The complex relationship between the use of antidepressants and suicidal behaviour is one of the hottest topics of our contemporary psychiatry. Based on the literature, this paper summarizes the author's view on antidepressant-resistant depression and antidepressant-associated suicidal behaviour. Antidepressant-resistance, antidepressant-induced worsening of depression, antidepressant-associated (hypo)manic switches, mixed depressive episode, and antidepressant-associated suicidality among depressed patients are relatively most frequent in bipolar/bipolar spectrum depression and in children and adolescents. As early age at onset of major depressive episode and mixed depression are powerful clinical markers of bipolarity and the manic component of bipolar disorder (and possible its biological background) shows a declining tendency with age antidepressant-resistance/worsening, antidepressant-induced (hypo)manic switches and “suicide-inducing” potential of antidepressants seem to be related to the underlying bipolarity. 1. Introduction Treatment-resistant and particularly antidepressant-resistant major depression (AD-RD) is a great clinical challenge both in the cases of unipolar and bipolar depression [1, 2]. While it is well documented that the optimal clinical response to antidepressants is much rare in bipolar I and II than in unipolar major depression [3–5] only the most recent clinical studies have focused on the boundaries between treatment-resistant unipolar major depressive disorder and bipolar disorder. These studies seem to be more promising in understanding both antidepressant-resistance and antidepressant-associated suicidal behaviour in patients with major mood disorders. 2. Antidepressant Resistance in Major Depressive Episode: Its Relationship with Bipolar Disorder The generally accepted definition of AD-RD refers that the depressed patient does not show a clinically significant response after at least two adequate trials of different classes of antidepressants. In spite of the fact that there are several causes of AD-RD in general [1, 6], one of the most common sources of it is the unrecognized bipolar nature of the “unipolar” major depressive disorder, when the patients receive antidepressant monotherapy—unprotected by mood stabilizers/atypical antipsychotics [4–11]. Unrecognized bipolar depressives are generally treated as “unipolar” major depressives which means that these patients do not receive mood stabilizers [3, 12]. This can result in a very high rate of treatment resistance, which is about two-times higher than in patients with
References
[1]
M. Fava and A. J. Rush, “Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice,” Psychotherapy and Psychosomatics, vol. 75, no. 3, pp. 139–153, 2006.
[2]
I. Pacchiarotti, L. Mazzarini, F. Colom et al., “Treatment-resistant bipolar depression: towards a new definition,” Acta Psychiatrica Scandinavica, vol. 120, no. 6, pp. 429–440, 2009.
[3]
S. N. Ghaemi, J. Y. Ko, and F. K. Goodwin, “"Cade's disease" and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder,” Canadian Journal of Psychiatry, vol. 47, no. 2, pp. 125–134, 2002.
[4]
S. N. Ghaemi, K. J. Rosenquist, J. Y. Ko, C. F. Baldassano, N. J. Kontos, and R. J. Baldessarini, “Antidepressant treatment in bipolar versus unipolar depression,” American Journal of Psychiatry, vol. 161, no. 1, pp. 163–165, 2004.
[5]
J. K. Rybakowski, A. Suwalska, D. Lojko, J. Rymaszewska, and A. Kiejna, “Types of depression more frequent in bipolar than in unipolar affective illness: results of the polish DEP-BI study,” Psychopathology, vol. 40, no. 3, pp. 153–158, 2007.
[6]
Y. S. Woo, J. H. Chae, T. Y. Jun, K. S. Kim, and W. M. Bahk, “The bipolar diathesis of treatment-resistant major depressive disorder,” International Journal of Psychiatry in Clinical Practice, vol. 12, no. 2, pp. 142–146, 2008.
[7]
H. S. Akiskal and G. Mallya, “Criteria for the 'soft' bipolar spectrum: treatment implications,” Psychopharmacology Bulletin, vol. 23, no. 1, pp. 68–73, 1987.
[8]
V. Sharma, “Loss of response to antidepressants and subsequent refractoriness: diagnostic issues in a retrospective case series,” Journal of Affective Disorders, vol. 64, no. 1, pp. 99–106, 2001.
[9]
R. S. EI-Mallakh and A. Karippot, “Antidepressant-associated chronic irritable dysphoria (acid) in bipolar disorder: a case series,” Journal of Affective Disorders, vol. 84, no. 2-3, pp. 267–272, 2005.
[10]
C. O'Donovan, J. S. Garnham, T. Hajek, and M. Alda, “Antidepressant monotherapy in pre-bipolar depression; predictive value and inherent risk,” Journal of Affective Disorders, vol. 107, no. 1–3, pp. 293–298, 2008.
[11]
J. K. Rybakowski, J. Angst, D. Dudek et al., “Polish version of the Hypomania Checklist (HCL-32) scale: the results in treatment-resistant depression,” European Archives of Psychiatry and Clinical Neuroscience, vol. 260, no. 2, pp. 139–144, 2010.
[12]
P. Zimmermann, T. Brückl, A. Nocon et al., “Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity,” Archives of General Psychiatry, vol. 66, no. 12, pp. 1341–1352, 2009.
[13]
H. S. Akiskal, F. Benazzi, G. Perugi, and Z. Rihmer, “Agitated "unipolar" depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy,” Journal of Affective Disorders, vol. 85, no. 3, pp. 245–258, 2005.
[14]
R. S. El-Mallakh, S. N. Ghaemi, K. Sagduyu et al., “Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients,” Journal of Affective Disorders, vol. 111, no. 2-3, pp. 372–377, 2008.
[15]
Z. Rihmer and H. Akiskal, “Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries,” Journal of Affective Disorders, vol. 94, no. 1–3, pp. 3–13, 2006.
[16]
H. S. Akiskal, “Developmental pathways to bipolarity: are juvenile-onset depressions pre-bipolar?” Journal of the American Academy of Child and Adolescent Psychiatry, vol. 34, no. 6, pp. 754–763, 1995.
[17]
F. Benazzi and H. S. Akiskal, “How best to identify a bipolar-related subtype among major depressive patients without spontaneous hypomania: superiority of age at onset criterion over recurrence and polarity?” Journal of Affective Disorders, vol. 107, no. 1–3, pp. 77–88, 2008.
[18]
F. J. Kochman, E. G. Hantouche, P. Ferrari, S. Lancrenon, D. Bayart, and H. S. Akiskal, “Cyclothymic temperament as a prospective predictor of bipolarity and suicidality in children and adolescents with major depressive disorder,” Journal of Affective Disorders, vol. 85, no. 1-2, pp. 181–189, 2005.
[19]
R. J. Baldessarini, G. L. Faedda, and J. Hennen, “Risk of mania with antidepressants,” Archives of Pediatrics and Adolescent Medicine, vol. 159, no. 3, pp. 298–299, 2005.
[20]
T. Usala, A. Clavenna, A. Zuddas, and M. Bonati, “Randomised controlled trials of selective serotonin reuptake inhibitors in treating depression in children and adolescents: a systematic review and meta-analysis,” European Neuropsychopharmacology, vol. 18, no. 1, pp. 62–73, 2008.
[21]
J. D. Amsterdam and J. Shults, “Does tachyphylaxis occur after repeated antidepressant exposure in patients with Bipolar II major depressive episode?” Journal of Affective Disorders, vol. 115, no. 1-2, pp. 234–240, 2009.
[22]
H. S. Akiskal and F. Benazzi, “Psychopathologic correlates of suicidal ideation in major depressive outpatients: is it all due to unrecognized (bipolar) depressive mixed states?” Psychopathology, vol. 38, no. 5, pp. 273–280, 2005.
[23]
F. Benazzi, “Family history validation of a definition of mixed depression,” Comprehensive Psychiatry, vol. 46, no. 3, pp. 159–166, 2005.
[24]
F. Benazzi, “Mood patterns and classification in bipolar disorder,” Current Opinion in Psychiatry, vol. 19, no. 1, pp. 1–8, 2006.
[25]
F. Benazzi, “Bipolar disorder-focus on bipolar II disorder and mixed depression,” Lancet, vol. 369, no. 9565, pp. 935–945, 2007.
[26]
F. Benazzi and H. S. Akiskal, “Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes,” Journal of Affective Disorders, vol. 67, no. 1–3, pp. 115–122, 2001.
[27]
J. F. Goldberg, R. H. Perlis, C. L. Bowden et al., “Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD,” American Journal of Psychiatry, vol. 166, no. 2, pp. 173–181, 2009.
[28]
H. S. Akiskal and F. Benazzi, “Family history validation of the bipolar nature of depressive mixed states,” Journal of Affective Disorders, vol. 73, no. 1-2, pp. 113–122, 2003.
[29]
R. Bottlender, T. Sato, N. Kleindienst, A. Strau？, and H. J. M？ller, “Mixed depressive features predict maniform switch during treatment of depression in bipolar I disorder,” Journal of Affective Disorders, vol. 78, no. 2, pp. 149–152, 2004.
[30]
Z. Rihmer and J. Angst, “Epidemiology of bipolar disorder,” in Handbook of Bipolar Disorder, S. Kasper and R. M. A. Hirschfeld, Eds., pp. 21–35, Marcel Dekker, New York, NY, USA, 2005.
[31]
J. Balázs, F. Benazzi, Z. Rihmer, A. Rihmer, K. K. Akiskal, and H. S. Akiskal, “The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention,” Journal of Affective Disorders, vol. 91, no. 2-3, pp. 133–138, 2006.
[32]
M. Maj, R. Pirozzi, L. Magliano, A. Fiorillo, and L. Bartoli, “Agitated "unipolar" major depression: prevalence, phenomenology, and outcome,” Journal of Clinical Psychiatry, vol. 67, no. 5, pp. 712–719, 2006.
[33]
Z. Rihmer, “Suicide risk in mood disorders,” Current Opinion in Psychiatry, vol. 20, no. 1, pp. 17–22, 2007.
[34]
H. M. Valtonen, K. Suominen, J. Haukka et al., “Differences in incidence of suicide attempts during phases of bipolar I and II disorders,” Bipolar Disorders, vol. 10, no. 5, pp. 588–596, 2008.
[35]
M. A. Frye, G. Helleman, S. L. McElroy et al., “Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression,” American Journal of Psychiatry, vol. 166, no. 2, pp. 164–172, 2009.
[36]
R. Bottlender, D. Rudolf, A. Strau？, and H. J. M？ller, “Mood-stabilisers reduce the risk of developing antidepressant-induced maniform states in acute treatment of bipolar I depressed patients,” Journal of Affective Disorders, vol. 63, no. 1–3, pp. 79–83, 2001.
[37]
E. Mundo, E. Cattaneo, M. Russo, and A. C. Altamura, “Clinical variables related to antidepressant-induced mania in bipolar disorder,” Journal of Affective Disorders, vol. 92, no. 2-3, pp. 227–230, 2006.
[38]
V. Salvi, A. Fagiolini, H. A. Swartz, G. Maina, and E. Frank, “The use of antidepressants in bipolar disorder,” Journal of Clinical Psychiatry, vol. 69, no. 8, pp. 1307–1318, 2008.
[39]
A. Serretti, P. Artioli, R. Zanardi, and D. Rossini, “Clinical features of antidepressant associated manic and hypomanic switches in bipolar disorder,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 27, no. 5, pp. 751–757, 2003.
[40]
R. J. Baldessarini, L. Tondo, P. Davis, M. Pompili, F. K. Goodwin, and J. Hennen, “Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review,” Bipolar Disorders, vol. 8, no. 5, pp. 625–639, 2006.
[41]
A. J. Cutler, S. A. Montgomery, D. Feifel, A. Lazarus, M. ？str？m, and M. Brecher, “Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study,” Journal of Clinical Psychiatry, vol. 70, no. 4, pp. 526–539, 2009.
[42]
M. E. Thase, W. Macfadden, R. H. Weisler et al., “Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study),” Journal of Clinical Psychopharmacology, vol. 26, no. 6, pp. 600–609, 2006.
[43]
S. E. Hetrick, J. E. McKenzie, and S. N. Merry, “The use of SSRIs in children and adolescents,” Current Opinion in Psychiatry, vol. 23, no. 1, pp. 53–57, 2010.
[44]
R. A. Friedman and A. C. Leon, “Expanding the black box—depression, antidepressants, and the risk of suicide,” New England Journal of Medicine, vol. 356, no. 23, pp. 2343–2346, 2007.
[45]
J. E. Kraus, J. P. Horrigan, D. J. Carpenter, R. Fong, P. S. Barrett, and J. T. Davies, “Clinical features of patients with treatment-emergent suicidal behavior following initiation of paroxetine therapy,” Journal of Affective Disorders, vol. 120, no. 1–3, pp. 40–47, 2010.
[46]
M. Stone, T. Laughren, M. L. Jones et al., “Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration,” British Medical Journal, vol. 339, no. b2880, 2009.
[47]
C. Barbui, E. Esposito, and A. Cipriani, “Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies,” Canadian Medical Association Journal, vol. 180, no. 3, pp. 291–297, 2009.
[48]
S. Zisook, M. H. Trivedi, D. Warden et al., “Clinical correlates of the worsening or emergence of suicidal ideation during SSRI treatment of depression: an examination of citalopram in the STAR*D study,” Journal of Affective Disorders, vol. 117, no. 1-2, pp. 63–73, 2009.
[49]
S. C. Dilsaver, F. Benazzi, Z. Rihmer, K. K. Akiskal, and H. S. Akiskal, “Gender, suicidality and bipolar mixed states in adolescents,” Journal of Affective Disorders, vol. 87, no. 1, pp. 11–16, 2005.
[50]
P. J. Podrid, “Proarrhythmia, a serious complication of antiarrhythmic drugs,” Current Cardiology Reports, vol. 1, no. 4, pp. 289–296, 1999.
[51]
P. J. Podrid, “Aggravation of arrhythmia: a complication of antiarrhythmic drugs,” Journal of Cardiovascular Electrophysiology, vol. 4, no. 3, pp. 311–319, 2007.
