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

Department of Psychiatry, University of California, San Diego, San Diego, California, United States
Journal of Affective Disorders (Impact Factor: 3.71). 09/2006; 94(1-3):3-13. DOI: 10.1016/j.jad.2006.04.003
Source: PubMed

ABSTRACT Given that suicidality is a well-known symptom and outcome of untreated or inadequately treated depressive illness, the United States (US) Food and Drug Administration (FDA) warning of emergent suicidality in children and adolescents based on the antidepressant arm of placebo-controlled randomized trials (RCTs) has created understandable concern in clinical practice. The issues involved are of broader public health importance for all age groups. As in other branches of medicine, psychiatrists must always be vigilant of the rare risk of iatrogenesis when prescribing potent agents like antidepressants for patients with depressive disorders where the risk of suicidality is inherent. The overall evidence we review suggests that the widespread use of antidepressants in the new "SSRI-era" appear to have actually led to highly significant decline in suicide rates in most countries with traditionally high baseline suicide rates. The decline is particularly striking for women who, compared with men, seek more help for depression. Recent clinical data on large samples in the US too have revealed a protective effect of antidepressant against suicide. We argue that the discrepancy between RCTs (in children) and national and clinical suicide statistics (in adults) may reside in new provocative data documenting high rates of unrecognized pseudo-unipolar mixed states particularly in juvenile, but also in adult, clinical populations. Such an interpretation accords well with equally provocative data that bipolar II (which is often "mixed" in nature) may well represent a particularly vulnerable clinical substrate for suicidality. In this respect, the widespread (at least in the psychiatric sector) augmentation of antidepressants with benzodiazepines, atypical antipsychotics or mood stabilizers may represent one situation where current practice is superior to evidence-based medicine. We conclude that rather than being a threat, the judicious clinical use of antidepressants actually does serve to effectively treat and indeed protect depressed patients from suicidal outcome. The fact of being in treatment with regular clinical follow-up appears beneficial as well.

1 Follower
  • Source
    • "This state has also recently drawn attention as one of the strongest risk factors for suicidality (Balázs et al., 2006; Undurraga et al., 2012; Valtonen et al., 2008). In line with the phenomenological similarities between AS and DMX, Akiskal and Benazzi (2006) and Rihmer and Akiskal (2006) argued that AS could be understood as antidepressant-induced DMX. Faedda et al. (2004) retrospectively analyzed 57 patients with juvenile BP who had been given an antidepressant or psychostimulant and reported that 33 of the 57 (58%) patients so exposed developed mania with a median latency of 14 days. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Activation syndrome (AS) is a cluster of symptoms listed by the US Food and Drug Administration as possible suicidality precursors during antidepressant treatment. We aimed to clarify whether AS is associated with bipolar II disorder (BP-II) and its related disorder, i.e., bipolar disorder not otherwise specified (BP-NOS), which are often mistreated as major depressive disorder (MDD), as well as bipolar suggestive features in outpatients with depression. The frequency of AS, bipolar suggestive features, and background variables in consecutive outpatients with a major depressive episode (MDE) due to BP-II/BP-NOS or MDD, who were naturalistically treated with antidepressants, were investigated and analyzed retrospectively. Of 157 evaluable patients (46 BP-II/BP-NOS, 111 MDD), 39 (24.8%) experienced AS. Patients with BP-II/BP-NOS experienced AS significantly more frequently than patients with MDD (52.2% of BP-II/BP-NOS vs. 13.5% of MDD, p<0.01). Univariate analysis revealed that BP-II/BP-NOS diagnosis, cyclothymic temperament, early age at onset of first MDE, psychiatric comorbidities, and depressive mixed state (DMX) were significantly associated with AS development in the entire sample. Multivariate analysis revealed that BP-II/BP-NOS diagnosis and DMX were independent risk factors for AS. This is a retrospective and naturalistic study; therefore, patient selection bias could have occurred. Cautious monitoring of AS is needed during antidepressant trials in patients with BP-II/BP-NOS. Clinicians should re-evaluate underlying bipolarity when they confront AS. Antidepressants should be avoided for treating a current DMX beyond the unipolar-bipolar dichotomy. Prospective studies are needed to confirm these results.
    Journal of Affective Disorders 06/2013; 151(1). DOI:10.1016/j.jad.2013.05.077 · 3.71 Impact Factor
  • Source
    • "Our findings may indicate that SSRIs are at least as helpful for patients with PTSD and MDD as for those with MDD only. Among the antidepressants, the SSRIs are the most commonly prescribed pharmacological intervention for MDD, PTSD and comorbid PTSD and MDD (Ornstein et al., 2000; Stein et al., 2000; Albucher and Liberzon, 2002; Rihmer and Akiskal, 2006). The efficacy of SSRIs for the treatment of MDD is well established. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Comorbidity of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) is associated with higher morbidity including suicidal ideation and behavior. Selective serotonin reuptake inhibitors (SSRIs) are a known treatment for PTSD, MDD and comorbid PTSD and MDD. Since the patients with comorbid MDD and PTSD (PTSD-MDD) are sicker, we hypothesize a poorer response to treatment compared to patients with MDD only. Ninety-six MDD patients were included in the study: 76 with MDD only and 20 with PTSD-MDD. Demographic and clinical parameters at baseline were assessed. We examined clinical parameters before and after 3 months of open SSRI treatment in subjects with PTSD-MDD and compared this group to individuals with MDD only. At baseline, PTSD-MDD patients had higher Hamilton Depression Rating Scale and Buss-Durkee Hostility Scale scores compared with MDD only subjects. There was a significant decrease in scores on the Hamilton Depression Rating Scale, Beck Depression Inventory, Beck Hopelessness Scale, and Beck Scale for Suicidal Ideation after 3 months of treatment with SSRIs in both groups. The magnitude of improvement in Beck Scale for Suicidal Ideation scores was greater in the PTSD-MDD group compared to the MDD only subjects. Symptoms of depression including suicidal ideation improved in MDD patients with or without comorbid PTSD after 3 months of treatment with SSRIs but improvement in suicidal ideation was greater in the PTSD-MDD group. Our finding has not supported the hypothesis that a response to treatment is poorer in the PTSD-MDD group which may indicate that sicker patients benefit more from the treatment.
    Psychiatry Research 03/2012; 196(2-3):261-6. DOI:10.1016/j.psychres.2011.11.010 · 2.68 Impact Factor
  • Source
    • "Although antidepressants are the most effective treatment for depressive patients, there has been controversy if antidepressants, in particular serotonin reuptake inhibitors (SSRI), are implicated in the emergence or worsening of suicidal ideation (Masand et al, 1991; Teicher et al, 1990; Wirshing et al, 1992). Although treatment with antidepressants is associated with a significant reduction in suicides (Hall et al, 2003; Licinio and Wong, 2005; Morgan et al, 2004; Nakagawa et al, 2007; Rihmer and Akiskal, 2006) and was proven to have a suicide-preventive effect (Angst et al, 2005), there is some evidence that a subgroup of patients (4–14%) develop treatment-emergent suicidal ideation (TESI) in the first weeks following treatment initiation and dose adjustments (Jick et al, 2004; Licinio and Wong, 2005; March et al, 2007; Mulder et al, 2008; Perlis et al, 2007a; Seemuller et al, 2009). On the basis of a meta-analysis (Hammad et al, 2006), the US Food and Drug Administration (FDA), followed by regulatory bodies in Europe, issued a black box warning for a series of antidepressants, indicating that especially young patients under the age of 25 years may be at risk for this side effect (Marshall, 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Emergence of suicidal ideation (TESI) during treatment with antidepressants in major depression led to a black box warning. We performed a genome-wide association study to identify genetic markers, which increase the risk for this serious side effect. TESI was evaluated in depressed in-patients (N=397) and defined by an emergence of suicidal thoughts during hospitalization without suicidal thoughts at admission using the suicide item (3) of the Hamilton Depression Rating Scale. Genotype distribution of 405.383 single-nucleotide polymorphisms (SNPs) in patients with TESI (N=32/8.1%) was compared to patients without increase in suicidal ideation (N=329/82.9%) and to a subgroup never reported suicidal ideation (N=79/19.9%). Top results were analyzed in an independent sample (N=501). None variant reached genome-wide significance, the best associated SNP was rs1630535 (p-value=1.3 × 10(-7)). The top 79 SNPs could be analyzed in an independent sample, and 14 variants showed nominal significant association with the same risk allele in the replication sample. A discriminant analysis classifying patients using these 79 SNPs revealed a 91% probability to classify TESI vs non-TESI cases correctly in the replication sample. Although our data need to be interpreted carefully owing to the small numbers in both cohorts, they suggest that a combination of genetic markers might indeed be used to identify patients at risk for TESI.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2012; 37(3):797-807. DOI:10.1038/npp.2011.257 · 7.83 Impact Factor
Show more


Available from