Giulia Menculini1*
Gianmarco Cinesi1
Francesca Scopetta1
Matteo Cardelli1
Guido Caramanico1
Pierfrancesco Maria Balducci1,2Filippo De Giorgi3
Patrizia Moretti1
Alfonso Tortorella1- 1Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- 2Community Mental Health Center “CSM Terni”, Department of Psychiatry, Local Health Unit USL Umbria 2, Terni, Italy
- 3Division of Psychiatry, Clinical Psychology and Rehabilitation, General Hospital of Perugia, Perugia, Italy
Major depressive disorder (MDD) represents a major health issue in adolescents and young adults, leading to high levels of disability and profoundly impacting overall functioning. The clinical presentation of MDD in this vulnerable age group may slightly differ from what can be observed in adult populations, and psychopharmacological strategies do not always lead to optimal response. Resistance to antidepressant treatment has a prevalence estimated around 40% in youths suffering from MDD and is associated with higher comorbidity rates and suicidality. Several factors, encompassing biological, environmental, and clinical features, may contribute to the emergence of treatment-resistant depression (TRD) in adolescents and young adults. Furthermore, TRD may underpin the presence of an unrecognized bipolar diathesis, increasing the overall complexity of the clinical picture and posing major differential diagnosis challenges in the clinical practice. After summarizing current evidence on epidemiological and clinical correlates of TRD in adolescents and young adults, the present review also provides an overview of possible treatment strategies, including novel fast-acting antidepressants. Despite these pharmacological agents are promising in this population, their usage is expected to rely on risk-benefit ratio and to be considered in the context of integrated models of care.
1 Introduction: major depressive disorder in youth populations
Major depressive disorder (MDD) is a serious psychiatric disorder with a relevant impact on quality of life and overall functioning. According to the World Health Organization (WHO), MDD represents the main cause of years lived with disability worldwide, leading to decreased involvement in social and work activities and to increased medical comorbidities and health resource use (1). The lifetime prevalence of MDD may reach up to 30% in special populations (2), and is usually higher among women (3).
Depressive disorders, and particularly MDD, also represent a relevant health issue in adolescents and young adults, with an overall prevalence estimated around 2-3% (4, 5), reaching up to 20% at the end of puberty (6). The incidence of MDD during adolescence is estimated about 7.5% (2.3% for serious forms of the disorder) (7), with higher prevalence rates among young women (8). A meta-analysis of 80,879 youths conducted during the first year of the Coronavirus disease 2019 (COVID-19) pandemic concluded that the global prevalence of youths experiencing clinically significant depressive symptoms increased to 25% (9). Adolescence is a vulnerable period for developing mental health issues, and particularly depression, due to the interaction of different factors encompassing biological, environmental, and social determinants (10). Indeed, the onset of puberty, together with the exposure to social media, bullying and cyber-bullying episodes and education-related issues, make this life period extremely prone to the onset of psychopathology (11). Adolescents and young adults experience a number of symptoms during depressive episodes, including persistent sadness, irritability, weight change, loss of energy, and insomnia (12). The emergence of MDD during adolescence is associated with significant functional impairment and higher comorbidity rates (11), including medical diseases (13), as well as with an increase in substance abuse (14). More than 30% of youths suffering from MDD experience suicidal ideation, and over 10% attempt suicide, the latter being the second cause of death among youths aged 15-24 (15). Studies conducted among university students highlighted that MDD could seriously impact academic performances and lead to impaired social relationships and low self-esteem (16). Moreover, the onset of MDD during youth may lead to higher recurrence and relapse rates during the following years (17). Despite the relevance of MDD among youths under a clinical and epidemiological point of view, young people suffering from this disorder are often not likely to seek help. Hence, according to recent reports, only 35% of adolescents suffering from this condition accessed mental health resources and only 33% received adequate treatment (8).
In this narrative review, we decided to focus on one of the major challenges posed by MDD, which is treatment-resistance. Since a considerable percentage of MDD first episodes occur during adolescence or young adulthood, we believe that the appropriate identification of difficult-to-treat conditions is crucial to prevent functional impairment and chronicization during the following years. As a consequence, the main aim of this paper is to critically summarize evidence concerning treatment-resistant depression (TRD) in youths, with specific focus on: definition, epidemiology, impact, clinical correlates (including differential diagnosis issues), and possible treatment strategies, with particular interest in novel antidepressant strategies. To this attempt, we performed a literature review, variously combining the following keywords in PubMed, Scopus, and Web of Science databases: “major depressive disorder”, “depressive disorders”, “treatment-resistant depression”, “treatment resist*”, “youth*”, “adolescent*”, “young adult*”.
2 Treatment-resistant depression in youth populations: clinical challenges and impact
The currently accepted definition of TRD refers to a condition in which subjects do not respond, or reach remission, after treatment with at least two antidepressants at adequate dose and for an adequate period of time (18). Using this definition, the prevalence of TRD is estimated about 20-30% among subjects suffering from MDD (19), but rates vary from 12% to 55% (20). This huge variability is mainly due to the lack of homogenous criteria for TRD, as well as to various staging models that consider different number of failed antidepressant trials and different possible treatments, e.g., variably including also psychotherapies and electro-convulsant therapy (ECT) (21). Despite consensus has not been reached yet, most studies consider response as a reduction in depressive symptoms of at least 50%, as evaluated by well-validated rating scales (22). The minimum duration of antidepressant treatment should be 4 weeks (23), with a variable range of 4-12 weeks (24). Overall, subjects with MDD who undergo adequate treatment usually reach remission in 30% cases. Out of the remaining 70%, about 20% respond to treatment without reaching remission, while 50% do not respond at all (25). To note, the possibility for reaching remission significantly decreases after the second and third treatment strategy, as detected in the wide multicenter Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (26). Furthermore, in a relevant percentage of cases where a response is observed, residual symptoms may be present and impact overall quality of life of affected individuals (27).
TRD represents a complex clinical entity, underpinning different depression subtypes, as well as psychiatric and medical comorbidities (28). This condition should be conceptualized as a phenomenon that lies on a continuum ranging from partially responsive depression to multi-treatment resistant MDD (29). As we will elucidate later, TRD is also a multifaceted phenomenon, since several factors lead to reduced treatment effectiveness in MDD. Among possible risk factors for TRD, psychiatric comorbidities, particularly anxiety disorders (30, 31), psychotic features (18), and poor treatment adherence (32) have pointed out as the most common ones.
In youth populations, no specific criteria for TRD have been suggested, and research on the topic is scant (33, 34). A broad definition proposed for TRD in adolescents is a depressive disorder that does not respond to a two-month antidepressant treatment, namely a drug prescribed at a dose equivalent to 40 mg of fluoxetine and/or 8-16 sessions of cognitive-behavioral or interpersonal therapy (35, 36). Psychopharmacological treatment efficacy should be evaluated at intervals of at least four weeks, increasing doses in case of incomplete response (37). The main strength of this definition is the inclusion of psychotherapy among possible treatment strategies, which lacks in most adult TRD definitions (21). Indeed, psychotherapy demonstrated its efficacy in youth depression, alone or associated with pharmacological interventions, and is mentioned in the majority of treatment guidelines for this population (37–40). On the other hand, the different response to antidepressants in adolescents is not taken into account and the doses are similar to those advised for adults. It has anyway been largely demonstrated that young populations can develop activation symptoms, mood lability, and irritability in response to conventional antidepressant treatments, possibly leading to worsening of depression and suicidality (35). This is a major issue that experts should consider when defining TRD in adolescent and young adults, possibly reaching a more population-specific and comprehensive definition.
Based on the currently accepted description, a consistent percentage of adolescents and young adults with MDD – estimated around 40% - fail to respond to treatment with an antidepressant medication or evidence-based psychotherapy (33, 41), resulting in what is commonly referred to as TRD (34). To note, there is also a proportion of patients – about one third – initially reaching remission who do not maintain this outcome in the long-term (42). The impact of TRD on overall well-being has widely been recognized (43), together with the significant increase in mortality risk among affected individuals (44, 45). These aspects are particularly meaningful in youth populations. Indeed, TRD is associated with cognitive impairment (46), reduced coping abilities (47), and higher risk of developing medical diseases (48, 49), resulting in greater overall severity, poorer outcomes, and reduced functioning in different areas (50–52). High mortality rates are linked to comorbidities and to increased suicide risk (53). In most cases, TRD leads to higher use of healthcare resources, with subsequent increased health costs (54–56), which is even more relevant if we focus on young populations at their very first working experiences. As a result, quality of life is significantly impaired in adolescents and young adults suffering from TRD (57).
3 Clinical correlates of TRD in youth populations
The clinical presentation of MDD in youths, and particularly adolescents, can significantly differ from what can be observed in adult populations, although diagnostic criteria are the same. Depressive symptoms can sensitively be different across the lifespan, which lead to low diagnostic validity of traditional nosographic categories in this population (58). In early and mid-adolescents some features, particularly irritability, somatic symptoms, and anxiety, can be ever more prevalent than low mood and sadness, while in older adolescents and young adults affective and cognitive symptoms are prominent and closely resemble those observed in adults (59). Among youths, somatic and autonomic symptoms - including eating and sleep disturbances – could in some cases prevail on cognitive features and anhedonia and may lead to increased duration and severity of the depressive episode (36). Moreover, different clinical pictures may be observed also based on possible pathways leading to the development of depressive symptoms and depressive disorders. The impact that substance abuse, as well as the co-occurrence of behavioral addictions, e.g., pathological internet and social media use, can exert on the clinical picture may indeed be crucial. Sex differences have also been described, including a higher prevalence of eating and body image disorders in females, while somatic symptoms, attention deficits, restlessness, and anhedonia are more frequent in males, increasing the risk of developing conduct disorders and substance use (59). Another not negligible influence is represented by cultural and societal determinants, since the development of depression may be affected by specific factors, e.g., belonging to a minority or being culturally vulnerable in challenging environments, such as huge urban contexts (60, 61). This is a crucial points if we consider the progressive increase of migrant families belonging to ethnic minorities in European countries and the high prevalence of mood disorders in this population (62), with major challenges for psychiatric care. Indeed, symptom presentation significantly vary across cultures, as demonstrated for most psychiatric disorders, and thus require more time to be adequately identified. Moreover, adolescents coming from socially disadvantaged groups may encounter major barriers in accessing mental health care (63), which summed up to internal and external stigma-related issues determines reduced rates of help-seeking and possibly influences the emergence of treatment-resistance due to delay in symptom recognition. Cultural differences may also be experienced when it comes to how depression is perceived among youths belonging to different contexts and could influence crucial aspects such as the acceptance of the proposed treatments and the risk of drop-out, which significantly impacts the efficacy of treatment strategies (64).
Depressive episodes in youth populations are not of univocal interpretation and should be treated with particular attention especially in case of treatment resistance. Frequently, TRD during adolescence underpins the presence of an underlying bipolar diathesis. Indeed, most subjects who suffer from early onset bipolar disorder (BD) present a depressive polarity at their first episode, and it has been argued that up to 28% of young patients who are at first diagnosed with MDD develop subsequent hypomanic or manic episodes within 5-10 years (65). To note, bipolar depression is usually resistant to antidepressant treatment, which can also lead to a shift towards manic symptoms (66) and worsening of depression (67). Treatment strategies may differ significantly in case of a bipolar diathesis, since antidepressants should be used with caution in subjects suffering from, or at-risk for, BD, evaluating the risk/benefit ratio (68). In younger patients, bipolar depression may be difficult to distinguish from MDD, due to the depressive onset and the absence of previous episodes of opposite polarity. Some clinical features may anyway be evaluated as possible “red flags” and should thus be always considered. The main factor suggesting underlying bipolarity in youths with a depressive episode is positive familiar history for BD, which already suggests the presence of an at-risk state for BD according to previously proposed criteria (69). A positive history of psychotic disorders and suicide among first-grade relatives should also be taken into account, as well as illness characteristics, since higher severity and younger age at onset could be more frequently associated with the emergence of BD among offsprings (39). As already stated, hypomanic episodes are often under-reported or considered as ego syntonic in this population. The presence of under-threshold hypomanic symptoms should anyway be systematically investigated, and clinicians should screen patients for the presence of short periods – usually, less than four days – during which clinical features such as increased self-esteem, decreased need for sleep, talkativeness, distractibility, and increased goal-directed activity occurred (69). Course characteristics of the current depressive episode should also be considered, particularly early and abrupt onset and a positive history for recurrent depressive episodes that, as already stated, fail in responding to antidepressant treatment or present worsening of depression (39, 67). Finally, further potential predictors of underlying BD include atypical or mixed features, psychotic symptoms, psychomotor retardation, and catatonia, as well as the comorbidity with substance abuse (70–72).
When TRD occurs in early onset mood disorders, it may underpin biological, clinical, and social correlates representing possible risk factors for this condition. The first point is that depression during youth may result from altered connectivity in brain regions, e.g., amygdala, involved in emotional-affective processing and regulation, during a period when they are still under development. This can result in aberrant responses to classical antidepressant treatments, even when administered for a long period of time. Genetics plays a key role in resistance to psychopharmacotherapy, as shown by previous studies on lithium response (73, 74). The main alleles involved in TRD include those encoding for steroid hormone receptors, e.g., FKBP5 (75) and for serotonin transporter (76). Being a fast metabolizer has also been associated with a reduced response to pharmacological treatment (77). Neurometabolic alterations, such as GTP cyclohydrolase deficiency, represent additional risk factors for TRD and were thus pointed out as potentially treatable causes of this condition (78, 79). Biological sex also seems to affect response to antidepressants, since girls present higher risk of experiencing recurrence and treatment resistance (80). Neurodevelopmental disorders, such as attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), represent additional risk factors for TRD in the young (81–84). This may be due to different reasons. First, the presence of untreated ADHD can reduce functioning, self-esteem, and treatment compliance, directly contributing to the development of depressive symptoms. In addition, the presence of ADHD is a risk factor for substance abuse, which further contributes to TRD. ADHD should thus be investigated in youths presenting with treatment-resistant mood disorders, since its clinical management can improve functioning, depressive symptoms, and treatment compliance, also reducing the risk for substance abuse. It was also reported that people with ASD are four times more likely to experience depression, especially in case of high functioning (85): however, autistic children and adolescents treated with selective serotonin reuptake inhibitors (SSRI) may have a higher risk of side effects, such as impulsive or irritable behavior and trouble sleeping (86). Other clinical factors that may contribute to the development of TRD are represented by overall greater illness severity during a depressive episode, high levels of anxiety, and suicidality (87–90). Psychiatric comorbidities, such as eating disorders and personality disorders, contribute to treatment resistance in youths who suffer from depression (36, 59). Moreover, adolescent depression is associated with a higher prevalence of substance-related disorders when compared to the general population (91), leading to increased disease severity and higher risk of TRD, especially in males (80, 92). The use of specific pharmacological agents and combinations, such as trazodone in association with fluoxetine, has been pointed out as a potential contributor to treatment resistance or symptom worsening in depressed young patients, but different confounding factors, e.g., pharmacokinetic interactions, make this findings anecdotical (93). Among comorbid medical conditions, early onset thyroid disorders may also cause depressive symptoms and contribute to TRD in the young (94). Finally, social factors including parental depression, early adversity or trauma, and belonging to a minority, have been identified as more prevalent in TRD young patients (95–99).
4 Treatment strategies in youth TRD
The issue of treating TRD in adolescents and young adults is challenging, due to different reasons. Indeed, no psychopharmacological treatment has specifically been approved for TRD in this population and no univocal guidelines have been reached yet. It should also be underlined that, despite some antidepressant drugs – e.g., SSRIs – are approved and considered as first-line treatments in youth depression, their use is controversial and data on their efficacy is limited. Previous literature highlighted that not only SSRIs, but also tricyclic antidepressants (TCA), present reduced effectiveness in the treatment of MDD in adolescents when compared to adult populations (100–105). Similarly, third-generation antidepressants, such as serotonin and noradrenaline reuptake inhibitors (SNRI) and mirtazapine, did not show higher efficacy when compared to placebo (101, 105). It should also be underlined that treatment indications for this age range should transcend general approaches. Indeed, there is huge variability in the clinical manifestations of depressive disorders among youths, which suggests that a precision psychiatry methodology should always be used and treatments should target symptom dimensions rather than diagnostic categories (106).
In case of non-response to the first antidepressant trial, and after considering all the factors that may impact treatment outcomes, e.g., physical and medical comorbidities (107), one possible strategy is switching to another antidepressant, usually another SSRI on a SNRI. These two treatment options showed similar response rates in previous studies (47% vs 48%, p=0.83), despite SNRIs and particularly venlafaxine presented greater effects on blood pressure and heart rates (33) In case of switching to another antidepressant, the long latency of action may represent a crucial limitation (108). As a consequence, combination and augmentation strategies are often chosen, especially in case of a partial response to the first prescribed treatment (36). As a result, adolescents with TRD frequently receive numerous psychotropic medications, including multiple drugs acting on monoaminergic systems, mood stabilizers, particularly lithium (36, 109), and atypical antipsychotics (80), but remission rates remain low and many experience adverse effects (110). The use of combination strategies in youth TRD may also present major issues in the long-term. Indeed, despite lithium appears to be a promising treatment in this population, also due to its effects in reducing self-harm and suicidality in adults (111), its clinical use in adolescents is limited by the narrow therapeutic window and by potential adverse effects, mainly those on kidney and thyroid function (36). Similarly, long-term use of second generation antipsychotics is burdened by the considerable risk of weight gain and metabolic syndrome (112), which limits their tolerability in this population.
Previous research also focused on non-pharmacological treatments, which could limit drug-related safety issues, with the strongest evidence supporting the use of cognitive behavioral therapy (CBT) in youth populations. Indeed, the efficacy of CBT has been demonstrated even in monotherapy, with evidence on its possible usefulness in relapse prevention (113, 114). As for the effectiveness of CBT as add-on treatment in TRD, it has been suggested that it should be added to psychotropic agents as early as possible, and possibly at least after one treatment failure, representing the gold standard in this population (115). On the other hand, there are also trials supporting poor response to combined CBT-antidepressant treatment, which suggests that the profile of young patients responding to psychotherapy for depressive episodes should be better characterized (116). Despite CBT being the approach with strongest literature evidence (33, 117, 118), interpersonal therapy (IPT) also demonstrated its efficacy in adolescents with TRD (119). The effectiveness of IPT for the treatment of depression arises from its focus on social and interpersonal stressors that may trigger depressive episodes and can be significantly impactful in youth populations. Due to encouraging results in adult depression, adolescent-focused IPT protocols were designed and showed to be effective (120), despite more comparative studies would be needed. Promising results were also reported for further approaches, e.g., short-term psychoanalytic psychotherapy (121), and it was thus suggested that youths failing to respond to one first trial should switch to another approach (36).
As for non-pharmacological treatments that specifically target TRD, preliminary evidence is available for physical therapies, such as transcranial magnetic stimulation (TMS), which demonstrated to be safe and tolerable in this population acting on both depressive and anxiety symptoms (122, 123). Similarly, data concerning ECT in youths is scant and its usage is limited. This may be due to restricted knowledge on the topic, caused by scantiness of clinical trials and legal restrictions in the implementation of this treatment (124, 125). Despite this, novel protocols tailored to this age group have been implemented with some positive results concerning efficacy and tolerability (90). Particularly, the use of ECT in youth populations suffering from TRD with suicidal ideation (126) or psychotic symptoms (127) appeared to be particularly effective, with response rates ranging from 50% to 90% depending on the considered report (124, 125, 128). One major issue for the use of physical therapies in adolescents and young adults could be related to possible impairment of cognitive performances, which represent one of the main domains impacting overall functioning in this population, but the tolerability profile appeared to be similar to those evidenced in adults (128).
On the basis of what stated above, the need for novel, tolerable, fast-acting antidepressants represents a crucial need in youth TRD. Several pathophysiological pathways appear to underlie TRD (129). Among the most studied mechanisms, a reduction in glutamate levels in prefrontal areas has been detected (130). This hypothesis has been supported by the antidepressant efficacy of ketamine and esketamine, modulating glutamatergic activity (131–133). At first approved as anesthetic drug in the 1970s, ketamine raised interest among the scientific community also due to its quick and long-lasting antidepressant activity (134–138). This pharmacological agent acts as a modulator of glutamatergic systems by N-methyl-D-aspartate (NMDA) antagonism (136). Other pathophysiological pathways targeted by treatment with ketamine include the modulation of prefrontal GABAergic neurons (132) and the stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (139, 140). These treatments lead to changes in neuroplasticity on mTOR/brain-derived neurotrophic factor (BDNF) signaling (141, 142). To note, the chronic use of ketamine is also associated with increase in blood neurotrophins, such as BDNF (143).
Despite clinical recommendations for TRD have been developed during the last decades (see, e.g (144), widely accepted guidelines have not been implemented yet. Anyway, increasing evidence is being provided for what concerns recently approved treatments for TRD, among which the main one is intranasal esketamine (145). Emerging evidence supports the use of ketamine and esketamine in youths with TRD. As already elucidated, several randomized studies demonstrated that ketamine infusion lead to significant reduction in depressive symptoms compared to placebo in TRD (138, 146–149). Recent evidence also showed that ketamine may act on suicidal ideation with rapid action and minimal side effects (131, 150–157). Since the use of SSRI in adolescents suffering from depression has been associated with increased suicidal risk (158), with a pooled relative risk of 1.28 (95% CI: 1.09–1.51) as detected by a recent meta-analytic study (159), the possible effect of ketamine on this dimension gains even higher importance. Another psychopathological domain on which antidepressants were demonstrated to exert low effectiveness in young populations is anhedonia (87), possibly representing another promising target of treatment with ketamine as demonstrated by previous reports on bipolar depression, demonstrating reductions of anhedonia levels at different times during the 14 days after the infusion, not depending on the effect on other depressive dimensions (160). Despite literature on the topic is still scant, recent studies showed encouraging results concerning the use of intravenous ketamine in youth populations. Indeed, a randomized controlled trial pointed out towards the efficacy of one single dose of intravenous ketamine, compared to active placebo (midazolam), in reducing depressive symptoms in adolescents who did not respond to previous treatments (161). During the 3 days following infusion, the prevalence of response to ketamine treatment was 76% (p=0.046) compared with 35% of responders in the active placebo group, with a mean difference in the Montgomery-Åsberg Depression Rating Scale (MADRS) of -8.69 ± 15.08 and an effect size of 0.78 (161, 162). Further data from open-label trials and case reports/case series also suggested that low-dose ketamine had a rapidly acting antidepressant effect in adolescents. In particular, an open label trial investigating the efficacy of six ketamine infusions (0.5 mg/kg) over two weeks on adolescent (12-18 years old) TRD demonstrated a reduction of 42.5% (p.<0.01) at the Children’s Depression Rating Scale - Revised (CDRS-R) (163, 164). Intravenous ketamine treatment appeared to be safe and well-tolerated in this population, with transitory dissociative and hemodynamic symptoms that resolved after few hours (161, 163, 165). The neural correlates of intravenous ketamine treatment in adolescent TRD may reside in the reduced activation of corticolimbic, corticostriatal, and default mode networks, which underpins an increase in hedonic capacity associated with reduced negativity bias and attitude towards positivity (166). To note, the use of ketamine would appear more appropriate among specific sub-populations of TRD patients, as confirmed by adult studies. Indeed, it has been suggested that the most appropriate use of ketamine would be as a short-term treatment in acute settings, especially in case of suicidal risk, which appears to decrease even before the improvements of depressive symptoms (167). Anyway, the latter were faster than those obtained with other antidepressant drugs, e.g., SSRIs (168). Moreover, studies conducted in adult populations elucidated that efficacy on specific domains, e.g., cognitive symptoms, was obtained only in TRD patients with anxious depression when compared to non-anxious ones (164). Similarly, it can be hypothesized that response to ketamine treatment in youths could depend on specific factors. Most evidence so far showed that response to ketamine in youth populations is associated with a shorter duration and lower severity of the current episode, treatment with SSRIs rather than SNRIs, and ADHD comorbidity (169).
Esketamine, the S-enantiomer of ketamine, was demonstrated to be a precious therapeutic option when combined with serotoninergic drugs in adult TRD (170) and was thus approved by regulatory agencies for the treatment of this condition (171–173). Due to its higher affinity for NMDA receptor and to its intranasal formulation, esketamine offers interesting therapeutic perspectives for outpatient use, and is thus the only treatment approved for TRD in European countries when combined with SSRIs or SNRIs (174). Previous reports showed promising results concerning the use of esketamine in adolescent populations. In a randomized-controlled trial, three intravenous infusions of esketamine (0.25 mg/kg) were associated with higher antidepressant and anti-suicidal effects according to greater reductions in the scoring of depression severity (MADRS total score mean changes: -15.3 ± 11.2 vs -8.8 ± 9.4, p=0.002) and suicide-related measures (Columbia Suicide Severity Rating Scale (CSSRS) ideation score mean changes: -2.6 ± 2 vs -1.7 ± 2.2, p=0.007; CSSRS intensity score mean changes: -10.6 ± 8.4 vs -5 ± 7.4, p=0.002) when compared to active placebo in adolescents aged 13-18 (175). In the esketamine treatment group, a significant improvement in some cognitive domains, particularly processing speed (drug main effect: F=6.607, p=0.013) was also observed, while no impairment of the other domains were reported (176). A double-blind, randomized, midazolam-controlled study of intranasal esketamine for adolescents with MDD at imminent risk of suicide showed that pooled esketamine doses (56 mg, 84 mg) were superior over midazolam in reducing CDRS-R at 24 hours after the initial dose (p=0.037), with relatively low incidence of serious adverse events (28 mg: 13.8%, 56 mg: 22.6%, 84 mg: 4.3%) that did not cause treatment discontinuation in any case (177). Further evidence coming from case report studies (178) confirmed that intranasal esketamine use in youth populations could be tolerable with minimum adverse reactions, despite its efficacy has not been proved yet (175, 176). As for possible issues related to the use of ketamine and esketamine in the long-term, it has been argued that vigilance for possible cognitive effects and the emergence of abuse is essential, despite preliminary data on adult population is encouraging (179). Current evidence for intravenous ketamine treatment in adolescent populations is based on preclinical studies. Despite most of these showed no later cognitive impairment and an overall good tolerability in the long-term with the administration of low-dose ketamine (180, 181), further data underlines a reduction of spatial working memory together with morphological and degenerative brain changes when administering higher doses to adolescent rats (182). This suggests that detrimental effects of ketamine on brain development may depend on the chronicity and dose of administration, but it should also be noted that clinical doses of this medication are significantly lower than those used in these experimental settings (183). As for esketamine, no long-term studies assessed its safety in adolescent populations. To note, encouraging results come from trials conducted in clinical settings evaluating long-term esketamine use in adults, which showed overall good tolerability, with no relevant incidence of serious adverse effects, including abuse (173, 184, 185).
To note, further treatments for TRD are being evaluated, such as psychedelics and cannabidiol, with promising results in adult populations but no preliminary evidence, including preclinical studies, in adolescents (108). Among classical psychedelics, psylocibin is being evaluated for the treatment of affective - and particularly depressive - disorders, with preliminary clinical evidence in adult populations (186). Based on animal models, the antidepressant efficacy of this compound may rely on its effect on 5HT-2A receptors, possibly increasing serotonin and glutamate levels and modulating the excitability of pyramidal neurons and synaptic plasticity processes (187). As for cannabidiol, its possible usefulness in the improvement of affective and stress-induced symptoms has been widely proved by preclinical studies, despite its efficacy may vary on the basis of different biological determinants, e.g., sex (188, 189). Preclinical evidence is also available for the use of the compound in adolescence, confirming its effectiveness at lower doses than those needed in adulthood (190). Contrasting results on cannabidiol length of action in adolescent rodents were provided, suggesting that the fast-acting antidepressant action may not be sustained over time (190, 191), but these data require further validation. Since evidence for novel antidepressant strategies has not been confirmed by clinical studies on adolescent populations and preclinical data is still scant, no conclusions can be drawn on possible uses of these molecules in youths so far.
Despite some novel agents, particularly ketamine and esketamine, have demonstrated to be rapid and effective treatments, it is crucial to correctly assess the risk-benefit ratio for each subject, to make informed decisions about treatment appropriateness, especially in vulnerable populations. Indeed, together with the already-cited dissociative symptoms, further side effects, such as alterations in blood pressure levels and the risk of developing addiction, should be considered. Moreover, not all subjects with TRD respond positively to this treatment: severity of depression, comorbidities, and previous treatment history should be considered in order to select individuals that are most likely to benefit from the treatment (192). Is should also be noticed that the long-term impact of these drugs on young people’s physical, cognitive, and emotional development has not been fully studied yet (193). Further research is thus needed in order to consider these aspects, together with legal and ethical issues that safeguard the well-being of young subjects with TRD (194). Providing psychiatric care to young people, and particularly minors, rises a series of ethical and legal concerns that fully reflect the dynamism of this field, always facing new challenges related to broader changes at societal level. One major issue is the capacity of providing informed consent to treatments, which remains controversial. In case of minors, parents have the power to guide treatment choices, expressing their preference and eventually outweighing children’s willingness to undergo specific therapies (195). On the other hand, there are specific jurisdictions that consider the possibility of adolescents with a clear understanding of their condition expressing their informed consent, as well as emancipation following marriage or economic independence (196). Prescribing principles are similar for adult and adolescent populations and are based on beneficence and nonmaleficence, since clinicians should always evaluate the best treatment choice for their patients and avoid short- and long-term harmful effects (197). To note, most prescriptions in adolescent populations may come from psychiatrists working with adults and not receiving specific training. In this context, prescription of specific pharmacological agents, e.g., antidepressants, may result in further criticalities, being burdened by warnings due to possible adverse effects and issues like worsening of depression and the emergence of suicidal ideation. This may be particularly relevant in case of new pharmacological strategies that have not been studied in depth in youth, and particularly adolescent, populations, due to scant knowledge concerning their possible effects on rapidly developing brains. Apart from the already-elucidated possible effects on cognitive function and the development of structural and functional alterations in the central nervous system (198), it should also be noted that depressive symptoms in youths could underpin the later emergence of further conditions, such as schizophrenia-spectrum disorders (178). In this case, the use of ketamine and esketamine should be cautious due to the potential influence on the development of psychosis (199).
Several challenges need to be addressed to ensure adequate treatment for youth populations suffering from TRD, as well as appropriate and safe usage of new pharmacological agents in these patients. Indeed, current literature on the topic of youth TRD lacks a precision approach in the identification of this major health problem, since a univocal definition has not yet been provided and symptom domains that could more clearly characterize the clinical picture have not been examined in depth. Addressing these issues would help a more accurate selection of patients included in clinical trials, helping to establish treatment efficacy and safety of novel pharmacological agents. Studies on fast-acting antidepressants in youths with TRD are scant and are based on small sample sizes, not always following a randomized-controlled design, which limits the generalizability of their findings. This is also a major issue that contributed to the narrative approach of this review, since the possibility of a quantitative and meta-analytic synthesis of the study results was lacking. Despite this, we believe that the promising results obtained by preclinical and clinical studies warrant further investigation. Moreover, we should underline that differential diagnosis, risk assessment, patient selection, long-term monitoring, and ethical concerns are crucial elements to consider even since the diagnostic process and should contribute to treatment choices in youth TRD. A multidisciplinary approach is important for optimizing the usage of ketamine and esketamine in youth populations, and safeguard the well-being of subjects during and after the treatment process, also considering that integrated treatments are expected to be proposed since very early illness stages in order to reduce the overall impact of youth psychopathology on overall well-being (200, 201).
5 Conclusions
Resistance to treatment during a major depressive episode remains a relevant challenge in youth populations, with different possible correlates including an unrecognized bipolar diathesis. The lack a of a univocal definition of this condition suggests that future research on the topic is needed in order to better clarify its clinical correlates. Further characterization of this condition is strongly needed also in order to optimize treatment strategies in a precision psychiatric perspective that goes beyond traditional nosographic descriptions. Moreover, treatments suggested for youth treatment-resistant depression are not population-specific and the current clinical practice advocates the use of strategies that follow those adopted in adults. Despite this, the use of traditional antidepressant agents in adolescents and young adults is burdened by effectiveness and safety concerns. Further research on integrated treatment strategies should clarify the role of non-pharmacological interventions in this population, also considering new psychotherapeutic approaches and psychosocial treatments. Results from this narrative review also suggest that fast-acting antidepressants are promising in this population and appear to be well-tolerated and effective. Despite this, the scantness of clinical studies, the limitations posed by ethical and legal issues, together with the lack of long-term safety and effectiveness data, advises that further research on the topic would be needed. Future studies are thus expected to provide further evidence concerning this population, where risk-benefit ratio should always be taken into account when addressing treatment choices.
Author contributions
GM: Conceptualization, Writing – review & editing. GCi: Writing – original draft. FS: Writing – original draft. MC: Writing – original draft. GCa: Writing – original draft. PB: Writing – review & editing. FDG: Writing – review & editing. PM: Writing – review & editing. AT: Supervision, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
2. Luppa M, Sikorski C, Luck T, Ehreke L, Konnopka A, Wiese B, et al. Age- and gender-specific prevalence of depression in latest-life–systematic review and meta-analysis. J Affect Disord. (2012) 136:212–21. doi: 10.1016/j.jad.2010.11.033
3. Salk RH, Hyde JS, Abramson LY. Gender differences in depression in representative national samples: Meta-analyses of diagnoses and symptoms. Psychol Bull. (2017) 143:783–822. doi: 10.1037/bul0000102
4. Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J Child Psychol Psychiatry. (2015) 56:345–65. doi: 10.1111/jcpp.12381
5. Sacco R, Camilleri N, Eberhardt J, Umla-Runge K, Newbury-Birch D. A systematic review and meta-analysis on the prevalence of mental disorders among children and adolescents in Europe. Eur Child Adolesc Psychiatry. (2022) 1:1–18. doi: 10.1007/S00787-022-02131-2/METRICS
6. Williams SB, O’Connor EA, Eder M, Whitlock EP. Screening for child and adolescent depression in primary care settings: a systematic evidence review for the US Preventive Services Task Force. Pediatrics. (2009) 123:e716-35. doi: 10.1542/peds.2008-2415
7. Avenevoli S, Swendsen J, He JP, Burstein M, Merikangas KR. Major depression in the national comorbidity survey-adolescent supplement: prevalence, correlates, and treatment. J Am Acad Child Adolesc Psychiatry. (2015) 54:37–44.e2. doi: 10.1016/j.jaac.2014.10.010
8. Walter HJ, Abright AR, Bukstein OG, Diamond J, Keable H, Ripperger-Suhler J, et al. Clinical practice guideline for the assessment and treatment of children and adolescents with major and persistent depressive disorders. J Am Acad Child Adolesc Psychiatry. (2023) 62:479–502. doi: 10.1016/j.jaac.2022.10.001
9. Racine N, McArthur BA, Cooke JE, Eirich R, Zhu J, Madigan S. Global prevalence of depressive and anxiety symptoms in children and adolescents during COVID-19: A meta-analysis. JAMA Pediatr. (2021) 175:1142–50. doi: 10.1001/jamapediatrics.2021.2482
10. Khalfan AF, Campisi SC, Lo RF, McCrindle BW, Korczak DJ. The association between adolescent depression and dyslipidemia. J Affect Disord. (2023) 338:239–45. doi: 10.1016/j.jad.2023.06.017
11. Keyes KM, Platt JM. Annual Research Review: Sex, gender, and internalizing conditions among adolescents in the 21st century - trends, causes, consequences. J Child Psychol Psychiatry. (2024) 65:384–407. doi: 10.1111/jcpp.13864
12. Rice F, Riglin L, Lomax T, Souter E, Potter R, Smith DJ, et al. Adolescent and adult differences in major depression symptom profiles. J Affect Disord. (2019) 243:175–81. doi: 10.1016/j.jad.2018.09.015
13. Weavers B, Heron J, Thapar AK, Stephens A, Lennon J, Bevan Jones R, et al. The antecedents and outcomes of persistent and remitting adolescent depressive symptom trajectories: a longitudinal, population-based English study. Lancet Psychiatry. (2021) 8:1053–61. doi: 10.1016/S2215-0366(21)00281-9
14. Fergusson DM, Woodward LJ. Mental health, educational, and social role outcomes of adolescents with depression. Arch Gen Psychiatry. (2002) 59:225–31. doi: 10.1001/archpsyc.59.3.225
15. Centers for disease control and prevention. Deaths, Percent of Total Deaths, and Death Rates for the 15 Leading Causes of Death in 5-Year Age Groups, by Race and Sex: United States, 1999–2015. Hyattsville (U.S (2017).
16. Farabaugh A, Bitran S, Nyer M, Holt DJ, Pedrelli P, Shyu I, et al. Depression and suicidal ideation in college students. Psychopathology. (2012) 45:228–34. doi: 10.1159/000331598
17. Dunn V, Goodyer IM. Longitudinal investigation into childhood- and adolescence-onset depression: psychiatric outcome in early adulthood. Br J Psychiatry. (2006) 188:216–22. doi: 10.1192/bjp.188.3.216
18. Rybak YE, Lai KSP, Ramasubbu R, Vila-Rodriguez F, Blumberger DM, Chan P, et al. Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment. Depress Anxiety. (2021) 38:456–67. doi: 10.1002/da.23135
19. McLachlan G. Treatment resistant depression: what are the options? BMJ. (2018) 363:k5354. doi: 10.1136/bmj.k5354
20. Zhdanava M, Pilon D, Ghelerter I, Chow W, Joshi K, Lefebvre P, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry. (2021) 82:20m13699. doi: 10.4088/JCP.20m13699
21. McIntyre RS, Alsuwaidan M, Baune BT, Berk M, Demyttenaere K, Goldberg JF, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. (2023) 22:394–412. doi: 10.1002/wps.21120
22. Bartova L, Dold M, Kautzky A, Fabbri C, Spies M, Serretti A, et al. Results of the European Group for the Study of Resistant Depression (GSRD) - basis for further research and clinical practice. World J Biol Psychiatry. (2019) 20:427–48. doi: 10.1080/15622975.2019.1635270
23. Gaynes BN, Lux L, Gartlehner G, Asher G, Forman-Hoffman V, Green J, et al. Defining treatment-resistant depression. Depress Anxiety. (2020) 37:134–45. doi: 10.1002/da.22968
24. Ng CH, Kato T, Han C, Wang G, Trivedi M, Ramesh V, et al. Definition of treatment-resistant depression - Asia Pacific perspectives. J Affect Disord. (2019) 245:626–36. doi: 10.1016/j.jad.2018.11.038
25. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. (2006) 163:28–40. doi: 10.1176/appi.ajp.163.1.28
26. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. (2006) 163:1905–17. doi: 10.1176/ajp.2006.163.11.1905
27. Vitiello B, Emslie G, Clarke G, Wagner KD, Asarnow JR, Keller MB, et al. Long-term outcome of adolescent depression initially resistant to selective serotonin reuptake inhibitor treatment: a follow-up study of the TORDIA sample. J Clin Psychiatry. (2011) 72:388–96. doi: 10.4088/JCP.09m05885blu
28. Berlim MT, Fleck MP, Turecki G. Current trends in the assessment and somatic treatment of resistant/refractory major depression: an overview. Ann Med. (2008) 40:149–59. doi: 10.1080/07853890701769728
29. McAllister-Williams RH, Christmas DMB, Cleare AJ, Currie A, Gledhill J, Insole L, et al. Multiple-therapy-resistant major depressive disorder: a clinically important concept. Br J Psychiatry. (2018) 212:274–8. doi: 10.1192/bjp.2017.33
30. De Carlo V, Calati R, Serretti A. Socio-demographic and clinical predictors of non-response/non-remission in treatment resistant depressed patients: A systematic review. Psychiatry Res. (2016) 240:421–30. doi: 10.1016/j.psychres.2016.04.034
31. Kautzky A, Dold M, Bartova L, Spies M, Kranz GS, Souery D, et al. Clinical factors predicting treatment resistant depression: affirmative results from the European multicenter study. Acta Psychiatr Scand. (2019) 139:78–88. doi: 10.1111/acps.12959
32. Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry. (2005) 62:629–40. doi: 10.1001/archpsyc.62.6.629
33. Brent D, Emslie G, Clarke G, Wagner KD, Asarnow JR, Keller M, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA. (2008) 299:901–13. doi: 10.1001/jama.299.8.901
34. Strawn JR, Aaronson ST, Elmaadawi AZ, Schrodt GR, Holbert RC, Verdoliva S, et al. Treatment-resistant depression in adolescents: clinical features and measurement of treatment resistance. J Child Adolesc Psychopharmacol. (2020) 30:261–6. doi: 10.1089/cap.2020.0008
35. Ayvaci ER, Croarkin PE. Special populations: treatment-resistant depression in children and adolescents. Psychiatr Clin North Am. (2023) 46:359–70. doi: 10.1016/j.psc.2023.02.007
36. Dwyer JB, Stringaris A, Brent DA, Bloch MH. Annual Research Review: Defining and treating pediatric treatment-resistant depression. J Child Psychol Psychiatry. (2020) 61:312–32. doi: 10.1111/jcpp.13202
37. Birmaher B, Brent D, Bernet W, Bukstein O, Walter H, Benson R, et al. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. (2007) 46:1503–26. doi: 10.1097/chi.0b013e318145ae1c
38. Hughes CW, Emslie GJ, Crismon ML, Posner K, Birmaher B, Ryan N, et al. Texas children’s medication algorithm project: update from Texas consensus conference panel on medication treatment of childhood major depressive disorder. J Am Acad Child Adolesc Psychiatry. (2007) 46:667–86. doi: 10.1097/chi.0b013e31804a859b
39. Korczak DJ, WestwellRoper C, Sassi R. Diagnosis and management of depression in adolescents. CMAJ : Can Med Assoc J. (2023) 195:E739. doi: 10.1503/cmaj.220966
40. National Institute for Health Care and Excellence. Depression in children and young people: Identification and management. NICE guidelines. (2019).
41. March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. (2004) 292:807–20. doi: 10.1001/jama.292.7.807
42. Kennard BD, Silva SG, Tonev S, Rohde P, Hughes JL, Vitiello B, et al. Remission and recovery in the Treatment for Adolescents with Depression Study (TADS): acute and long-term outcomes. J Am Acad Child Adolesc Psychiatry. (2009) 48:186–95. doi: 10.1097/CHI.0b013e31819176f9
43. Wilkinson P, Izmeth Z. Continuation and maintenance treatments for depression in older people. Cochrane Database Syst Rev. (2016) 9:CD006727. doi: 10.1002/14651858.CD006727.PUB3
44. Cuijpers P, Smit F. Excess mortality in depression: A meta-analysis of community studies. J Affect Disord. (2002) 72:227–36. doi: 10.1016/S0165-0327(01)00413-X
45. van der Weele GM, Gussekloo J, de Waal MWM, de Craen AJM, van der Mast RC. Co-occurrence of depression and anxiety in elderly subjects aged 90 years and its relationship with functional status, quality of life and mortality. Int J Geriatr Psychiatry. (2009) 24:595–601. doi: 10.1002/gps.2162
46. Feng L, Yap KB, Ng TP. Depressive symptoms in older adults with chronic kidney disease: mortality, quality of life outcomes, and correlates. Am J Geriatr Psychiatry. (2013) 21:570–9. doi: 10.1016/j.jagp.2012.12.020
47. Bjørkløf GH, Engedal K, Selbæk G, Kouwenhoven SE, Helvik AS. Coping and depression in old age: a literature review. Dement Geriatr Cognit Disord. (2013) 35:121–54. doi: 10.1159/000346633
48. Walker J, Holm Hansen C, Martin P, Sawhney A, Thekkumpurath P, Beale C, et al. Prevalence of depression in adults with cancer: a systematic review. Ann Oncol. (2013) 24:895–900. doi: 10.1093/annonc/mds575
49. Ho CS, Feng L, Fam J, Mahendran R, Kua EH, Ng TP. Coexisting medical comorbidity and depression: multiplicative effects on health outcomes in older adults. Int Psychogeriatr. (2014) 26:1221–9. doi: 10.1017/S1041610214000611
50. Jaffe DH, Rive B, Denee TR. The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry. (2019) 19:247. doi: 10.1186/s12888-019-2222-4
51. Olfson M, Amos TB, Benson C, McRae J, Marcus SC. Prospective service use and health care costs of medicaid beneficiaries with treatment-resistant depression. J Manag Care Spec Pharm. (2018) 24:226–36. doi: 10.18553/jmcp.2018.24.3.226
52. Mrazek DA, Hornberger JC, Altar CA, Degtiar I. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv. (2014) 65:977–87. doi: 10.1176/appi.ps.201300059
53. Souery D, Oswald P, Massat I, Bailer U, Bollen J, Demyttenaere K, et al. Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J Clin Psychiatry. (2007) 68:1062–70. doi: 10.4088/JCP.v68n0713
54. Halaris A, Sohl E, Whitham EA. Treatment-resistant depression revisited: A glimmer of hope. J Pers Med. (2021) 11:1–28. doi: 10.3390/jpm11020155
55. Caraci F, Calabrese F, Molteni R, Bartova L, Dold M, Leggio GM, et al. International union of basic and clinical pharmacology CIV: the neurobiology of treatment-resistant depression: from antidepressant classifications to novel pharmacological targets. Pharmacol Rev. (2018) 70:475–504. doi: 10.1124/pr.117.014977
56. Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep. (2007) 9:449–59. doi: 10.1007/s11920-007-0061-3
57. Spielmans GI, Gerwig K. The efficacy of antidepressants on overall well-being and self-reported depression symptom severity in youth: a meta-analysis. Psychother Psychosom. (2014) 83:158–64. doi: 10.1159/000356191
58. Blom EH, Forsman M, Yang TT, Serlachius E, Larsson J-O. Latent classes of symptoms related to clinically depressed mood in adolescents. Scand J Child Adolesc Psychiatr Psychol. (2014) 2:19–28. doi: 10.21307/sjcapp-2014-004
59. Nardi B, Francesconi G, Dell’Osso MC, Bellantuono C. Adolescent depression: clinical features and therapeutic strategies. Eur Rev Med Pharmacol Sci. (2013) 17:1546–51.
60. Warren BJ. The synergistic influence of life experiences and cultural nuances on development of depression: A cognitive behavioral perspective. Issues Ment Health Nurs. (2020) 41:3–6. doi: 10.1080/01612840.2019.1675828
61. Hong JS, Peguero AA, Espelage DL. Experiences in bullying and/or peer victimization of vulnerable, marginalized, and oppressed children and adolescents: An introduction to the special issue. Am J Orthopsy. (2018) 88:399–401. doi: 10.1037/ort0000330
62. Lachal J, Moro MR, Carretier E, Simon A, Barry C, Falissard B, et al. Assessment of transcultural psychotherapy to treat resistant major depressive disorder in children and adolescents from migrant families: Protocol for a randomized controlled trial using mixed method and Bayesian approaches. Int J Methods Psychiatr Res. (2020) 29:1–10. doi: 10.1002/mpr.1847
63. Stewart SM, Simmons A, Habibpour E. Treatment of culturally diverse children and adolescents with depression. J Child Adolesc Psychopharmacol. (2012) 22:72–9. doi: 10.1089/cap.2011.0051
64. de Haan AM, Boon AE, de Jong JTVM, Vermeiren RRJM. A review of mental health treatment dropout by ethnic minority youth. Transcult Psychiatry. (2018) 55:3–30. doi: 10.1177/1363461517731702
65. Angst J, Sellaro R, Stassen HH, Gamma A. Diagnostic conversion from depression to bipolar disorders: Results of a long-term prospective study of hospital admissions. J Affect Disord. (2005) 84:149–57. doi: 10.1016/S0165-0327(03)00195-2
66. Barbuti M, Menculini G, Verdolini N, Pacchiarotti I, Kotzalidis GD, Tortorella A, et al. A systematic review of manic/hypomanic and depressive switches in patients with bipolar disorder in naturalistic settings: The role of antidepressant and antipsychotic drugs. Eur Neuropsychopharmacol. (2023) 73:1–15. doi: 10.1016/j.euroneuro.2023.04.013
67. Perugi G, Pacchiarotti I, Mainardi C, Verdolini N, Menculini G, Barbuti M, et al. Patterns of response to antidepressants in major depressive disorder: Drug resistance or worsening of depression are associated with a bipolar diathesis. Eur Neuropsychopharmacol. (2019) 29:825–34. doi: 10.1016/j.euroneuro.2019.06.001
68. Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H, Licht RW, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. (2013) 170:1249–62. doi: 10.1176/appi.ajp.2013.13020185
69. Bechdolf A, Ratheesh A, Cotton SM, Nelson B, Chanen AM, Betts J, et al. The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: a prospective study. Bipolar Disord. (2014) 16:493–504. doi: 10.1111/bdi.12205
70. Tondo L, Visioli C, Preti A, Baldessarini RJ. Bipolar disorders following initial depression: modeling predictive clinical factors. J Affect Disord. (2014) 167:44–9. doi: 10.1016/j.jad.2014.05.043
71. Vöhringer PA, Perlis RH. Discriminating between bipolar disorder and major depressive disorder. Psychiatr Clinics North America. (2016) 39:1–10. doi: 10.1016/j.psc.2015.10.001
72. Barbuti M, Mainardi C, Pacchiarotti I, Verdolini N, Maccariello G, Angst J, et al. The role of different patterns of psychomotor symptoms in major depressive episode: Pooled analysis of the BRIDGE and BRIDGE-II-MIX cohorts. Bipolar Disord. (2019) 21(8):785–793. doi: 10.1111/bdi.12816
73. Yee CS, Hawken ER, Baldessarini RJ, Vázquez GH. Maintenance pharmacological treatment of juvenile bipolar disorder: review and meta-analyses. Int J Neuropsychopharmacol. (2019) 22:531–40. doi: 10.1093/ijnp/pyz034
74. Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, et al. Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study. Lancet. (2016) 387:1085–93. doi: 10.1016/S0140-6736(16)00143-4
75. Brent D, Melhem N, Ferrell R, Emslie G, Wagner KD, Ryan N, et al. Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study. Am J Psychiatry. (2010) 167:190–7. doi: 10.1176/appi.ajp.2009.09040576
76. Kronenberg S, Apter A, Brent D, Schirman S, Melhem N, Pick N, et al. Serotonin transporter polymorphism (5-HTTLPR) and citalopram effectiveness and side effects in children with depression and/or anxiety disorders. J Child Adolesc Psychopharmacol. (2007) 17:741–50. doi: 10.1089/cap.2006.0144
77. Axelson DA, Perel JM, Birmaher B, Rudolph GR, Nuss S, Bridge J, et al. Sertraline pharmacokinetics and dynamics in adolescents. J Am Acad Child Adolesc Psychiatry. (2002) 41:1037–44. doi: 10.1097/00004583-200209000-00003
78. Pan L, McKain BW, Madan-Khetarpal S, Mcguire M, Diler RS, Perel JM, et al. GTP-cyclohydrolase deficiency responsive to sapropterin and 5-HTP supplementation: relief of treatment-refractory depression and suicidal behavior. BMJ Case Rep. (2011) 2011:bcr0320113927. doi: 10.1136/bcr.03.2011.3927
79. Pan LA, Martin P, Zimmer T, Segreti AM, Kassiff S, McKain BW, et al. Neurometabolic disorders: potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior. Am J Psychiatry. (2017) 174:42–50. doi: 10.1176/appi.ajp.2016.15111500
80. Emslie GJ, Mayes T, Porta G, Vitiello B, Clarke G, Wagner KD, et al. Treatment of Resistant Depression in Adolescents (TORDIA): week 24 outcomes. Am J Psychiatry. (2010) 167:782–91. doi: 10.1176/appi.ajp.2010.09040552
81. Chen MH, Pan TL, Hsu JW, Huang KL, Su TP, Li CT, et al. Attention-deficit hyperactivity disorder comorbidity and antidepressant resistance among patients with major depression: A nationwide longitudinal study. Eur Neuropsychopharmacol. (2016) 26:1760–7. doi: 10.1016/j.euroneuro.2016.09.369
82. White MJ. Treatment-resistant depression: consider autism. Br J Gen Pract. (2019) 69:14. doi: 10.3399/bjgp19X700373
83. Joshi G, Petty C, Wozniak J, Henin A, Fried R, Galdo M, et al. The heavy burden of psychiatric comorbidity in youth with autism spectrum disorders: a large comparative study of a psychiatrically referred population. J Autism Dev Disord. (2010) 40:1361–70. doi: 10.1007/s10803-010-0996-9
84. Maalouf FT, Atwi M, Brent DA. Treatment-resistant depression in adolescents: review and updates on clinical management. Depress Anxiety. (2011) 28:946–54. doi: 10.1002/da.v28.11
85. Defilippis M. Depression in children and adolescents with autism spectrum disorder. Children (Basel). (2018) 5:112. doi: 10.3390/children5090112
86. Walkup J, Labellarte M. Complications of SSRI treatment. J Child Adolesc Psychopharmacol. (2001) 11:1–4. doi: 10.1089/104454601750143320
87. McMakin DL, Olino TM, Porta G, Dietz LJ, Emslie G, Clarke G, et al. Anhedonia predicts poorer recovery among youth with selective serotonin reuptake inhibitor treatment-resistant depression. J Am Acad Child Adolesc Psychiatry. (2012) 51:404–11. doi: 10.1016/j.jaac.2012.01.011
88. Maalouf FT, Porta G, Vitiello B, Emslie G, Mayes T, Clarke G, et al. Do sub-syndromal manic symptoms influence outcome in treatment resistant depression in adolescents? A latent class analysis from the TORDIA study. J Affect Disord. (2012) 138:86–95. doi: 10.1016/j.jad.2011.12.021
89. Strawn JR, Dobson ET, Giles LL. Primary pediatric care psychopharmacology: focus on medications for ADHD, depression, and anxiety. Curr Probl Pediatr Adolesc Health Care. (2017) 47:3–14. doi: 10.1016/j.cppeds.2016.11.008
91. Harmanci D, Edelman N, Richardson D, Lunt A, Llewellyn C. How are young people’s mental health related to their sexual health and substance use? A systematic review of UK literature. Int J Adolesc Med Health. (2023) 35:131–58. doi: 10.1515/ijamh-2022-0090
92. Carton L, Pignon B, Baguet A, Benradia I, Roelandt JL, Vaiva G, et al. Influence of comorbid alcohol use disorders on the clinical patterns of major depressive disorder: A general population-based study. Drug Alcohol Depend. (2018) 187:40–7. doi: 10.1016/j.drugalcdep.2018.02.009
93. Shamseddeen W, Clarke G, Keller MB, Wagner KD, Birmaher B, Emslie GJ, et al. Adjunctive sleep medications and depression outcome in the treatment of serotonin-selective reuptake inhibitor resistant depression in adolescents study. J Child Adolesc Psychopharmacol. (2012) 22:29–36. doi: 10.1089/cap.2011.0027
94. Joffe RT. Refractory depression: Treatment strategies, with particular reference to the thyroid axis. J Psychiatry Neurosci. (1997) 22:327–31.
95. Shamseddeen W, Asarnow JR, Clarke G, Vitiello B, Wagner KD, Birmaher B, et al. Impact of physical and sexual abuse on treatment response in the Treatment of Resistant Depression in Adolescent Study (TORDIA). J Am Acad Child Adolesc Psychiatry. (2011) 50:293–301. doi: 10.1016/j.jaac.2010.11.019
96. Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. Am J Psychiatry. (2012) 169:141–51. doi: 10.1176/appi.ajp.2011.11020335
97. Rengasamy M, Mansoor BM, Hilton R, Porta G, He J, Emslie GJ, et al. The bi-directional relationship between parent-child conflict and treatment outcome in treatment-resistant adolescent depression. J Am Acad Child Adolesc Psychiatry. (2013) 52:370–7. doi: 10.1016/j.jaac.2013.01.012
98. Swartz HA, Cyranowski JM, Cheng Y, Zuckoff A, Brent DA, Markowitz JC, et al. Brief psychotherapy for maternal depression: impact on mothers and children. J Am Acad Child Adolesc Psychiatry. (2016) 55:495–503.e2. doi: 10.1016/j.jaac.2016.04.003
99. Russell ST, Fish JN. Mental health in lesbian, gay, bisexual, and transgender (LGBT) youth. Annu Rev Clin Psychol. (2016) 12:465–87. doi: 10.1146/annurev-clinpsy-021815-093153
100. Hazell P, O’connell D, Heathcote D, Robertson J, Henry D. Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis. BMJ. (1995) 310:897. doi: 10.1136/bmj.310.6984.897
101. Thapar A, Collishaw S, Pine DS, Thapar AK. Depression in adolescence. Lancet. (2012) 379:1056–67. doi: 10.1016/S0140-6736(11)60871-4
102. Hazell P, Mirzaie M. Tricyclic drugs for depression in children and adolescents. Cochrane Database Syst Rev. (2013) 2013:CD002317. doi: 10.1002/14651858.CD002317.PUB2
103. Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B, Whittington C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet. (2016) 388:881–90. doi: 10.1016/S0140-6736(16)30385-3
104. Garland EJ, Kutcher S, Virani A, Elbe D. Update on the use of SSRIS and SNRIS with children and adolescents in clinical practice. J Can Acad Child Adolesc Psychiatry. (2015) 25:4–10.
105. Locher C, Koechlin H, Zion SR, Werner C, Pine DS, Kirsch I, et al. Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: A systematic review and meta-analysis. JAMA Psychiatry. (2017) 74:1011–20. doi: 10.1001/jamapsychiatry.2017.2432
106. Janiaud P, Cornu C, Lajoinie A, Djemli A, Cucherat M, Kassai B. Is the perceived placebo effect comparable between adults and children? A meta-regression analysis. Pediatr Res. (2017) 81:11–7. doi: 10.1038/pr.2016.181
107. DeFilippis M, Wagner KD. Management of treatment-resistant depression in children and adolescents. Paediatr Drugs. (2014) 16:353–61. doi: 10.1007/s40272-014-0088-y
108. Ledesma-Corvi S, Jornet-Plaza J, Gálvez-Melero L, García-Fuster MJ. Novel rapid treatment options for adolescent depression. Pharmacol Res. (2024) 201:107085. doi: 10.1016/j.phrs.2024.107085
109. Voineskos AN, Mulsant BH, Dickie EW, Neufeld NH, Rothschild AJ, Whyte EM, et al. Effects of antipsychotic medication on brain structure in patients with major depressive disorder and psychotic features: neuroimaging findings in the context of a randomized placebo-controlled clinical trial. JAMA Psychiatry. (2020) 77:674–83. doi: 10.1001/jamapsychiatry.2020.0036
110. Hayden JD, Horter L, Parsons T, Ruble M, Townsend S, Klein CC, et al. Metabolic monitoring rates of youth treated with second-generation antipsychotics in usual care: results of a large US national commercial health plan. J Child Adolesc Psychopharmacol. (2020) 30:119–22. doi: 10.1089/cap.2019.0087
111. Smith KA, Cipriani A. Lithium and suicide in mood disorders: Updated meta-review of the scientific literature. Bipolar Disord. (2017) 19:575–86. doi: 10.1111/bdi.12543
112. Stafford MR, Mayo-Wilson E, Loucas CE, James A, Hollis C, Birchwood M, et al. Efficacy and safety of pharmacological and psychological interventions for the treatment of psychosis and schizophrenia in children, adolescents and young adults: a systematic review and meta-analysis. PloS One. (2015) 10:e0117166. doi: 10.1371/journal.pone.0117166
113. March JS, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, et al. The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety outcomes. Arch Gen Psychiatry. (2007) 64:1132–44. doi: 10.1001/archpsyc.64.10.1132
114. Emslie GJ, Kennard BD, Mayes TL, Nakonezny PA, Moore J, Jones JM, et al. Continued effectiveness of relapse prevention cognitive-behavioral therapy following fluoxetine treatment in youth with major depressive disorder. J Am Acad Child Adolesc Psychiatry. (2015) 54:991–8. doi: 10.1016/j.jaac.2015.09.014
115. Suresh V, Mills JA, Croarkin PE, Strawn JR. What next? A Bayesian hierarchical modeling re-examination of treatments for adolescents with selective serotonin reuptake inhibitor-resistant depression. Depress Anxiety. (2020) 37:926–34. doi: 10.1002/da.23064
116. Curry J, Rohde P, Simons A, Silva S, Vitiello B, Kratochvil C, et al. Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. (2006) 45:1427–39. doi: 10.1097/01.chi.0000240838.78984.e2
117. Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al. A randomised controlled trial of cognitive behavior therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. ADAPT trial. Health Technol Assess. (2008) 12:iii–iv, ix–60. doi: 10.3310/hta12140
118. Glass RM. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. J Pediatr. (2005) 146:145. doi: 10.1016/j.jpeds.2004.10.032
119. Weersing VR, Jeffreys M, Do MCT, Schwartz KTG, Bolano C. Evidence base update of psychosocial treatments for child and adolescent depression. J Clin Child Adolesc Psychol. (2017) 46:11–43. doi: 10.1080/15374416.2016.1220310
120. Mufson L, Sills R. Interpersonal Psychotherapy for depressed adolescents (IPT-A): an overview. Nord J Psychiatry. (2006) 60:431–7. doi: 10.1080/08039480601022397
121. Goodyer IM, Reynolds S, Barrett B, Byford S, Dubicka B, Hill J, et al. Cognitive behavioral therapy and short-term psychoanalytical psychotherapy versus a brief psychosocial intervention in adolescents with unipolar major depressive disorder (IMPACT): a multicentre, pragmatic, observer-blind, randomised controlled superiority trial. Lancet Psychiatry. (2017) 4:109–19. doi: 10.1016/S2215-0366(16)30378-9
122. Croarkin PE, Zuckerman S, Middleton VJ, Monira N, Kriske J, Bowman J, et al. Clinical outcomes in adolescents undergoing sequential bilateral 1 Hz/20 Hz transcranial magnetic stimulation for treatment resistant depression. Brain Stimul. (2024) 17:431–3. doi: 10.1016/j.brs.2024.03.018
123. Thai M, Nair AU, Klimes-Dougan B, Albott S, Silamongkol T, Corkrum M, et al. Deep transcranial magnetic stimulation for adolescents with treatment-resistant depression: A preliminary dose-finding study exploring safety and clinical effectiveness. J Affect Disord. (2024) 354:589–600. doi: 10.1016/j.jad.2024.03.061
124. Karayağmurlu A, Coşkun M, Elboğa G, Ghaziuddin N, Karayağmurlu E, Gökçen C, et al. Efficacy and safety of electroconvulsive therapy in adolescents: A retrospective chart review study from Turkey. J ECT. (2020) 36:54–9. doi: 10.1097/YCT.0000000000000602
125. Freeman B. Pathway to electroconvulsive treatment for minors. Child Adolesc Psychiatr Clin N Am. (2019) 28:1–19. doi: 10.1016/j.chc.2018.07.001
126. Weiner RD, Reti IM. Key updates in the clinical application of electroconvulsive therapy. Int Rev Psychiatry. (2017) 29:54–62. doi: 10.1080/09540261.2017.1309362
127. Consoli A, Benmiloud M, Wachtel L, Dhossche D, Cohen D, Bonnot O. Electroconvulsive therapy in adolescents with the catatonia syndrome: efficacy and ethics. J ECT. (2010) 26:259–65. doi: 10.1097/YCT.0b013e3181fb3924
128. Castaneda-Ramirez S, Becker TD, Bruges-Boude A, Kellner C, Rice TR. Systematic review: Electroconvulsive therapy for treatment-resistant mood disorders in children and adolescents. Eur Child Adolesc Psychiatry. (2023) 32:1529–60. doi: 10.1007/s00787-022-01942-7
129. Papp M, Cubala WJ, Swiecicki L, Newman-Tancredi A, Willner P. Perspectives for therapy of treatment-resistant depression. Br J Pharmacol. (2022) 179:4181–200. doi: 10.1111/bph.15596
130. Kim YK, Na KS. Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry. (2016) 70:117–26. doi: 10.1016/j.pnpbp.2016.03.009
131. DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. (2010) 71:1605–11. doi: 10.4088/JCP.09m05327blu
132. Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Sci (1979). (2012) 338:68–72. doi: 10.1126/science.1222939
133. Zarate CA, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry. (2013) 74:257–64. doi: 10.1016/j.biopsych.2012.10.019
134. Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. (2015) 30:152–63. doi: 10.1002/hup.2475
135. McGirr A, Berlim MT, Bond DJ, Fleck MP, Yatham LN, Lam RW. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. (2015) 45:693–704. doi: 10.1017/S0033291714001603
136. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. (2015) 172:950–66. doi: 10.1176/appi.ajp.2015.15040465
137. Bobo WV, Voort JLV, Croarkin PE, Leung JG, Tye SJ, Frye MA. KETAMINE FOR TREATMENT-RESISTANT UNIPOLAR AND BIPOLAR MAJOR DEPRESSION: CRITICAL REVIEW AND IMPLICATIONS FOR CLINICAL PRACTICE. Depress Anxiety. (2016) 33:698–710. doi: 10.1002/da.22505
138. Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. (2016) 173:816–26. doi: 10.1176/appi.ajp.2016.16010037
139. Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. (2019) 102:75–90. doi: 10.1016/j.neuron.2019.03.013
140. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. (2016) 533:481–6. doi: 10.1038/nature17998
141. Ricci V, Martinotti G, Gelfo F, Tonioni F, Caltagirone C, Bria P, et al. Chronic ketamine use increases serum levels of brain-derived neurotrophic factor. Psychopharmacol (Berl). (2011) 215:143–8. doi: 10.1007/s00213-010-2121-3
142. Ardalan M, Elfving B, Rafati AH, Mansouri M, Zarate CA, Mathe AA, et al. Rapid effects of S-ketamine on the morphology of hippocampal astrocytes and BDNF serum levels in a sex-dependent manner. Eur Neuropsychopharmacol. (2020) 32:94–103. doi: 10.1016/j.euroneuro.2020.01.001
143. Rossi GN, Hallak JEC, Baker G, Dursun SM, dos Santos RG. The effects of ketamine and classic hallucinogens on neurotrophic and inflammatory markers in unipolar treatment-resistant depression: a systematic review of clinical trials. Eur Arch Psychiatry Clin Neurosci. (2023) 273:129–55. doi: 10.1007/s00406-022-01460-2
144. Bennabi D, Charpeaud T, Yrondi A, Genty JB, Destouches S, Lancrenon S, et al. Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental. BMC Psychiatry. (2019) 19:262. doi: 10.1186/s12888-019-2237-x
145. Voineskos D, Daskalakis ZJ, Blumberger DM. Management of treatment-resistant depression: challenges and strategies. Neuropsychiatr Dis Treat. (2020) 16:221–34. doi: 10.2147/NDT.S198774
146. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. (2013) 170:1134–42. doi: 10.1176/appi.ajp.2013.13030392
147. Diamond PR, Farmery AD, Atkinson S, Haldar J, Williams N, Cowen PJ, et al. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. J Psychopharmacol. (2014) 28:536–44. doi: 10.1177/0269881114527361
148. Cusin C, Ionescu DF, Pavone KJ, Akeju O, Cassano P, Taylor N, et al. Ketamine augmentation for outpatients with treatment-resistant depression: Preliminary evidence for two-step intravenous dose escalation. Aust N Z J Psychiatry. (2017) 51:55–64. doi: 10.1177/0004867416631828
149. Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. (2006) 63:856–64. doi: 10.1001/archpsyc.63.8.856
150. Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. (2009) 66:522–6. doi: 10.1016/j.biopsych.2009.04.029
151. Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, et al. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res. (2014) 58:161–6. doi: 10.1016/j.jpsychires.2014.07.027
152. Mathew SJ, Shah A, Lapidus K, Clark C, Jarun N, Ostermeyer B, et al. Ketamine for treatment-resistant unipolar depression: current evidence. CNS Drugs. (2012) 26:189–204. doi: 10.2165/11599770-000000000-00000
153. Reinstatler L, Youssef NA. Ketamine as a potential treatment for suicidal ideation: a systematic review of the literature. Drugs R D. (2015) 15:37–43. doi: 10.1007/s40268-015-0081-0
154. Wilkinson ST, Sanacora G. KETAMINE: A POTENTIAL RAPID-ACTING ANTISUICIDAL AGENT? Depress Anxiety. (2016) 33:711–7. doi: 10.1002/da.22498
155. Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Slonena EE, Vande Voort JL, et al. Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. J Clin Psychiatry. (2014) 75:e932–8. doi: 10.4088/JCP.14m09049
156. Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Focus (Am Psychiatr Publ). (2019) 17:55–65. doi: 10.1176/appi.focus.17105
157. Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: A midazolam-controlled randomized clinical trial. Am J Psychiatry. (2018) 175:327–35. doi: 10.1176/appi.ajp.2017.17060647
158. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. (2006) 63:332–9. doi: 10.1001/archpsyc.63.3.332
159. Li K, Zhou G, Xiao Y, Gu J, Chen Q, Xie S, et al. Risk of suicidal behaviors and antidepressant exposure among children and adolescents: A meta-analysis of observational studies. Front Psychiatry. (2022) 13:880496/FULL. doi: 10.3389/FPSYT.2022.880496/FULL
160. Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry. (2014) 4:e469. doi: 10.1038/tp.2014.105
161. Dwyer JB, Landeros-Weisenberger A, Johnson JA, Tobon AL, Flores JM, Nasir M, et al. Efficacy of intravenous ketamine in adolescent treatment-resistant depression: A randomized midazolam-controlled trial. Am J Psychiatry. (2021) 178:352–62. doi: 10.1176/appi.ajp.2020.20010018
162. Shin C, Kim YK. Ketamine in major depressive disorder: mechanisms and future perspectives. Psychiatry Investig. (2020) 17:181–92. doi: 10.30773/pi.2019.0236
163. Cullen KR, Amatya P, Roback MG, Albott CS, Westlund Schreiner M, Ren Y, et al. Intravenous ketamine for adolescents with treatment-resistant depression: an open-label study. J Child Adolesc Psychopharmacol. (2018) 28:437–44. doi: 10.1089/cap.2018.0030
164. Liu W, Zhou Y, Zheng W, Wang C, Zhan Y, Lan X, et al. Repeated intravenous infusions of ketamine: Neurocognition in patients with anxious and nonanxious treatment-resistant depression. J Affect Disord. (2019) 259:1–6. doi: 10.1016/j.jad.2019.08.012
165. Di Vincenzo JD, Siegel A, Lipsitz O, Ho R, Teopiz KM, Ng J, et al. The effectiveness, safety and tolerability of ketamine for depression in adolescents and older adults: A systematic review. J Psychiatr Res. (2021) 137:232–41. doi: 10.1016/j.jpsychires.2021.02.058
166. Thai M, Başgöze Z, Klimes-Dougan B, Mueller BA, Fiecas M, Lim KO, et al. Neural and behavioral correlates of clinical improvement to ketamine in adolescents with treatment resistant depression. Front Psychiatry. (2020) 11:820. doi: 10.3389/fpsyt.2020.00820
167. Marshall R, Valle K, Sheridan D, Kothari J. Ketamine for treatment-resistant depression and suicidality in adolescents: an observational study of 3 cases. J Clin Psychopharmacol. (2023) 43:460–2. doi: 10.1097/JCP.0000000000001730
168. Emslie GJ. Editorial: novel approaches to the treatment of suicidality and depression in youth. J Am Acad Child Adolesc Psychiatry. (2023) 63(5):500–1. doi: 10.1016/j.jaac.2023.06.019
169. Lineham A, Avila-Quintero VJ, Bloch MH, Dwyer J. Exploring predictors of ketamine response in adolescent treatment-resistant depression. J Child Adolesc Psychopharmacol. (2024) 34:63–9. doi: 10.1089/cap.2023.0047
170. McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. (2021) 178:383–99. doi: 10.1176/appi.ajp.2020.20081251
171. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: A randomized double-blind active-controlled study. Am J Psychiatry. (2019) 176:428–38. doi: 10.1176/appi.ajp.2019.19020172
172. Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. (2018) 75:139–48. doi: 10.1001/jamapsychiatry.2017.3739
173. Wajs E, Aluisio L, Holder R, Daly EJ, Lane R, Lim P, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. (2020) 81:19m12891. doi: 10.4088/JCP.19m12891
174. Mahase E. Esketamine is approved in Europe for treating resistant major depressive disorder. BMJ. (2019) 367:l7069. doi: 10.1136/bmj.l7069
175. Zhou Y, Lan X, Wang C, Zhang F, Liu H, Fu L, et al. Effect of repeated intravenous esketamine on adolescents with major depressive disorder and suicidal ideation: A randomized active-placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. (2023) 63(5):507–18. doi: 10.1016/j.jaac.2023.05.031
176. Lan X, Wang C, Zhang F, Liu H, Li W, Ye Y, et al. Short-term cognitive effects of repeated-dose esketamine in adolescents with major depressive disorder and suicidal ideation: a randomized controlled trial. Child Adolesc Psychiatry Ment Health. (2023) 17:108. doi: 10.1186/s13034-023-00647-2
177. DelBello MP, Kosik-Gonzalez C, Fu D-J, Chen L, Lane R, Drevets WC, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of depressive symptoms in adolescents with MDD at imminent risk for suicide: results of a double-blind, randomized, psychoactive-controlled study. J Am Acad Child Adolesc Psychiatry. (2023) 62:S319–20. doi: 10.1016/j.jaac.2023.09.513
178. Skala K, Doganay K, Eder H, Mairhofer D, Neubacher K, Plener PL. Intranasal esketamine as therapeutic option: a case report of an adolescent with treatment resistant depression. Front Psychiatry. (2023) 14:1118737. doi: 10.3389/fpsyt.2023.1118737
179. Hope J, Copolov D, Tiller J, Galbally M, Hopwood M, Newton R, et al. What clinicians need to know about intranasal esketamine for treatment-resistant depression? Australas Psychiatry. (2023) 31:841–5. doi: 10.1177/10398562231211171
180. Bates MLS, Trujillo KA. Long-lasting effects of repeated ketamine administration in adult and adolescent rats. Behav Brain Res. (2019) 369:111928. doi: 10.1016/j.bbr.2019.111928
181. Jornet-Plaza J, García-Fuster MJ. SEX DIFFERENCES IN THE ANTIDEPRESSANT-LIKE RESPONSE OF KETAMINE IN ADOLESCENT RATS: EVALUATING LONG-TERM SAFETY THROUGH COGNITION. IBRO Neurosci Rep. (2023) 15:S586. doi: 10.1016/j.ibneur.2023.08.1161
182. Onaolapo AY, Ayeni OJ, Ogundeji MO, Ajao A, Owolabi AR, Onaolapo OJ. Subchronic ketamine alters behavior, metabolic indices and brain morphology in adolescent rats: Involvement of oxidative stress, glutamate toxicity and caspase-3-mediated apoptosis. J Chem Neuroanat. (2019) 96:22–33. doi: 10.1016/j.jchemneu.2018.12.002
183. Kim S, Rush BS, Rice TR. A systematic review of therapeutic ketamine use in children and adolescents with treatment-resistant mood disorders. Eur Child Adolesc Psychiatry. (2021) 30:1485–501. doi: 10.1007/s00787-020-01542-3
184. Zaki N, Chen L, Lane R, Doherty T, Drevets WC, Morrison RL, et al. Long-term safety and maintenance of response with esketamine nasal spray in participants with treatment-resistant depression: interim results of the SUSTAIN-3 study. Neuropsychopharmacology. (2023) 48:1225–33. doi: 10.1038/s41386-023-01577-5
185. Nikayin S, Murphy E, Krystal JH, Wilkinson ST. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opin Drug Saf. (2022) 21:777–87. doi: 10.1080/14740338.2022.2066651
186. Becker AM, Holze F, Grandinetti T, Klaiber A, Toedtli VE, Kolaczynska KE, et al. Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Clin Pharmacol Ther. (2022) 111:886–95. doi: 10.1002/cpt.2487
187. Chen T, Cheng L, Ma J, Yuan J, Pi C, Xiong L, et al. Molecular mechanisms of rapid-acting antidepressants: New perspectives for developing antidepressants. Pharmacol Res. (2023) 194:106837. doi: 10.1016/j.phrs.2023.106837
188. Silote GP, Gatto MC, Eskelund A, Guimarães FS, Wegener G, Joca SRL. Strain-, sex-, and time-dependent antidepressant-like effects of cannabidiol. Pharm (Basel). (2021) 14:1269. doi: 10.3390/ph14121269
189. Martín-Sánchez A, González-Pardo H, Alegre-Zurano L, Castro-Zavala A, López-Taboada I, Valverde O, et al. Early-life stress induces emotional and molecular alterations in female mice that are partially reversed by cannabidiol. Prog Neuropsychopharmacol Biol Psychiatry. (2022) 115:110508. doi: 10.1016/j.pnpbp.2021.110508
190. Bis-Humbert C, García-Cabrerizo R, García-Fuster MJ. Decreased sensitivity in adolescent versus adult rats to the antidepressant-like effects of cannabidiol. Psychopharmacol (Berl). (2020) 237:1621–31. doi: 10.1007/s00213-020-05481-4
191. Ledesma-Corvi S, Hernández-Hernández E, García-Fuster MJ. Exploring pharmacological options for adolescent depression: a preclinical evaluation with a sex perspective. Transl Psychiatry. (2022) 12:220. doi: 10.1038/s41398-022-01994-y
192. Sapkota A, Khurshid H, Qureshi IA, Jahan N, Went TR, Sultan W, et al. Efficacy and safety of intranasal esketamine in treatment-resistant depression in adults: A systematic review. Cureus. (2021) 13:e17352. doi: 10.7759/cureus.17352
193. Yavi M, Lee H, Henter ID, Park LT, Zarate CA. Ketamine treatment for depression: a review. Discover Ment Health. (2022) 2:9. doi: 10.1007/s44192-022-00012-3
194. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. (2012) 6:369–88. doi: 10.2147/PPA.S29716
195. de Jesus VD, Liem A, Borra D, Appel JM. Who’s the boss? Ethical dilemmas in the treatment of children and adolescents. Focus: J Life Long Learn Psychiatry. (2022) 20:215. doi: 10.1176/APPI.FOCUS.20210037
196. Appel JM. A role for psychiatry in parental override cases. Int J Adolesc Med Health. (2015) 27:107. doi: 10.1515/ijamh-2015-5000
197. Dell ML. Child and adolescent depression: psychotherapeutic, ethical, and related nonpharmacologic considerations for general psychiatrists and others who prescribe. Psychiatr Clin North Am. (2012) 35:181–201. doi: 10.1016/j.psc.2011.12.002
198. Hung CC, Liu YH, Huang CC, Chou CY, Chen CM, Duann JR, et al. Effects of early ketamine exposure on cerebral gray matter volume and functional connectivity. Sci Rep. (2020) 10:15488. doi: 10.1038/s41598-020-72320-z
199. Zimmermann KS, Richardson R, Baker KD. Esketamine as a treatment for paediatric depression: questions of safety and efficacy. Lancet Psychiatry. (2020) 7:827–9. doi: 10.1016/S2215-0366(19)30521-8
200. Sarakbi D, Groll D, Tranmer J, Sears K. Achieving quality integrated care for adolescent depression: A scoping review. J Prim Care Community Health. (2022) 13:21501319221131684. doi: 10.1177/21501319221131684
Keywords: major depressive disorder, treatment-resistant depression, adolescents, youth psychopathology, fast-acting antidepressants, ketamine, esketamine, glutamate
Citation: Menculini G, Cinesi G, Scopetta F, Cardelli M, Caramanico G, Balducci PM, De Giorgi F, Moretti P and Tortorella A (2024) Major challenges in youth psychopathology: treatment-resistant depression. A narrative review. Front. Psychiatry 15:1417977. doi: 10.3389/fpsyt.2024.1417977
Received: 15 April 2024; Accepted: 20 June 2024;
Published: 11 July 2024.
Edited by:
Vassilis Martiadis, Department of Mental Health, ItalyReviewed by:
Alessandro Cuomo, University of Siena, ItalyPasquale Scognamiglio, ASL Napoli 3 Sud, Torre del Greco, Italy
Copyright © 2024 Menculini, Cinesi, Scopetta, Cardelli, Caramanico, Balducci, De Giorgi, Moretti and Tortorella. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Giulia Menculini, Z2l1bGlhLm1lbmN1bGluaUB1bmlwZy5pdA==