Monoamine-Based Treatments in Schizophrenia: Time to Change the Paradigm?
Functional deficit in the prefrontal cortex (PFC), also known as hypofrontality, is one of the major manifestations in schizophrenia. This is characterized by a failure of the PFC to support behavior. Although the neuronal mechanisms underlying hyporontality are still under debate, most of the neuroimaging findings have been consistent with a hypofunctional PFC state in response to working memory tasks. These cognitive impairments are typically evidenced by lack of PFC activation (for review see Manoach, 2003). However, there are also studies showing either no changes or increased activation of the dorsolateral PFC (Manoach et al., 1999, 2000; Callicott et al., 2000, 2003a, b; Honey et al., 2002). Perhaps these apparently contradictory findings could simply reflect the different strategy used to examine PFC activation and the nonlinear relationship between PFC activation and task demand (Braver et al., 1997; Goldberg et al., 1998; Callicott et al., 1999; Manoach, 2003). PFC response increases parametrically with working memory load until the demand exceeds the functional capacity, during which activation decrease. Despite the fact that patients suffering schizophrenia usually exhibit a relative lower task performance than controls, a similar nonlinear relationship between PFC activation and task demand may also exist in schizophrenia, but shifted toward the left of the curve. A relative decrease or increase of PFC activation could be obtained in schizophrenia subjects depending on the loads required to perform the task and the actual cortical functional level.
Since the early 1950s to our days, pharmacologically oriented treatments in schizophrenia have been monopolized by monoamine modulating drugs. Beginning with the first generation of relatively pure dopamine (DA) antagonists followed by a second generation of antipsychotic drugs with dual DA and serotonin (5HT) antagonist effects, and more recently by partial DA agonists and acetylcholine (Ach) receptor modulating drugs, modern pharmacological interventions in schizophrenia have been fueled with the idea of changing the curse of this devastating disorder by modifying brain monoamine function. However, despite the effectiveness of treating psychotic symptoms, these monoamine-based drugs have very limited effect in restoring the cognitive and emotional disabilities associated to schizophrenia.
In this chapter we will discuss and provide insights on how and why drugs that target the central monoamine system are not necessary effective to prevent cognitive and emotional impairments in schizophrenia. We will summarize evidence indicating that this failure in treating cognitive deficits could be caused by at least two factors. First, most of the cognitive and emotional deteriorations in schizophrenia appear during early adolescence, years before the emergence of psychosis. Secondly, DA antagonists may interfere with several neuronal signaling pathways critically involved in maintaining normal cognitive functions. We hypothesize that a new generation of glutamate modulating drugs could be used to prevent cognitive deteriorations related to schizophrenia in high risk adolescents.
KeywordsPrefrontal Cortex NMDA Receptor Antipsychotic Drug NMDA Antagonist Biol Psychiatry
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- Arnsten, A.F. (2004) Adrenergic targets for the treatment of cognitive deficits in schizophre-nia. Psychopharmacology (Berl). 174, 25-31.Google Scholar
- Arnsten, A.F. and Goldman-Rakic, P.S. (1998) Noise stress impairs prefrontal cortical cogni-tive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psy-chiatry. 55, 362-368.Google Scholar
- Bartha, R., Williamson, P.C., Drost, D.J., Malla, A., Carr, T.J., Cortese, L., Canaran, G., Rylett, R.J. and Neufeld, R.W. (1997) Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy. Arch Gen Psychiatry. 54, 959-965.PubMedGoogle Scholar
- Braver, T.S., Cohen, J.D., Nystrom, L.E., Jonides, J., Smith, E.E. and Noll, D.C. (1997) A parametric study of prefrontal cortex involvement in human working memory. Neuroi-mage. 5, 49-62.Google Scholar
- Breier, A.F., Malhotra, A.K., Su, T.P., Pinals, D.A., Elman, I., Adler, C.M., Lafargue, R.T., Clifton, A. and Pickar, D. (1999) Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psy-chiatry. 156, 294-298.Google Scholar
- Carpenter, W.T. (2004) Carpenter WT. Is glutamatergic therapy efficacious in schizophrenia? ACNP, San Juan, Puerto Rico.Google Scholar
- Castner, S.A., Williams, G.V. and Goldman-Rakic, P.S. (2000) Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Sci-ence. 287, 2020-2022.Google Scholar
- Chou, Y.H., Halldin, C. and Farde, L. (2006) Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study. Psychopharmacology (Berl). 185, 29-35.Google Scholar
- Conley, R.R., Tamminga, C.A., Kelly, D.L. and Richardson, C.M. (1999) Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol Psychia-try. 46, 73-77.Google Scholar
- Cosway, R., Byrne, M., Clafferty, R., Hodges, A., Grant, E., Abukmeil, S.S., Lawrie, S.M., Miller, P. and Johnstone, E.C. (2000) Neuropsychological change in young people at high risk for schizophrenia: results from the first two neuropsychological assessments of the Edinburgh High Risk Study. Psychol Med. 30, 1111-1121.PubMedGoogle Scholar
- Damadzic, R., Bigelow, L.B., Krimer, L.S., Goldenson, D.A., Saunders, R.C., Kleinman, J.E. and Herman, M.M. (2001) A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of sig-nificant astrocytosis. Brain Res Bull. 55, 611-618.PubMedGoogle Scholar
- Dorph-Petersen, K.A., Pierri, J.N., Perel, J.M., Sun, Z., Sampson, A.R. and Lewis, D.A. (2005) The influence of chronic exposure to antipsychotic medications on brain size be-fore and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 30, 1649-1661.PubMedGoogle Scholar
- Eastwood, S.L., Burnet, P.W. and Harrison, P.J. (2005) Decreased hippocampal expression of the susceptibility gene PPP3CC and other calcineurin subunits in schizophrenia. Biol Psy-chiatry. 57, 702-710.Google Scholar
- Gogtay, N., Giedd, J.N., Lusk, L., Hayashi, K.M., Greenstein, D., Vaituzis, A.C., Nugent, T.F., 3rd, Herman, D.H., Clasen, L.S., Toga, A.W., Rapoport, J.L. and Thompson, P.M. (2004) Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA. 101, 8174-8179.PubMedGoogle Scholar
- Kapur, S., Langlois, X., Vinken, P., Megens, A.A., De Coster, R. and Andrews, J.S. (2002) The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats. J Pharmacol Exp Ther. 302, 1129-1134.PubMedGoogle Scholar
- Keefe, R.S., Seidman, L.J., Christensen, B.K., Hamer, R.M., Sharma, T., Sitskoorn, M.M., Rock, S.L., Woolson, S., Tohen, M., Tollefson, G.D., Sanger, T.M. and Lieberman, J.A. (2006a) Long-term neurocognitive effects of olanzapine or low-dose haloperidol in first-episode psychosis. Biol Psychiatry. 59, 97-105.PubMedGoogle Scholar
- Kellendonk, C., Simpson, E.H., Polan, H.J., Malleret, G., Vronskaya, S., Winiger, V., Moore, H. and Kandel, E.R. (2006) Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. 49, 603-615.PubMedGoogle Scholar
- Krystal, J.H., Karper, L.P., Seibyl, J.P., Freeman, G.K., Delaney, R., Bremner, J.D., Heninger, G.R., Bowers, M.B., Jr. and Charney, D.S. (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 51, 199-214.PubMedGoogle Scholar
- Krystal, J.H., D'Souza, D.C., Mathalon, D., Perry, E., Belger, A. and Hoffman, R. (2003) NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl). 169, 215-233.Google Scholar
- Leslie, C.A., Robertson, M.W., Cutler, A.J. and Bennett, Jr., J.P., (1991) Postnatal develop-ment of D1 dopamine receptors in the medial prefrontal cortex, striatum and nucleus accumbens of normal and neonatal 6-hydroxydopamine treated rats: a quantitative autora-diographic analysis. Brain Res Dev Brain Res. 62, 109-114.PubMedGoogle Scholar
- Lieberman, J., Chakos, M., Wu, H., Alvir, J., Hoffman, E., Robinson, D. and Bilder, R. (2001a) Longitudinal study of brain morphology in first episode schizophrenia. Biol Psy-chiatry. 49, 487-499.Google Scholar
- Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O., Keefe, R.S., Davis, S.M., Davis, C.E., Lebowitz, B.D., Severe, J. and Hsiao, J.K. (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 353, 1209-1223.PubMedGoogle Scholar
- Manoach, D.S., Gollub, R.L., Benson, E.S., Searl, M.M., Goff, D.C., Halpern, E., Saper, C.B. and Rauch, S.L. (2000) Schizophrenic subjects show aberrant fMRI activation of dorso-lateral prefrontal cortex and basal ganglia during working memory performance. Biol Psy-chiatry. 48, 99-109.Google Scholar
- McEvoy, J.P., Lieberman, J.A., Stroup, T.S., Davis, S.M., Meltzer, H.Y., Rosenheck, R.A., Swartz, M.S., Perkins, D.O., Keefe, R.S., Davis, C.E., Severe, J. and Hsiao, J.K. (2006) Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 163, 600-610.PubMedGoogle Scholar
- Millar, J.K., Pickard, B.S., Mackie, S., James, R., Christie, S., Buchanan, S.R., Malloy, M.P., Chubb, J.E., Huston, E., Baillie, G.S., Thomson, P.A., Hill, E.V., Brandon, N.J., Rain, J.C., Camargo, L.M., Whiting, P.J., Houslay, M.D., Blackwood, D.H., Muir, W.J. and Porteous, D.J. (2005) DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science. 310, 1187-1191.PubMedGoogle Scholar
- Ninan, I., Jardemark, K.E. and Wang, R.Y. (2003) Olanzapine and clozapine but not haloperidol reverse subchronic phencyclidine-induced functional hyperactivity of N-methyl-D-aspartate receptors in pyramidal cells of the rat medial prefrontal cortex. Neuropharmacology. 44, 462-472.PubMedGoogle Scholar
- Reichenberg, A., Weiser, M., Rapp, M.A., Rabinowitz, J., Caspi, A., Schmeidler, J., Knobler, H.Y., Lubin, G., Nahon, D., Harvey, P.D. and Davidson, M. (2005) Elaboration on premorbid intellectual performance in schizophrenia: premorbid intellectual decline and risk for schizophrenia. Arch Gen Psychiatry. 62, 1297-1304.PubMedGoogle Scholar
- Rothman, D.L., Sibson, N.R., Hyder, F., Shen, J., Behar, K.L. and Shulman, R.G. (1999) In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. Philos Trans R Soc Lond B Biol Sci. 354, 1165-1177.PubMedGoogle Scholar
- Rowland, L.M., Bustillo, J.R., Mullins, P.G., Jung, R.E., Lenroot, R., Landgraf, E., Barrow, R., Yeo, R., Lauriello, J. and Brooks, W.M. (2005) Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry. 162, 394-396.PubMedGoogle Scholar
- Rund, B.R., Melle, I., Friis, S., Larsen, T.K., Midboe, L.J., Opjordsmoen, S., Simonsen, E., Vaglum, P. and McGlashan, T. (2004) Neurocognitive dysfunction in first-episode psy-chosis: correlates with symptoms, premorbid adjustment, and duration of untreated psy-chosis. Am J Psychiatry. 161, 466-472.PubMedGoogle Scholar
- Tauscher, J., Hussain, T., Agid, O., Verhoeff, N.P., Wilson, A.A., Houle, S., Remington, G., Zipursky, R.B. and Kapur, S. (2004) Equivalent occupancy of dopamine D1 and D2 recep-tors with clozapine: differentiation from other atypical antipsychotics. Am J Psychiatry. 161, 1620-1625.PubMedGoogle Scholar
- Theberge, J., Bartha, R., Drost, D.J., Menon, R.S., Malla, A., Takhar, J., Neufeld, R.W., Rogers, J., Pavlosky, W., Schaefer, B., Densmore, M., Al-Semaan, Y. and Williamson, P.C. (2002) Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am J Psychiatry. 159, 1944-1946.PubMedGoogle Scholar
- Tseng, K.Y., Lewis, B.L. Lipska, B.K. and O’Donnell, P. (2007) Post-pubertal disruption of medical prefrontal cortical dopamine-glutamate interactions in a developmental animal model of schizophrenia. Biol. Psychiatry. Jan 2; [Epub ahead of print]Google Scholar
- Volavka, J., Czobor, P., Cooper, T.B., Sheitman, B., Lindenmayer, J.P., Citrome, L., McEvoy, J.P. and Lieberman, J.A. (2004) Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry. 65, 57-61.PubMedGoogle Scholar
- Wiersma, D., Wanderling, J., Dragomirecka, E., Ganev, K., Harrison, G., An Der Heiden, W., Nienhuis, F.J. and Walsh, D. (2000) Social disability in schizophrenia: its development and prediction over 15 years in incidence cohorts in six European centres. Psychol Med. 30, 1155-1167.PubMedGoogle Scholar