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Augmentation Strategies in the Treatment of Schizophrenia

Published online by Cambridge University Press:  07 November 2014

Donald C. Goff ,
Oliver Freudenreich  and
A. Eden Evins
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Abstract

Use of augmenting agents in schizophrenia is a common practice in response to resistant symptoms or comorbid illness. Increasingly, clinicians are combining more than one antipsychotic agent, despite a lack of evidence from controlled studies to support this approach. A rationale can be made for adding higher-potency agents to clozapine in an attempt to optimize D2 dopamine receptor blockade, but this strategy requires further study before it should be adopted in clinical practice. Older reports have explored the use of antidepressants, mood stabilizers, and anxiolytics as augmenting agents. These agents appear to improve comorbid affective or anxiety symptoms, but earlier evidence of improvement in psychotic or negative symptoms has not been replicated consistently. Glutamatergic agents acting at the glycine coagonist site of the N-methyl-D-aspartate receptor, including glycine, D-cycloserine, and D-serine, have demonstrated impressive therapeutic effects for negative symptoms when added to conventional neuroleptic agents, but do not appear to enhance clozapine efficacy. Given the high rates of symptom persistence and disability associated with schizophrenia, the need for augmentation strategies is great, but no approach has clearly emerged as effective for a substantial portion of patients. Although certain approaches may prove helpful for individual patients, augmentation should not be used unless monotherapy has been optimized, and should not be continued long-term unless benefits are clear.

Type
Feature Articles
Information
CNS Spectrums , Volume 6 , Issue 11: Investigating and Treating Psychosis , November 2001 , pp. 904 - 911
Copyright
Copyright © Cambridge University Press 2001

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References

REFERENCES

1. Wang, PS, West, JC, Tanielian, T, Pincus, HA. Recent patterns and predictors of antipsychotic, medication regimens used to treat schizophrenia and other psychotic disorders. Schizophr Bull. 2000;26:451–457.CrossRefGoogle ScholarPubMed
2. Peacock, L, Gerlach, J. Clozapine treatment in Denmark: concomitant psychotropic medication and hematologic monitoring in a system with liberal usage practices. J Clin Psychiatry. 1994;55:44–49.Google Scholar
3. Farde, L, Nordstrom, AL, Wiesel, FA, et al. Positron emission tomographic analysis of central D1, and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49:538–544.CrossRefGoogle ScholarPubMed
4. Kapur, S, Seeman, P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry. 2001;158:360–369.CrossRefGoogle ScholarPubMed
5. Henderson, DC, Goff, DC, Connolly, CE, Borba, CP, Hayden, D. Risperidone added to clozapine: impact on serum prolactin levels. J Clin Psychiatry. 2001;62:605–608.CrossRefGoogle ScholarPubMed
6. Shiloh, R, Zemishlany, Z, Aizenberg, D, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled study. Br J Psychiatry. 1997;171:569–573.CrossRefGoogle ScholarPubMed
7. Kapur, S, Roy, P, Daskalakis, J, Remington, G, Zipursky, R. Increased dopamine D2 receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine. Am J Psychiatry. 2001;158:311–314.CrossRefGoogle ScholarPubMed
8. Potter, WZ, Ko, GN, Zhang, LD, Yan, W. Clozapine in China: a review and preview of US/PRC collaboration. Psychopharmacology (Berl). 1989;99:S87–S91.CrossRefGoogle Scholar
9. Henderson, D, Goff, D. Risperidone as an adjunct to clozapine therapy in chronic schizophrenics. J Clin Psychiatry. 1996;57:395–397.Google ScholarPubMed
10. Friedman, J, Ault, K, Powchik, P. Pimozide augmentation for the treatment of schizophrenic patients who are partial responders to clozapine. Biol Psychiatry. 1997;42:522–523.CrossRefGoogle ScholarPubMed
11. Mowerman, S, Siris, SG. Adjunctive loxapine in a clozapine-resistant cohortof schizophrenic patients. Ann Clin Psychiatry. 1996;8:193–197.CrossRefGoogle Scholar
12. de Groot, IW, Heck, AH, van Harten, PN. Addition of risperidone to clozapine therapy in chronically psychotic inpatients [letter]. J Clin Psychiatry. 2001;62:129–130.CrossRefGoogle ScholarPubMed
13. Tyson, SC, Devane, CL, Risch, SC. Pharmacokinetic interaction between risperidone and clozapine. Am J Psychiatry. 1995;152:1401–1402.Google ScholarPubMed
14. Koreen, AR, Lieberman, JA, Kronig, M, Cooper, TB. Cross-tapering clozapine and risperidone [letter]. Am J Psychiatry. 1995;152:1690.Google ScholarPubMed
15. Kramer, M, Vogel, W, DiJohnson, C, et al. Antidepressants in depressed schizophrenic inpatients: a controlled trial. Arch Gen Psychiatry. 1989;46:922–928.CrossRefGoogle ScholarPubMed
16. Siris, SG, Adan, F, Cohen, M, et al. Targeted treatment of depression-like symptoms in schizophrenia. Psychopharmacol Bull. 1987;23:85–89.Google ScholarPubMed
17. Siris, S, Bermazohn, P, Mason, S, Shuwall, M. Maintenance imipramine therapy for secondary depression in schizophrenia. Arch Gen Psychiatry. 1994;51:109–115.CrossRefGoogle ScholarPubMed
18. Hogarty, GE, McEvoy, JP, Ulrich, RF, et al. Pharmacotherapy of impaired affect in recovering schizophrenic patients. Arch Gen Psychiatry. 1995;52:29–41.CrossRefGoogle ScholarPubMed
19. Evins, A, Goff, D. Adjunctive antidepressant drug therapies in the treatment of negative symptoms of schizophrenia. CNS Drugs. 1996;6:130–147.CrossRefGoogle Scholar
20. Goff, D, Midha, K, Sarid-Segal, O, Hubbard, J, Amico, E. A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology (Berl). 1995;117:417–423.CrossRefGoogle ScholarPubMed
21. Lee, MD, Kim, YK, Lee, SK, Suh, KY. A double-blind study of adjunctive sertraline in haloperidol-stabilized patients with chronic schizophrenia. J Clin Psychopharmacol. 1998;18:399–403.CrossRefGoogle ScholarPubMed
22. Salokangas, RKR, Saarijarvi, S, Taiminen, T, et al. Citalopram as an adjuvant in chronic schizophrenia: a double-blind placebo-controlled study. Acta Psychiatr Scand. 1996;94:175–180.CrossRefGoogle ScholarPubMed
23. Buchanan, RW, Kirkpatrick, B, Bryant, N, Ball, P, Breier, A. Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am J Psychiatry. 1996;153:1625–1627.Google ScholarPubMed
24. Stanford, SC. Prozac: panacea or puzzle? TiPS. 1996;17:150–154.Google ScholarPubMed
25. Goff, D, Baldessarini, R. Drug interactions with antipsychotic agents. J Clin Psychopharmacol. 1993;13:57–67.CrossRefGoogle ScholarPubMed
26. Wetzel, H, Anghelescu, I, Szegedi, A, et al. Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psychopharmacol. 1998;18:2–9.CrossRefGoogle ScholarPubMed
27. Berk, M, Ichim, C, Brook, S. Efficacy of mirtazapine add on therapy to haloperidol in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Int Clin Psychopharmacol. 2001;16:87–92.CrossRefGoogle Scholar
28. Evins, AE, Mays, VK, Rigotti, NA, et al. A pilot trial of bupropion added to cognitive behavioral therapy for smoking cessation in schizophrenia. Nicotine Tob Res. 2001;3:1–7.CrossRefGoogle ScholarPubMed
29. Citrome, L, Levine, J, Allingham, B. Changes in use of valproate and other mood stabilizers for patients with schizophrenia from 1994 to 1998. Psychiatr Serv. 2000;51:634–638.CrossRefGoogle ScholarPubMed
30. Christison, G, Kirch, D, Wyatt, R. When symptoms persist: choosing among alternative somatic treatments for schizophrenia. Schizophr Bull. 1991;17:217–245.CrossRefGoogle ScholarPubMed
31. Carmen, JS, Bigelow, LB, Wyatt, RJ. Lithium combined with neuroleptics in chronic schizophrenic and schizoaffective patients. J Clin Psychiatry. 1981;42:124–128.Google Scholar
32. Growe, GA, Crayton, JW, Klass, DB, Evans, H, Stizich, M. Lithium in chronic schizophrenia. Am J Psychiatry. 1979;7:178–182.Google Scholar
33. Small, JG, Kellams, JJ, Milstein, V, Moore, J. A placebo-controlled study of lithium combined with neuroleptics in chronic schizophrenic patients. Am J Psychiatry. 1975;132:1315–1317.Google ScholarPubMed
34. Collins, PJ, Larkin, EP, Shubsachs, AP. Lithium carbonate in chronic schiz-ophrenia—a brief trial of lithium carbonate added to neuroleptics for treatment of resistant schizophrenic patients. Ada Psychiatr Scand. 1991;84:150–154.CrossRefGoogle ScholarPubMed
35. Wilson, WH. Addition of lithium to haloperidol in non-affective, antipsychotic nonresponsive schizophrenia: a double-blind, placebo-controlled parallel design clinical trial. Psychopharmacology (Berl). 1993;111:359–366.CrossRefGoogle ScholarPubMed
36. Terao, T, Oga, T, Nozaki, S, et al. Lithium addition to neuroleptic treatment in chronic schizophrenia: a randomized, double-blind, placebo-controlled, cross-over study. Ada Psychiatr Scand. 1995;92:220–224.CrossRefGoogle ScholarPubMed
37. Schulz, SC, Thompson, PA, Jacobs, M, et al. Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients. J Clin Psychiatry. 1999;60:366–372.CrossRefGoogle ScholarPubMed
38. Chong, S-A, Remington, G. Clozapine augmentation: safety and efficacy. Schizophr Bull. 2000;26:421–440.CrossRefGoogle ScholarPubMed
39. Wassef, AA, Dott, SG, Harris, A, et al. Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. J Clin Psychopharmacol. 2000;20:357–361.CrossRefGoogle ScholarPubMed
40. Ko, GN, Korpi, ER, Freed, WJ, Zalcman, SJ, Bigelow, LB. Effect of valproic acid on behavior and plasma amino acid concentrations in chronic schizophrenic patients. Biol Psychiatry. 1985;20:199–228.CrossRefGoogle ScholarPubMed
41. Dose, M, Hellweg, R, Yassouridis, A, Theison, M, Emrich, HM. Combined treatment of schizophrenic psychoses with haloperidol and valproate. Pharmacopsychiatry. 1998;31:122–125.CrossRefGoogle ScholarPubMed
42. Hesslinger, B, Normann, C, Langosch, JM, et al. Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients. J Clin Psychopharmacol. 1999;19:310–315.CrossRefGoogle ScholarPubMed
43. Simhandl, C, Meszaros, K. The use of carbamazepine in the treatment of schizophrenic and schizoaffective psychoses: a review. J Psychiatr Neurosci. 1992;17:1–14.Google ScholarPubMed
44. Neppe, VM. Carbamazepine as adjunctive treatment in nonepileptic chronic inpatients with EEG temporal lobe abnormalities. J Clin Psychiatry. 1983;44:326–331.Google ScholarPubMed
45. Carpenter, WT, Kurz, R, Kirkpatrick, B, et al. Carbamazepine maintenance treatment in outpatient schizophrenics. Arch Gen Psychiatry. 1991;48:69–72CrossRefGoogle ScholarPubMed
46. Arana, GW, Gof f, DC, Friedman, H, et al. Does carbamazepine-induced reduction of plasma haloperidol levels worsen psychotic symptoms? Am J Psychiatry. 1986;143:650–651.Google ScholarPubMed
47. Wolokowitz, OM, Pickar, D. Benzodiazepines in the treatment of schizophrenia: a review and reappraisal. Am J Psychiatry. 1991;148:714–726.Google Scholar
48. Csernansky, JG, Riney, SJ, Lombrozo, L, Overall, JE, Hollister, LE. Double-blind comparison of alprazolam, diazepam, and placebo for the treatment of negative schizophrenic symptoms. Arch Gen Psychiatry. 1988;45:655–659.CrossRefGoogle ScholarPubMed
49. Dixon, L, Weiden, PJ, Frances, AJ, Sweeney, J. Alprazolam intolerance in stable schizophrenic outpatients. Psychopharmacol Bull. 1989;25:213–214.Google ScholarPubMed
50. Wolkowitz, OM, Breier, A, Doran, A, et al. Alprazolam augmentation of the antipsychotic effects of fluphenazine in schizophrenic patients. Arch Gen Psychiatry. 1988;143:664–671.CrossRefGoogle Scholar
51. Arana, G, Ornsteen, ML, Kanter, F, et al. The use of benzodiazepines for psychiatric disorders: a literature review and preliminary findings. Psychopharmacol Bull. 1986;22:77–87.Google Scholar
52. Cohen, S, Khan, A. Adjunctive benzodiazepines in acute schizophrenia. Neuropsychobiology. 1987;18:9–12.CrossRefGoogle ScholarPubMed
53. Garza-Trevino, ES, Hollister, LE, Overall, JE, Alexander, WF. Efficacy of combinations of intramuscular antipsychotics and sedative-hypnotics for control of psychotic agitation. Am J Psychiatry. 1989;146:1598–1601.Google ScholarPubMed
54. Salzman, C, Green, Al, Rodriguez-Villa, F, Jaskiw, GI. Benzodiazepines combined with neuroleptics for management of severe disruptive behavior. Psychosomatics. 1986;27(supp l):17–22.CrossRefGoogle ScholarPubMed
55. Carpenter, WRJ, Buchanan, RW, Kirkpatrick, B, Breier, AF. Diazepam treatment of early signs of exacerbation in schizophrenia. Am J Psychiatry. 1999;156:199–303.CrossRefGoogle ScholarPubMed
56. Angrist, B, Peselow, E, Rubinstein, M, Corwin, J, Rotrosen, J. Partial improvement in negative schizophrenic symptoms after amphetamine. Psychopharmacology (Berl). 1982;78:128–130.CrossRefGoogle ScholarPubMed
57. Van Kammen, DP, Boronow, JJ. Dextro-amphetamine diminishes negative symptoms in schizophrenia [abstract]. Int Clin Psychopharmacol. 1988;3:111–121.CrossRefGoogle ScholarPubMed
58. Mathew, RJ, Wilson, WH. Changes in cerebral blood flow and mental state after amphetamine challenge in schizophrenic patients. Neuropsychobiology. 1989;21:117–123.CrossRefGoogle ScholarPubMed
59. Sanfilipo, M, Wolkin, A, Angrist, B, et al. Amphetamine and negative symptoms of schizophrenia. Psychopharmacology (Berl). 1996;123:211–214.CrossRefGoogle ScholarPubMed
60. Goldberg, T, Bigelow, LB, Weinberger, DR, Daniel, DG, Kleinman, JE. Cognitive and behavioral effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia. Am J Psychiatry. 1991;148:78–84.Google ScholarPubMed
61. Daniel, DG, Weinberger, DR, Jones, DW, et al. The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia. J Neurosci. 1991;ll:1907–1917.CrossRefGoogle Scholar
62. Casey, JF, Hollister, LE, Klett, CJ, Lasky, JJ, Caffey, EM. Combined drug therapy of chronic schizophrenics: controlled evaluation of placebo, dextro-amphetamine, imiprarnine, isocarboxazid and trifluoperazine added to maintenance doses of chlorpromazine. Am J Psychiatry. 1961;117:997–1003.CrossRefGoogle Scholar
63. Carpenter, WTJ, Breier, A, Buchanan, RW, Kirkpatrick, B, Shepard, P, Weiner, E. Mazindol treatment of negative symptoms. Neuropsychopharmacology. 2000;23:365–374.CrossRefGoogle ScholarPubMed
64. Levin, ED, Wilson, W, Rose, JE, McEvoy, J. Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology. 1996;15:429–436.CrossRefGoogle ScholarPubMed
65. Adler, LA, Hoffer, LD, Wiser, A, Freedman, R. Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry. 1993;150:1856–1861.Google ScholarPubMed
66. Olincy, A, Ross, R, Young, D, Roath, M, Freedman, R. Improvement in smooth pursuit eye movement after cigarette smoking in schizophrenic patients. Neuropsychopharmacology. 1998;18:175–185.CrossRefGoogle ScholarPubMed
67. Adler, LE, Hoffer, LJ, Griffith, J, Waldo, MC, Freedman, R. Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol Psychiatry. 1992;32:607–616.CrossRefGoogle ScholarPubMed
68. Goff, DC, Coyle, JT. The emerging role of glutamate in schizophrenia. Am J Psychiatry. 2001;158:1367–1377.CrossRefGoogle ScholarPubMed
69. Krystal, JH, Karper, LP, Seibyl, JP, et al. Subanesthetie effects of the non-competitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51:199–214.CrossRefGoogle Scholar
70. Lahti, AC, Koffel, B, LaPorte, D, Tamminga, CA. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995;13:9–19.CrossRefGoogle ScholarPubMed
71. Malhotra, A, Pinals, D, Adler, C, et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology. 1997;17:141–150.CrossRefGoogle ScholarPubMed
72. Lawlor, BA, Davis, KL. Does modulation of glutamatergic function represent a viable therapeutic strategy in Alzheimer's disease? Biol Psychiatry. 1992;31:337–350.CrossRefGoogle ScholarPubMed
73. Javitt, DC, Zylberman, I, Zukin, SR, Heresco, LU, Lindenmayer, JP. Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry. 1994;151:1234–1236.Google ScholarPubMed
74. Heresco-Levy, U, Javitt, D, Ermilov, M, et al. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry. 1999;56:29–36.CrossRefGoogle ScholarPubMed
75. Javitt, DC, Balla, A, Sershen, H, Lajtha, A. Reversal of the behavioral and neurochemical effects of phencyclidine by glycine and glycine transport inhibitors. Biol Psychiatry. 1999;45:668–679.CrossRefGoogle ScholarPubMed
76. Henderson, G, Johnson, JW, Ascher, P. Competitive antagonists and partial agonists at the glycine modulatory site of the mouse N-methyl-D-aspartate receptor. J Physiol. 1990;430:189–212.CrossRefGoogle ScholarPubMed
77. Goff, D, Tsai, G, Levitt, J, et al. A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry. 1999;56:21–27.CrossRefGoogle ScholarPubMed
78. Tsai, G, Yang, P, Chung, L-C, Lange, N, Coyle, J. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 1998;44:1081–1089.CrossRefGoogle ScholarPubMed
79. Goff, D, Henderson, D, Evins, A, Amico, E. A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry. 1999;45:512–514.CrossRefGoogle ScholarPubMed
80. Potkin, S, Jin, Y, Bunney, B, Costa, J, Gulasekaram, B. Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am J Psychiatry. 1999;156:145–147.CrossRefGoogle ScholarPubMed
81. Evins, A, Fitzgerald, S, Wine, L, Roselli, R, Goff, D. A placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry. 2000;157:826–828.CrossRefGoogle ScholarPubMed
82. Tsai, G, Yang, P, Chung, LC, et al. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry. 1999:156:1822–1825.CrossRefGoogle ScholarPubMed
83. Stern, RG, Schmeidler, J, Davidson, M. Limitations of controlled augmentation trials in schizophrenia. Biol Psychiatry. 1997;42:138–143.CrossRefGoogle ScholarPubMed