnerability indicators, thought disorder, and negative symptoms. Schizophrenia Bulletin, 12, 408–426.Google Scholar
Ondo, W.G., Fayle, R., Atassi, F., & Jankovic, J. (2005). Modafinil for daytime somnolence in Parkinson's disease: double blind, placebo controlled parallel trial. Journal of Neurology Neurosurgery and Psychiatry, 76, 1636–1639.Google Scholar
Overall, J.E., & Gorham, D.R. (1962). The brief psychiatric rating scale. Psychological Report, 10, 799–812.Google Scholar
Pierre, J.M., Peloian, J.H., Wirshing, D.A., Wirshing, W.C., & Marder, S.R. (2007). A randomized, double-blind, placebo-controlled trial of modafinil for negative symptoms in schizophrenia. The Journal of Clinical Psychiatry, 68, 705–710. Copyright 2007, Physicians Postgraduate Press. Adapted or reprinted by permission.Google Scholar
Pigeau, R., Naitoh, P., Buguet, A., McCann, C., Baranski, J., Taylor, M., et al. (1995). Modafinil, D-amphetamine and placebo during 64 hours of sustained mental work, 1: effects of mood, fatigue, cognitive performance and body temperature. Journal of Sleep Research, 4, 212–228.Google Scholar
Rammohan, K.W., Rosenberg, J.H., Lynn, D.J., Blumenfeld, A.M., Pollack, C.P., & Nagaraja, H.N. (2002). Efficacy and safety of modafinil (provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. Journal of Neurology Neurosurgery and Psychiatry, 72, 179–183.Google Scholar
Ranjan, S., & Chandra, P.S. (2005). Modafinil-induced irritability and aggression? A report of 2 bipolar patients. Journal of Clinical Psychopharmacology, 25, 628–629.Google Scholar
Roder, V., Zorn, P., Muller, D., & Brenner, H.D. (2001). Improving recreational, residential, and vocational outcomes for patients with schizophrenia. Psychiatric Services, 52, 1439–1441.Google Scholar
Rosenheck, R., Dunn, L., Peszke, M., Cramer, J., Xu, W., Thomas, J., et al. (1999). Impact of clozapine on negative symptoms and on the deficit syndrome in refractory schizophrenia. American Journal of Psychiatry, 156, 88–93.Google Scholar
Rosenthal, M.H., & Bryant, S.L. (2004). Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia. Clinical Neuropharmacology, 27, 38–43.Google Scholar
Rummel, C., Kissling, W., & Leucht, S. (2005). Antidepressants as add-on treatment to antipsychotics for people with schizophrenia and pronounced negative symptoms: a systematic review of randomized trials. Schizophrenia Research, 80, 85–97.Google Scholar
Scammell, T.E., Estabrooke, I.V., McCarthy, M.T., Chemelli, R.M., Yanagisawa, M., Miller, M.S., et al. (2000). Hypothalamic arousal regions are activated during modafinil-induced wakefulness. Journal of Neuroscience, 20, 8620–8628.Google Scholar
Sepehry, A.A., Potvin, S., Elie, R., & Stip, E. (2007). Selective serotonin reuptake inhibitor (SSRI) add-on therapy for the negative symptoms of schizophrenia: a meta-analysis. Journal of Clinical Psychiatry, 68, 604–610.Google Scholar
Sevy, S., Rosenthal, M.H., Alvir, J., Meyer, S., Visweswaraiah, H., Gunduz-Bruce, H., et al. (2005). Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic mediations. Journal of Clinical Psychiatry, 66, 839–843.Google Scholar
Shean, G.D. (2007). Recent developments in psychosocial treatments for schizophrenic patients. Expert Reviews on Neurotherapy, 7, 817–827.Google Scholar
Silver, H. (2003). Selective serotonin reuptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia. International Clinical Psychopharmacology, 18, 305–313.Google Scholar
Spence, S.A., Green, R.D., Wilkinson, I.D., & Hunter, M.D. (2005). Modafinil modulates anterior cingulated function in chronic schizophrenia. British Journal of Psychiatry, 187, 55–61.Google Scholar
Stankoff, B., Waubant, E., Confavreux, C., Edan, G., Debouverie, M., Rumbach, L., et al. (2005). Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology, 64, 1139–1143.Google Scholar
Stone, J.M., Morrison, P.D., & Pilowsky, L.S. (2007). Glutamate and dopamine dysregulation in schizophrenia – a synthesis and selective review. Journal of Psychopharmacology, 21, 440–452.Google Scholar
Tamminga, C.A., Buchanan, R.W., & Gold, J.W. (1998). The role of negative symptoms and cognitive dysfunction in schizophrenia outcome. International Clinical Psychopharmacology, 13, S21–S26.Google Scholar
Taneja, I., Haman, K., Shelton, R.C., & Robertson, D. (2007). A randomized, double-blind, crossover trial of modafinil on mood. Journal of Clinical Psychopharmacology, 27, 76–79.Google Scholar
Teitelman, E. (2001). Off-label uses of modafinil. American Journal of Psychiatry, 158, 1341.Google Scholar
Turner, D.C., Clark, L., Pomarol-Clotet, E., McKenna, P., Robbins, T.W., & Sahakian, B.J. (2004). Modafinil improves cognition and attention set shifting in patient with chronic schizophrenia. Neuropsychopharmacology, 29, 1363–1373.Google Scholar
US Modafinil in Narcolepsy Multicenter Study Group (1998). Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Annals of Neurology, 43, 88–97.Google Scholar
Vorspan, F., Warot, D., Consoli, A., Cohen, D., & Mazet, P. (2005). Mania in a boy treated with modafinil for narcolepsy. American Journal of Psychiatry, 162, 813–814.Google Scholar
Wolf, J., Fiedler, U., Anghelescu, I., & Schwertferger, N. (2006). Manic switch in a patient with treatment-resistant bipolar depression treated with modafinil. Journal of Clinical Psychiatry, 67, 1817.Google Scholar
Yu, B.P., & Maguire, G.A. (2002). Can a wakefulness-promoting agent augment schizophrenia treatment? Current Psychiatry, 1, 52–57.Google Scholar