Low-dose Ketamine Infusion Among Adolescents With Treatment-resistant Depression: a Randomized, Double-blind Placebo-control Study

1. Treatment-resistant depression (TRD) in adolescence:

Major depressive disorder (MDD) in adolescents is characterized by a high risk of suicidality, recurrence, and chronicity and has been a topic of concern for decades in the fields of public health and clinical psychiatry (Goodyer, Dubicka et al. 2007; Garber and Weersing 2010). The estimated prevalence of MDD is 8%-20% in the adolescent population (Yorbik, Birmaher et al. 2004; Thapar, Collishaw et al. 2012). Longitudinal studies on community-based and clinic-based population samples have suggested that 60%-90% of adolescents reported to have depression achieve remission within a year; moreover, follow-up studies have indicated that 50% to 70% of patients who remit report subsequent depressive episodes within 5 years (Dunn and Goodyer 2006; Thapar, Collishaw et al. 2012).

Relevant studies have reported that adolescents with depression have less response to antidepressants and lower remission rates than adults with depression, which may indicate a higher prevalence of TRD in adolescent population (Michael and Crowley 2002; Kennard, Silva et al. 2009; Zhou, Michael et al. 2014). The Treatment for Adolescents with Depression Study (TADS) reported that the remission rate following 12-week antidepressant monotherapy or combination treatment using antidepressants and cognitive-behavioral therapy (CBT) was approximately 60% in adolescents with MDD, which may indicate that at least one-third of adolescents with MDD did not respond to treatment or achieve remission after adequate antidepressant, CBT, or combined treatment (Kennard, Silva et al. 2009). The Adolescent Depression, Antidepressants, and Psychotherapy Trial reported that only 57% of adolescents with depression exhibited moderate or substantial improvement after 28 weeks of SSRI or CBT treatment and that up to 20% demonstrated no improvement (Goodyer, Dubicka et al. 2007). Furthermore, Curry et al. evaluated the predictors of response to fluoxetine treatment in adolescents with depression and reported that those with more psychiatric comorbidities, including anxiety disorders, attention deficit hyperactivity disorder (ADHD), and disruptive behavioral disorders, were less likely to benefit from treatment than their counterparts (Curry, Rohde et al. 2006). Hilton et al. further investigated the efficacy of changing antidepressant treatment to another selective serotonin reuptake inhibitor (SSRI) or venlafaxine in adolescents with SSRI-resistant depression and determined that those who did not achieve remission exhibited increased anxiety, ADHD, and behavioral symptoms than those who did (Hilton, Rengasamy et al. 2013).

However, current guidelines for TRD in adolescent patients with depression remain inadequate despite the high morbidity and severe impairment in these young patients (Zhou, Michael et al. 2014). A recent meta-analysis showed that the overall response rate for the active treatments, including the combination therapy with psychotherapy or second antidepressants, augmentation therapy with lithium/atypical antipsychotics, or the antidepressant-switching, was only 46% among adolescent patients with TRD. Approximately half of the adolescents who presented with TRD responded to active treatment, which suggests that practitioners should remain persistent in managing these challenging cases (Zhou, Michael et al. 2014). Treatment of Resistant Depression in Adolescents (TORDIA) study further suggested that the current clinical guidelines, which recommend pursuing a given treatment strategy for at least 8-12 weeks, may need to be revisited because their data support more vigorous intervention earlier in the course of treatment for nonresponding patients (Emslie, Mayes et al. 2010). 2. Suicide in adolescence:

The suicide rates in the last half century increased by 60% worldwide, it is estimated that by 2020, suicide would account more than 1 million deaths. The WHO reports that Taiwan is one of the countries with the highest prevalence of suicide mortality (>13/100,000) worldwide (2012; Fazel, Wolf et al. 2013). In Taiwan, the prevalence of suicide mortality reached a peak in 2006 (19.3/100,000). The Taiwan suicidal prevention program was implemented in 2005, and in the following years (2008~2011), the prevalence of suicide mortality declined gradually to 15.1/100,000. But, the prevalence of suicide mortality rebounded up to 16.2/100,000 again in 2012 (Cicinelli, Pasqualetti et al. 2003). More than suicide mortality and committed suicide, the suicide attempt and suicide ideation also gained the clinical and public health attention and concerns in this decades (2012; Fazel, Wolf et al. 2013).