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.
