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).
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).
Suicide among adolescents has gained substantial clinical attention in the psychiatric
field in the recent decade and has become a major public health concern worldwide (2012;
Fazel, Wolf et al. 2013). The U.S. National Institute of Mental Health reported that
suicide was the country's third leading cause of mortality among adolescents and young
adults aged 15 to 24 years (2012; Fazel, Wolf et al. 2013). In Taiwan, the Ministry of
Health and Welfare indicated that suicide was the second leading cause of mortality
among adolescents and young adults, accounting for the death of 7.1/100,000 adolescents
and young adults (Cicinelli, Pasqualetti et al. 2003).
A Taiwan report in 2013, a nationally representative sample of 2835 college students,
demonstrated that a surprisingly high prevalence of college students (about 12% of
females and 9% of males) had at least one time of attempted suicide in the preceding 12
months (Chou, Ko et al. 2013). Previous studies have demonstrated that more than 70% of
adolescents and young adults who attempt suicide or have suicidal ideation have
psychiatric disorders, including major depressive disorder, bipolar disorder, anxiety
disorders, disruptive behavior disorders, and alcohol and substance use disorders
(Brent, Perper et al. 1994; Gould, King et al. 1998; Kelly, Cornelius et al. 2002;
Hauser, Galling et al. 2013). Any form of suicide, including suicide ideation, suicide
attempt, and suicide mortality, would cause a great amount of physical, mental, and
financial loss and burden to the sufferers, the family, the community, and the society.
Furthermore, those suicide ideators and suicide attempters remain vulnerable to costly
health and social problems in their later life.
Low-dose ketamine infusion in adolescent depression:
Based on the higher treatment resistance and the greater suicidal risk in adolescent
depression, increasing evidence suggests the potential therapeutic effect of low-dose
ketamine infusion in adolescent patients with TRD although there was no any randomized,
double-blind, placebo-control clinical trial to investigate this important clinical topic
until now. Ketamine is safe, tolerable, and commonly used in the pediatric anesthesia in the
past decades (Brewer, Davidson et al. 1972; Raju 1980; Green, Klooster et al. 2001; Koruk,
Mizrak et al. 2010). In 2017, Dwyer et al reported the first case report study for the
ketamine infusion as a treatment for adolescent depression (Dwyer, Beyer et al. 2017). They
described the personal history and clinical course of this case: this patient was considered
to be at high risk for suicide. He had a history of three serious suicide attempts involving
near-lethal antifreeze ingestion, dextroamphetamine overdose, and self-strangulation. He
presented as hopeless about the prospect of psychiatric improvement and complained of
persistent thoughts of wanting to die. The patient had failed multiple levels of care
(outpatient, intensive outpatient, and residential) and multiple antidepressant medications,
with treatment informed by current practice parameters. This patient received intravenous
infusions of ketamine, dosed at 0.5 mg/kg over 40 minutes. This patient received 3 infusions
during the first week and weekly treatments thereafter, resulting in 7 infusions over an
8-week hospitalization (days 1, 3, 7, 14, 21, 28, 50). At 1 day after his first infusion, he
experienced a rapid reduction in his depressive symptoms (61% MADRS reduction; 32% CDRS
reduction), suicidal ideation (88% SSI-5 reduction), and hopelessness (57% BHS reduction).
The patient had an acute recovery with ketamine treatment, as has been described in adults
(Figure 4). He tolerated all infusions well, experiencing mild nausea and mild intrainfusion
dissociative symptoms (maximum CADSS of 7 [of a possible 92], which returned to 0 by 80
minutes) (Dwyer, Beyer et al. 2017).
This is a double-blind, randomized-controlled trial of ketamine infusion to test whether
0.5mg/kg ketamine infusion is a safe and effective add-on treatment for adolescents with TRD.