Skip to main content
SpringerLink
Log in

Antidepressive effects of traditional and second generation antipsychotics: a review of the clinical data

  • ORIGINAL PAPER
  • Published:
European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

For a long time,in the context of depressive symptoms in schizophrenia traditional neuroleptics were mostly discussed with respect to possible depressiogenic side effects, although some studies argued that they may also have certain antidepressive effects. However, this was not proven at that time in placebo-controlled studies. Placebo-controlled studies performed in recent years have shown that second generation antipsychotics have antidepressive effects which are significantly stronger than those of the traditional neuroleptics. In addition, it was demonstrated that this antidepressive effect can only partially be explained as being secondary to the improvement of positive and negative symptoms, and is apparently predominantly due to a direct (primary) effect on depressive symptoms. It is of special relevance in this context that the antidepressive effect of second generation antipsychotics was recently demonstrated in depression. The positive results from some studies in bipolar depression are especially impressive and underline the antidepressive potencies of novel antipsychotics beyond the spectrum of schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Adli M, Rossius W, Bauer M (1999) Olanzapine in the treatment of depressive disorders with psychotic symptoms. Nervenarzt 70:68–71

    Google Scholar 

  2. Amore M, Jori MC (2001) Faster response on amisulpride 50mg versus sertraline 50–100 mg in patients with dysthymia or double depression: a randomized, double-blind, parallel group study. Int Clin Psychopharmacol 16:317–324

    Google Scholar 

  3. Awad AG (1993) Subjective response to neuroleptics in schizophrenia. Schizophr Bull 19:609–618

    Google Scholar 

  4. Banov MD, Zarate CA Jr, Tohen M, Scialabba D, Wines JD Jr, Kolbrener M, Kim JW, Cole JO (1994) Clozapine therapy in refractory affective disorders: polarity predicts response in long-term follow-up. J Clin Psychiatry 55:295–300

    CAS  PubMed  Google Scholar 

  5. Bottlender R, Strauß A, Möller HJ (2000) Prevalence and background factors of depression in first admitted schizophrenic patients. Acta Psychiatr Scand 101:153–160

    Google Scholar 

  6. Boyer P, Lecrubier Y, Stalla-Bourdillon A, Fleurot O (1999) Amisulpride versus amineptine and placebo for the treatment of dysthymia. Neuropsychobiology 39:25–32

    Google Scholar 

  7. Browne S, Garavan J, Gervin M, Roe M, Larkin C, O’Callaghan E (1998) Quality of life in schizophrenia: insight and subjective response to neuroleptics. J Nerv Ment Dis 186:74–78

    Google Scholar 

  8. Calabrese J, MacFadden W, McCoy R, Minkwitz M, Wilson E, Mullen J (2004) Double-blind, placebo-controlled study of quetiapine in bipolar depression. Abstract presented at APA2004, NYC, USA

  9. Cassano GB, Jori MC (2002) Efficacy and safety of amisulpride 50 mg versus paroxetine 20 mg in major depression: a randomized, double-blind, parallel group study. Int Clin Psychopharmacol 17:27–32

    Google Scholar 

  10. Chacko RC, Hurley RA, Jankovic J (1993) Clozapine use in diffuse Lewy body disease. J Neuropsychiatry Clin Neurosci 5:206–208

    Google Scholar 

  11. Conley RR, Mahmoud R (2001) A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 158:765–774

    Article  CAS  PubMed  Google Scholar 

  12. Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M (1999) Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology 20:491–505

    Google Scholar 

  13. Dassa D, Kaladjian A, Azorin JM, Giudicelli S (1993) Clozapine in the treatment of psychotic refractory depression. Br J Psychiatry 163:822–824

    CAS  PubMed  Google Scholar 

  14. De Alarcon R, Carney MW (1969) Severe depressive mood changes following slow-release intramuscular fluphenazine injection. Br Med J 3:564–567

    Google Scholar 

  15. Dimova A (2003) The range of therapeutic efficacy of atypical antipsychotics: a critical evaluation. Med Hypotheses 61:259–264

    Google Scholar 

  16. Dube S, Paul S, Sanger T, Van Campen L, Corya S, Tollefson G (2002a) Olanzapine-fluoxetine combination in treatment-resistant depression. Eur Psychiatry 17(Suppl 1):98s

    Google Scholar 

  17. Dube S, Andersen SW, Paul S, Corya SA, Van Campen LE, Sanger TM, Welge L, Nanos J, Tollefson GD (2002b) Metaanalysis of olanzapine-fluoxetine use in treatment-resistant depression. Int J Neuropsychopharmacol 5(Suppl 1):S105

    Google Scholar 

  18. Dunner D, Amsterdam J, Shelton R, Hassman H, Rosenthal M, Romano S (2003) Adjunctive ziprasidone in treatment-resistant depression: A pilot study. Presented at the 156th APA Annual Meeting, San Francisco, CA, May 17–22, 2003

  19. Emsley RA, Buckley P, Jones AM, Greenwood MR (2003) Differential effect of quetiapine on depressive symptoms in patients with partially responsive schizophrenia. J Psychopharmacol 17:210–215

    Google Scholar 

  20. Floru L, Heinrich K, Wittek F (1975) The problem of post-psychotic schizophrenic depressions and their pharmacological induction. Long-term studies with fluspirilene and penfluridol and single-blind trial with fluphenazine-decanoate and flupenthixol-decanoate. Int Pharmacopsychiatry 10:230–239

    Google Scholar 

  21. Galdi J (1983) The causality of depression in schizophrenia. Br J Psychiatry 142:621–624

    Google Scholar 

  22. Galdi J, Rieder RO, Silber D, Bonato RR (1981) Genetic factors in the response to neuroleptics in schizophrenia: a psychopharmacogenetic study. Psychol Med 11:713–728

    Google Scholar 

  23. Häfner H, Loffler W, Maurer K, Hambrecht M, an-der-Heiden W (1999) Depression,negative symptoms, social stagnation and social decline in the early course of schizophrenia. Acta Psychiatr Scand 100:105–118

    Google Scholar 

  24. Helmchen H, Hippius H (1967) Depressive Syndrome im Verlauf neuroleptischer Therapie. Nervenarzt 38:455–458

    Google Scholar 

  25. Hillert A, Maier W, Wetzel H, Benkert O (1992) Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome—a functional approach. Pharmacopsychiatry 25:213–217

    Google Scholar 

  26. Hirose S, Ashby CR Jr (2002) An open pilot study combining risperidone and a selective serotonin reuptake inhibitor as initial antidepressant therapy. J Clin Psychiatry 63:733–736

    Google Scholar 

  27. Hirsch SR, Kissling W, Bauml J, Power A, O’Connor R (2002) A 28-week comparison of ziprasidone and haloperidol in outpatients with stable schizophrenia. J Clin Psychiatry 63:516–523

    Google Scholar 

  28. Jacobsen FM (1995) Risperidone in the treatment of affective illness and obsessive-compulsive disorder. J Clin Psychiatry 56:423–429

    Google Scholar 

  29. Johnson DA (1981) Depressions in schizophrenia: some observations on prevalence, etiology, and treatment. Acta Psychiatr Scand 291(Suppl):137–144

    Google Scholar 

  30. Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, Archibald D, Ingenito G, Marcus R, Pigott T (2003) Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol 6:325–337

    Google Scholar 

  31. Kay SR, Opler LA, Fiszbein A (1986) Positive and Negative Syndrome Scale (PANSS) Manual. Multi-Health Systems Inc, North Tonawanda NY

  32. Keck PE Jr, Wilson DR, Strakowski SM, McElroy SL, Kizer DL, Balistreri TM, Holtman HM, DePriest M (1995) Clinical predictors of acute risperidone response in schizophrenia, schizoaffective disorder, and psychotic mood disorders. J Clin Psychiatry 56:466–470

    Google Scholar 

  33. Keck PJ, Buffenstein A, Ferguson J, Feighner J, Jaffe W, Harrigan EP, Morrissey MR (1998) Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology (Berl) 140:173–184

    Article  Google Scholar 

  34. Knights A, Hirsch SR (1981) “Revealed” depression and drug treatment for schizophrenia. Arch Gen Psychiatry 38:806–811

    Google Scholar 

  35. Lecrubier Y, Boyer P, Turjanski S, Rein W (1997) Amisulpride versus imipramine and placebo in dysthymia and major depression. Amisulpride Study Group. J Affect Disord 43:95–103

    Article  CAS  PubMed  Google Scholar 

  36. Levinson DF, Umapathy C, Musthaq M (1999) Treatment of schizoaffective disorder and schizophrenia with mood symptoms. Am J Psychiatry 156:1138–1148

    Google Scholar 

  37. Marder SR, Davis JM, Chouinard G (1997) The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 58:538–546

    Google Scholar 

  38. McGlashan T, Carpenter WT (1976) Postpsychotic depression in schizophrenia. Arch Gen Psychiatry 33:231–329

    Google Scholar 

  39. Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam MZ, Kane J, et al. (2003) Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 60:82–91

    CAS  PubMed  Google Scholar 

  40. Meltzer HY, Okayli G (1995) Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. Am J Psychiatry 152:183–190

    CAS  PubMed  Google Scholar 

  41. Möller HJ (1990) Antidepressants and neuroleptics in treatment and prophylaxis of schizoaffective psychoses. In: Marneros A, Tsuang MT (eds) Affective and schizoaffective disorders. Berlin Heidelberg New York, Springer, pp 231–250

  42. Möller HJ (2000 a) Definition, psychopharmacological basis and clinical evaluation of novel/atypical neuroleptics: methodological issues and clinical consequences. World J Biol Psychiatry 1:75–91

    Google Scholar 

  43. Möller HJ (2000 b) State of the art of drug treatment of schizophrenia and the future position of the novel/atypical antipsychotics. World J Biol Psychiatry 1:204–214

    Google Scholar 

  44. Möller HJ (2004) Occurrence and treatment of depressive comorbidity/cosyndromality in schizophrenic psychoses: conceptual and treatment issues. Eur Arch Psychiatry Clin Neurosci (in press)

  45. Möller HJ (2005) Antipsychotic and antidepressive effects of second generation antipsychotics—two different pharmacological mechanisms? Eur Arch Psychiatry Clin Neurosci (in press)

  46. Möller HJ, Boyer P, Fleurot O, Rein W (1997) Improvement of acute exacerbations of schizophrenia with amisulpride: a comparison with haloperidol. PROD-ASLP Study Group. Psychopharmacology (Berl) 132:396–401

    Google Scholar 

  47. Möller HJ, Follmann U, Scharl W, von Zerssen D (1985) Background variables of depressive states upon discharge of schizophrenic inpatients treated with neuroleptics. Pharmacopsychiatry 18:50–51

    Google Scholar 

  48. Möller HJ, Müller H, Borison RL, Schooler NR, Chouinard G (1995) A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients. A re-evaluation of the North American risperidone study. Eur Arch Psychiatry Clin Neurosci 245:45–49

    Google Scholar 

  49. Möller HJ, von Zerssen D (1982) Depressive states occurring during the neuroleptic treatment of schizophrenia. Schizophr Bull 8:109–117

    Google Scholar 

  50. Möller HJ, von Zerssen D (1986) Depression in schizophrenia. In: Burrows GD, Norman TR, Rubinstein G (eds) Handbook of studies on schizophrenia. Amsterdam Oxford New York, Elsevier, pp 183–191

  51. Muller MJ, Wetzel H, Eich FX, Rein W, Puech A, Benkert O (2002) Dose-related effects of amisulpride on five dimensions of psychopathology in patients with acute exacerbation of schizophrenia. J Clin Psychopharmacol 22:554–560

    Google Scholar 

  52. Muller-Siecheneder F, Muller MJ, Hillert A, Szegedi A, Wetzel H, Benkert O (1998) Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome. J Clin Psychopharmacol 18:111–120

    Article  CAS  PubMed  Google Scholar 

  53. Naber D, Holzbach R, Perro C, Hippius H (1992) Clinical management of clozapine patients in relation to efficacy and side-effects. Br J Psychiatry Suppl:54–59

    Google Scholar 

  54. Nelson EB, Rielage E, Welge JA, Keck Jr PE (2001) An open trial of olanzapine in the treatment of patients with psychotic depression. Ann Clin Psychiatry 13:147–151

    Google Scholar 

  55. O’Connor M, Silver H (1998) Adding risperidone to selective serotonin reputake inhibitor improves chronic depression. J Clin Psychopharmacol 18:89–91

    Google Scholar 

  56. Ostroff RB, Nelson JC (1999) Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 60:256–259

    Google Scholar 

  57. Papakostas GI, Petersen TJ, Nierenberg AA, Murakami JL, Alpert JE, Rosenbaum JF, Fava M (2004) Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry 65:217–221

    Google Scholar 

  58. Parker G, Malhi G (2001) Are atypical antipsychotic drugs also atypical antidepressants? Aust N Z J Psychiatry 35:631–638

    Google Scholar 

  59. Parsa MA, Ramirez LF, Loula EC, Meltzer HY (1991) Effect of clozapine on psychotic depression and parkinsonism. J Clin Psychopharmacol 11:330–331

    Google Scholar 

  60. Peuskens J, Bech P, Moller HJ, Bale R, Fleurot O, Rein W (1999) Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study group. Psychiatry Res 88:107–117

    Google Scholar 

  61. Peuskens J, Moller HJ, Puech A (2002) Amisulpride improves depressive symptoms in acute exacerbations of schizophrenia: comparison with haloperidol and risperidone. Eur Neuropsychopharmacol 12:305–310

    Google Scholar 

  62. Peuskens J, Van Baelen B, De Smedt C, Lemmens P (2000) Effects of risperidone on affective symptoms in patients with schizophrenia. Int Clin Psychopharmacol 15:343–349

    Google Scholar 

  63. Puech A, Fleurot O, Rein W (1998) Amisulpride, and atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol. The Amisulpride Study Group. Acta Psychiatr Scand 98:65–72

    Google Scholar 

  64. Ranjan R, Meltzer HY (1996) Acute and long-term effectiveness of clozapine in treatment-resistant psychotic depression. Biol Psychiatry 40:253–258

    Google Scholar 

  65. Rapaport M, Canuso C, Loescher A, Lasser R, Gharabawi G (2003) Preliminary results from the ARISe-RD (Risperidone Augmentation in Resistant Depression) trial. Presented at the 156th APA Annual Meeting, San Francisco, CA, May 17–22, 2003

  66. Rein W, Fleurot O, Turjanski S (1998) Amisulpride improves affective symptoms in acute schizophrenia. Eur Psychiatry 13 (Suppl 4):S309

    Google Scholar 

  67. Rifkin A, Quitkin F, Klein DF (1975) Akinesia: a poorly recognized drug-induced extrapyramidal disorder. Arch Gen Psychiatry 32:672–674

    Google Scholar 

  68. Rocca P, Fonzo V, Ravizza L, Rocca G, Scotta M, Zanalda E, Bogetto F (2002) A comparison of paroxetine and amisulpride in the treatment of dysthymic disorder. J Affect Disord 70:313–317

    Google Scholar 

  69. Rothschild AJ (2003) Challenges in the treatment of depression with psychotic features. Biol Psychiatry 53:680–690

    Google Scholar 

  70. Rothschild AJ, Bates KS, Boehringer KL, Syed A (1999) Olanzapine response in psychotic depression. J Clin Psychiatry 60:116–118

    Google Scholar 

  71. Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A, Andersen SW, Van Campen LE, Sanger TM, Tollefson GD (2004) A doubleblind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol 24:365–373

    Google Scholar 

  72. Sajatovic M, Verbanac P, Ramirez LF, Meltzer HY (1991) Clozapine treatment of psychiatric symptoms resistant to neuroleptictreatment in patients with Huntington’s chorea. Neurology 41:156

    Google Scholar 

  73. Schar V, Leonhardt M, Agelink A, Klieser E (1995) Risperidone in the treatment of patients with delusional depression. Pharmacopsychiatry 28:210

    Google Scholar 

  74. Schmidt AW, Lebel LA, Howard HR, Jr., Zorn SH (2001) Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol 425:197–201

    Article  CAS  PubMed  Google Scholar 

  75. Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA et al. (2001) A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 158:131–134

    Article  CAS  PubMed  Google Scholar 

  76. Simpson GM, Glick ID, Weiden PJ, Romano SJ, Siu CO (2004) Randomized, controlled, double-blind multicenter comparison of the efficacy and tolerability of ziprasidone and olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder. Am J Psychiatry 161:1837–1847

    Google Scholar 

  77. Siris SG (2001) Suicide and schizophrenia. J Psychopharmacol 15:127–135

    CAS  PubMed  Google Scholar 

  78. Siris SG, Bench C (2003) Depression and schizophrenia. In: Hirsch SR, Weinberger DR (eds) Schizophrenia. Oxford, Blackwell Publishing, pp 142–167

  79. Spiker DG, Weiss JC, Dealy RS, Griffin SJ, Hanin I, Neil JF, Perel JM, Rossi AJ, Soloff PH (1985) The pharmacological treatment of delusional depression. Am J Psychiatry 142:430–436

    Google Scholar 

  80. Stoll AL, Haura G (2000) Tranylcypromine plus risperidone for treatment-refractory major depression. J Clin Psychopharmacol 20:495–496

    Google Scholar 

  81. Thase ME (2002) What role do atypical antipsychotic drugs have in treatment-resistant depression? J Clin Psychiatry 63:95–103

    Google Scholar 

  82. Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW et al. (2003) Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 60:1079–1088

    Google Scholar 

  83. Tollefson GD, Beasley CM Jr, Tran PV, Street JS, Krueger JA, Tamura RN, Graffeo KA, Thieme ME (1997) Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 154:457–465

    CAS  PubMed  Google Scholar 

  84. Tollefson GD, Sanger TM, Beasley CM, Tran PV (1998 a) A double-blind, controlled comparison of the novel antipsychotic olanzapine versus haloperidol or placebo on anxious and depressive symptoms accompanying schizophrenia. Biol Psychiatry 43:803–810

    Google Scholar 

  85. Tollefson GD, Sanger TM, Lu Y, Thieme ME (1998b) Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry 55:250–258

    Google Scholar 

  86. Van Putten T, May RP (1978) “Akinetic depression” in schizophrenia. Arch Gen Psychiatry 35:1101–1107

    Google Scholar 

  87. Vavrusova L (2002) Quetiapine in the treatment of non-psychotic depression. Int J Neuropsychopharmacol 5(Suppl 1):S104

    Google Scholar 

  88. Wassink TH, Flaum M, Nopoulos P, Andreasen NC (1999) Prevalence of depressive symptoms early in the course of schizophrenia. Am J Psychiatry 156:315–316

    Google Scholar 

  89. Wetzel H, Grunder G, Hillert A, Philipp M, Gattaz WF, Sauer H, Adler G, Schroder J, Rein W, Benkert O (1998) Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology—a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist. The Amisulpride Study Group. Psychopharmacology (Berl) 137:223–232

    Google Scholar 

  90. Whitehead C, Moss S, Cardno A, Lewis G (2002) Antidepressants for people with both schizophrenia and depression. Cochrane Database Syst Rev: CD002305

    Google Scholar 

  91. Wood MJ, Rubinstein M (1990) An atypical responder to clozapine. Am J Psychiatry 147:369

    Google Scholar 

  92. Zarate CA, Jr., Rothschild A, Fletcher KE, Madrid A, Zapatel J (2000) Clinical predictors of acute response with quetiapine in psychotic mood disorders. J Clin Psychiatry 61:185–189

    Google Scholar 

  93. Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD, Bymaster FP (2000) Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 23:250–262

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Ludwig-Maximilians-Universität München, Nussbaumstrasse 7, 80336, Munich, Germany

    Hans-Jürgen Möller

Authors
  1. Hans-Jürgen Möller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans-Jürgen Möller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Möller, HJ. Antidepressive effects of traditional and second generation antipsychotics: a review of the clinical data. Eur Arch Psychiatry Clin Neurosci 255, 83–93 (2005). https://doi.org/10.1007/s00406-005-0580-z

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00406-005-0580-z

Key words

Search

Navigation