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Abstract

Research in psychopharmacology in children and adolescents is an area of growing interest with numerous newer modalities becoming available in recent years. Nevertheless, it still lags significantly behind research in adult psychopharmacology although, in the last decade, the gap is beginning to be bridged with FDA approval for newer agents for the paediatric age group. The purpose of this selective narrative review is to examine the latest advances in psychopharmacology in the last decade and their safety, tolerability and applicability in children and adolescents. In methodology, we identified 4 main areas of recent advances in psychopharmacology, viz. Ketamine, Nitrous Oxide, Cannabidiol and cannabis derivates and the area of pharmacogenomics. We then conducted a comprehensive search of the literature using PubMed, Embase and Ovid databases to identify the most recent updates in these areas, especially focussed on the paediatric population. The search was limited to English language studies and focussed on recent updates in these four areas. In the results, it was seen that all the four identified areas have potential applicability in children and adolescents with some studies evaluating their safety and tolerability in the paediatric population. However, literature on the long-term safety and efficacy of these newer modalities in the paediatric population is limited and none of the identified agents are currently recommended for routine clinical use in children and adolescents. Overall, it could be concluded that the results of this selective narrative review suggest that newer modalities in psychopharmacology offer promising treatments for psychiatric disorders in children and adolescents. However, further research is needed to fully understand the long-term safety and efficacy of these treatments as well as optimal dosing and monitoring strategies to ensure their safe and effective use in the paediatric population.

Keywords

Psychopharmacology child and adolescent newer modalities psychiatry

Introduction

Psychopharmacology in children and adolescents has had a long but chequered history dating back to the first description of amphetamines for hyperactive children by Charles Bradley¹ in 1937. In a review in 1984, Werry² noted that pediatric psychopharmacology was a long way behind adult psychopharmacology. Some of the reasons discussed for this phenomenon were the nature of child psychiatry, absence of circumscribed disorders that approximate to a disease model, the interaction of a child’s behavior and their environment, and the difficulties in separating the “normal” from the “abnormal”. Indeed, given that most psychopharmacological agents, in and of themselves, do not offer a “cure” for a “disease”, psychopharmacology, especially in children and adolescents, continues to remain a modality of treatment that is usually adjunctive to behavioural/psychological treatments. Indeed, even in Attention Deficit Hyperactive Disorder (ADHD) where the Multimodal Treat-ment of ADHD (MTA) study³ has demonstrated the beneficial effects of stimulant medication, at least in the short term, the prescribing of stimulant medication to children has not been without controversy.⁴

Nonetheless, the use of psychotropic medications in children and adolescents has been growing worldwide. Between 1987 and 1996, the overall annual rate of psychotropic medication use in children and adolescents increased from 1.4 per 100 people to 3.9 per 100 people.⁵ The most notable increases were seen in stimulant medications and antidepressant medications. This trend is not limited to the United States and has also been noted in other countries across continents.^6-8

Research in the area of child and adolescent psychopharmacology has also lagged behind that of adult psychopharmacology with many medications in children being used “off label”, based on adult literature. One cross sectional study from Denmark evaluated over 5000 prescriptions for nearly 3000 patients and found that over 32% of prescriptions for 41% of children were “off-label.”⁹ This was historically because there was little incentive for pharmaceutical companies to conduct research in children after having conducted research in adults as this was deemed to be “harder” from ethical and pragmatic perspectives and also not financially appealing.¹⁰ The Paediatric Research Equity Act, 2003, aimed to address this imbalance by requiring that certain newer drugs undergo trials in children prior to approval being given for their use. The beneficial impact¹¹ of this was seen with 266 products studied in children between 2012 and 2018. Despite this, rates of off label prescriptions were noted to remain high in children in adolescents.^12,13

Newer options for treatment in child and adolescent psychiatry are the need of the hour and despite significant discoveries between 1937 and the present day, progress can feel glacial. Other than the MTA study in the late 1990s, there have not been any significant trials in psychopharmacology exclusively focused on children and adolescents. In the last decade and a half, newer modalities of treatments in adults have been evaluated and approved including novel antipsychotic agents with novel mechanisms,¹⁴ ketamine,¹⁵ and psychedelics,¹⁶ amongst others. Through this selective narrative review, we aim to discuss some of the newer modalities in pharmacotherapy for children and adolescents.

Methodology

We conducted a selective review of the literature focusing on the topics below using electronic databases Medline (PubMed), Embase and Ovid to find studies that focused on newer modalities in pharmacotherapy. The key search terms included psychopharmacology, pharmacotherapy, newer modalities, child and adolescent, and psychiatry for each of the topics considered below (ketamine, nitrous oxide, cannabidiol and cannabis derivates, pharmacogenomics). Selective articles that focused on updates in these areas were prioritized. The search was restricted to English language journals.

Ketamine

Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was first evaluated in humans in 1964 at the University of Michigan.¹⁷ Ketamine is a racemic mixture of the R-enantiomer and the S-enantiomer. It was introduced as a short acting anesthetic in humans in the 1970s and soon it became known that its side effects included psychomimetic effects and dissociation¹⁸ resulting in a reduction of its use, especially as newer anesthetics began to become available.

The first double blind placebo-controlled trial of ketamine for depression was reported in 2000 by Berman et al.¹⁵ Nine patients were enrolled in the study of which 7 completed it over 2 days. The study involved intravenous treatment with ketamine hydrochloride or saline under randomized double-blind conditions. Patients who had depression showed a significant improvement in depressive symptoms within 72 hours after ketamine but not placebo. This was subsequently replicated over the next decade in patients with treatment resistant depression.^{19, 20} The Price et al study²⁰ found a beneficial effect on suicidal ideations. This effect of ketamine was then replicated in 2011 by Larkin et al.²¹ They found that a single IV bolus dose of ketamine administered over 1 to 2 minutes reduced suicidal ideations significantly. This article, however, was later retracted due to concerns around the data but the ketamine story was well under way. A subsequent systematic review combined data from 15 independent randomized controlled trials (RCTs) that involved 572 participants and found that ketamine may have a short-term beneficial impact on suicidal thoughts in adults with mood disorders up to 72 hours post infusion.²² The effect of ketamine on suicidal ideations appear to be more short lived than that on depression and the authors cautioned that more sustained means of treatment need to be found. Repeated ketamine infusions have been found to be beneficial as a means of sustaining the short-term effect. One study administered 6 IV infusions of ketamine 3 times a week over 12 days and found that antidepressant effects were sustained at least for the duration of the infusion period.²³

To date, there is only one RCT on Ketamine in children conducted by Dwyer and colleagues.²⁴ The authors administered a single infusion of ketamine to 17 adolescents with major depressive disorder in a randomized double-blind single dose cross over trial with midazolam being the control. They found that depressive symptoms in the ketamine group as measured by Montomery-Asberg Depression Rating Scale (MADRS) 24 hours after the infusion were significantly reduced as compared to midazolam. Some transient self-limited dissociative symptoms were noted in the ketamine group. The authors concluded that ketamine was well tolerated and had significant short efficacy in reducing depressive symptoms compared to an active placebo.

A recent systematic review²⁵ analyzed 5 other studies in addition to the RCT and concluded that there is a potential role for ketamine in pediatric depression but that studies with large sample sizes and different mode of administration (as opposed to IV) are needed to better determine efficacy and safety in the pediatric population. At the current time, there is no evidence to recommend ketamine for routine clinical use in children and adolescents with depression.

Nitrous Oxide

Nitrous oxide, also known as laughing gas, is a compound of nitrogen and oxygen. It is commonly used as an inhaled anesthetic and analgesic, but recent research has also suggested its potential as a treatment for depression. Its mechanism of action is as an NMDA receptor antagonist but its precise mechanism of action in the treatment of depression is unclear.²⁶ It is generally a safe gas²⁷ and usually results in mild sedation. Occasionally, it may cause nausea, vomiting, headaches, dizziness, and euphoria but is not known to cause psychomimetic effects.

A proof-of-concept trial conducted by Nagele and colleagues²⁸ in 2015 first demonstrated that nitrous oxide had rapid and marked antidepressant effect in adult patients with treatment resistant depression. 20 patients were randomly assigned to 50% nitrous oxide/50% oxygen or 50% nitrogen/50% oxygen and evaluated 24 hours later using the Hamilton Depression Rating Scale (HDRS-21). Depressive symptoms reportedly improved significantly in the nitrous oxide group at both the 2 hour and 24-hour time period with no serious adverse effects. However, a subsequent letter by Gillman²⁹ cautioned against using a fixed dose of 50% nitrous oxide and oxygen raising concerns of anxiety, nausea, and vomiting. He recommended a dose titration as used by dentists. This was further evaluated by Nagele et al who found that a reduced dose of 25% nitrous oxide had comparable efficacy to the 50% dose and had fewer adverse effects.³⁰ The authors also stated that the antidepressant effect of nitrous oxide could last between 2 and 4 weeks.

Nitrous oxide has also been evaluated as a treatment for PTSD.³¹ Nitrous oxide was associated with a reduction in the frequency of intrusive thoughts associated with PTSD. This reduction was found to be much more rapid compared with placebo.

A concern regarding nitrous oxide is its potential for abuse³² but its addiction potential is thought to be minimal. Frequent use of nitrous oxide is also associated with Vit B12 deficiency³³ and patients may present with megaloblastic anemia or damage to the nervous system. This is unlikely to be a concern after single dose administration and is more a concern for chronic abusers of the drug. Currently there is no data on the safety or efficacy of nitrous oxide in depression or other mental disorders in children and adolescents. Lastly, nitrous oxide, as a greenhouse gas, has a significant global warming potential and its environmental sustainability in clinical practice has recently been questioned³⁴ which might limit its application in medical use in the future.

Cannabidiol and Cannabis Derivates

Cannabidiol (CBD) is a phytocannabinoid isolated from the plant Cannabis sativa and was first isolated³⁵ in 1940. It is not psychoactive in nature and has been reportedly beneficial in a range of pathological disorders as evidenced by testing in animal models including for Alzheimer’s disease,³⁶ epilepsy,³⁷ and several inflammatory diseases^38,39 amongst others. In the mental health area, it has been found to be effective against anxiety,⁴⁰ depression,⁴¹ and psychosis.⁴²

Trials on CBD in healthy humans were first conducted⁴³ in the 1970s and in a clinical population a decade ago.⁴⁴ The clinical study, which was a within subjects between condition comparison, suggested that CBD reduced anxiety in seasonal affective disorder and the authors hypothesized that this was related to its effects on activity in the limbic and paralimbic brain areas. A recent systematic review evaluating the role of CBD in clinical and pre-clinical anxiety did not find any identifiable relationship between anxiety outcomes and drug levels in both animal and human studies.⁴⁵ The authors concluded that anxiety reducing effects appear to be clustered in certain concentration ranges between species and were therefore unable to make any scientific recommendations with regards to the effective dose of CBD. They stated that this raised questions on the use of such a broad drug for anxiety and recommended that further meta analytic studies were required.

A case series reported in 2019 also showed that CBD appeared to offer relief to a subset of adults with PTSD who had frequent nightmares.⁴⁶ The evidence for CBD in depressive disorders is less clear with no clear evidence to suggest their efficacy in mood disorders.⁴⁷ Nonetheless, the authors suggested that the possible biological rationale of preclinical studies require further investigation and the conclusion of the review was mostly due to a lack of high-quality studies rather than evidence that CBD is ineffective in mood disorders. Cannabis derivates have also been shown to have beneficial effects in symptoms of psychosis⁴⁸ and substance abuse.^49,50

The use of CBD in children and adolescents has not yet been systematically evaluated for safety and efficacy. A recent case report⁵¹ described the administration of CBD capsules in a 16-year-old with diagnoses of multiple substance use disorder, severe depression, social phobia, and narcissistic personality disorder. The starting dose of CBD capsules was 100 mg od and increased to 600 mg od over 8 weeks after unsuccessful treatment with antidepressant medications. The authors state that CBD was well tolerated and there was symptomatic improvement in terms of depression, phobia, paranoia, and dissociation. The patient was also noted to quit illicit substances without any withdrawal symptoms.

In a recent open label trial⁵² consisting of 31 youth aged between 12 and 25 years with a DSM-5 diagnosis of anxiety disorder and no clinical improvement despite treatment, CBD was administered to this cohort for 12 weeks as an add on therapy. The dose was titrated on a fixed-flexible schedule up to 800 mg/day. Anxiety as measured by the OASIS (Overall Anxiety Severity and Impairment Scale) decreased significantly at week 12 corresponding to a 42.6% reduction. Depressive symptoms and functioning were also noted to improve significantly. The authors concluded that the study provided evidence of reduced anxiety severity for CBD in a population of youth with treatment resistant anxiety disorders. No serious adverse effects were reported during the trial.

Overall, there is some evidence that CBD is beneficial, especially in anxiety disorders, and future clinical trials will be required to allow for recommendation in routine clinical practice. The mechanism of action of CBD remains unclear and multiple mechanisms including facilitation of 5HT1A mediated neurotransmission in key brain areas, potentiation of anandamide mediated neurotransmission and activation of TRPV1 (Transient Receptor Potential sub-family V) channels have been proposed.⁵³

Pharmacogenomics

Pharmacogenomics studies the genetic basis of an individual’s response to drugs. The promise of personalized medicine and the ability for doctors to predict which patients will respond to treatment and who will suffer side effects has long been the holy grail in medicine and its potential is yet to be fully realized. In psychiatry, much of the work, until recently, has been focused in the domain of adult psychiatry with the first pharmacogenetic test using a microarray (AmpliChip CYP450) being approved by the FDA over 15 years ago.⁵⁴ In the last 10 years, a number of studies have evaluated pharmacogenomic testing in children and adolescents. Given that a high proportion of medications used in psychiatry are metabolized by the cytochrome P450 enzyme system, the genes that code for these enzymes have been the most studied in the field of psychiatry. Within this system, CYP2D6 is involved in the metabolism of a number of medications including fluoxetine, venlafaxine, and atomoxetine, and CYP2C19 is involved in the metabolism of citalopram and escitalopram and is indirectly involved in the metabolism of sertraline. The Clinical Pharmacogenetics Implementation Consortium, in its guidelines for dosing recommendations for sertraline, fluvoxamine, paroxetine, citalopram, and escitalopram based on pharmacogenetic testing of metabolizer status, noted the potential benefit of identifying patients at an increased risk of adverse effects or therapeutic failure.⁵⁵

Namerow and colleagues have summarized the current evidence for pharmacogenomics in child and adolescent psychiatry and state that while the evidence is still accumulating, there may be a role for pharmacogenomic testing in children.⁵⁶ Although the field is still in its infancy, the authors note that drug labelling for 2 medications commonly used in children (atomoxetine and citalopram) already include warnings for patients with CYP2D6 and CYP2C17 vulnerabilities demonstrating that pharmacogenomics has already entered the area of clinical practice.

In a recent study⁵⁷ assessing the acceptability, feasibility, and utility of integrating pharmacogenetic testing in a child psychiatry clinic, Claudio-Campos et al found that pharmacogenomic testing was feasible and well accepted by both providers and families of children with depression and anxiety. Initial concerns from families centered on the social and ethical implications of genetic testing. Physician concerns included lack of knowledge and skills in this area and the need for further education.

Caution is also advised as a recent study⁵⁸ by Vande Voort et al identified that there was no significant clinical impact when clinicians used combinatorial pharmacogenomic testing to guide treatment for depressed adolescents. The authors noted that the results of the testing sometimes influenced providers to more frequently prescribe medications that are not considered first line in the child and adolescent population, thus resulting in deviation from the existing evidence base.

Pharmacogenomics holds enormous potential in optimizing drug therapy in the field of child psychiatry. Indeed, in a 2001 systematic review,⁵⁹ Philipps et al had predicted that it could well be the standard of care in 2020; however, this prediction has not yet been realized. Before we can confidently recommend the use of pharmacogenomics in clinical practice in child psychiatry, prospective controlled studies focused on the child and adolescent population are required.

Other Recent Updates

In 2019, the FDA approved the Monarch external Trigeminal Nerve System (eTNS) for children between 7 and 12 years of age with ADHD who are not currently taking prescription medications. A 2014 clinical trial⁶⁰ evaluated neuromodulation in depression and in 2019⁶¹ and then in 2021⁶² it was shown that children with ADHD with executive function difficulties are more likely to show modulation of right frontal brain activity, improved executive function, and ADHD symptom reduction in response to TNS stimulation.

Saffron, a herb/spice used in cooking and known as Crocus sativus has been reported to have beneficial effects in ADHD. A trial by Baziar et al⁶³ showed that 20 to 30 mg/day of saffron extract evaluated in 50 patients with ADHD between the ages of 6 and 17 years was effective in reducing symptoms of ADHD.

Conclusion

In 1986, Michael Rutter, the father of child psychiatry took a shot at predicting the developments in the field over the next 30 years.⁶⁴ Particularly in the area of future research, he argued for a greater understanding of the neurochemical effects of drugs, the use of non-invasive brain imaging techniques, advances in electrophysiology, and advances in the understanding of the biological substrates of mental disorders in children and adolescents. While not all of these predictions have reached their fruition, there have a been significant advances in biological treatments and pharmacotherapy in the last 30 years. In this selective narrative review, we have attempted to describe the potential for advancements that appear almost imminent but also require considerable increase in knowledge before routine clinical use can be recommended.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Bradley

. The behavior of children receiving benzedrine. Am J Psychiatry. 1937 Nov;94(3):577–585.

Werry

. An overview of pediatric psychopharmacology. J Am Acad Child Psychiatry. 1982 Jan 1;21(1):3–9.

MTA Cooperative Group. Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the multimodal treatment study of children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999 Dec 1;56(12):1088–1096.

Greenhill

, Halperin

, Abikoff

. Stimulant medications. J Am Acad Child Adolesc Psychiatry. 1999 May 1;38(5):503–512.

Olfson

, Marcus

, Weissman

, Jensen

. National trends in the use of psychotropic medications by children. J Am Acad Child Adolesc Psychiatry. 2002 May 1;41(5):514–521.

Karanges

, Stephenson

, McGregor

. Longitudinal trends in the dispensing of psychotropic medications in Australia from 2009–2012: Focus on children, adolescents and prescriber specialty. Aust N Z J Psychiatry. 2014 Oct;48(10):917–931.

Steinhausen

. Recent international trends in psychotropic medication prescriptions for children and adolescents. Eur Child Adolesc Psychiatry. 2015 Jun;24(6):635–640.

Hsia

, Maclennan

. Rise in psychotropic drug prescribing in children and adolescents during 1992–2001: a population-based study in the, UK. Eur J Epidemiol. 2009 Apr;24(4):211–216.

Braüner

, Johansen

, Roesbjerg

, Pagsberg

. Off-label prescription of psychopharmacological drugs in child and adolescent psychiatry. J Clin Psychopharmacol. 2016 Oct 1;36(5):500–507.

10.

Drug Research and Children. Updated May 4, 2015. https://www.fda.gov/drugs/information-consumers-and-patients-drugs/drug-research-and-children. Accessed on January 25, 2023.

11.

Momper

, Green

, Park

, Burckart

, Snyder

. Ethical considerations for pediatric placebo-controlled trials: FDA outcomes and perspectives. Ther Innov Regul Sci. 2021 Mar;55(2):282–303.

12.

Bourgeois

, Hwang

. The pediatric research equity act moves into adolescence. JAMA. 2017 Jan 17;317(3):259–260.

13.

Carton

, Cottencin

, Lapeyre-Mestre

, A Geoffroy

, Favre

, Simon

, Bordet

, Rolland

. Off-label prescribing of antipsychotics in adults, children and elderly individuals: a systematic review of recent prescription trends. Curr Pharm Des. 2015 Jul 1;21(23):3280–3297.

14.

Sonnenschein

, Grace

. Insights on current and novel antipsychotic mechanisms from the MAM model of schizophrenia. Neuropharmacology. 2020 Feb 1;163:107632.

15.

Berman

, Cappiello

, Anand

, Oren

, Heninger

, Charney

, Krystal

. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351–354.

16.

Moreno

, Wiegand

, Taitano

, Delgado

. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry. 2006 Nov 11;67(11):1735–1740.

17.

Domino

, Warner

. Taming the ketamine tiger. J Am Soc Anesth. 2010 Sep 1;113(3):678–684.

18.

Krystal

, Karper

, Seibyl

, . Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994 Mar 1;51(3):199–214.

19.

Zarate

, Singh

, Carlson

, . A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug 1;63(8):856–64.

20.

Price

, Nock

, Charney

, Mathew

. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009 Sep 1;66(5):522–526.

21.

Larkin

, Beautrais

. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol. 2011 Sep 1;14(8):1127–1131.

22.

Witt

, Potts

, Hubers

, Grunebaum

, Murrough

, Loo

, Cipriani

, Hawton

. Ketamine for suicidal ideation in adults with psychiatric disorders: a systematic review and meta-analysis of treatment trials. Aust N Z J Psychiatry. 2020 Jan;54(1):29–45.

23.

Phillips

, Norris

, Talbot

, . Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019 May 1;176(5):401–409.

24.

Dwyer

, Landeros-Weisenberger

, Johnson

, . Efficacy of intravenous ketamine in adolescent treatment-resistant depression: a randomized midazolam-controlled trial. Focus. 2022 Apr;20(2):241–251.

25.

Meshkat

, Rosenblat

, Ho

, Rhee

, Cao

, Ceban

, Danayan

, Chisamore

, Di Vincenzo

, McIntyre

. Ketamine Use in Pediatric Depression: A Systematic Review. Psychiatry Research. 2022 Oct 15:114911.

26.

Nagele

, Zorumski

, Conway

. Exploring nitrous oxide as treatment for mood disorders: basic concepts. J Clin Psychopharmacol. 2018 Apr;38(2):144.

27.

Sanders

, Weimann

, Maze

, Warner

. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. J Am Soc Anesth. 2008 Oct 1;109(4):707–722.

28.

Nagele

, Duma

, Kopec

, . Nitrous oxide for treatment-resistant major depression: a proof-of-concept trial. Biol Psychiatry. 2015 Jul 1;78(1):10–18.

29.

Gillman

. Words of caution on using fixed 50% concentrations of nitrous oxide in psychiatry. J Clin Psychopharmacol. 2019 Jul 1;39(4):421–422.

30.

Nagele

, Palanca

, Gott

, . A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression. Sci Transl Med. 2021 Jun 9;13(597):eabe1376.

31.

Das

, Tamman

, Nikolova

, . Nitrous oxide speeds the reduction of distressing intrusive memories in an experimental model of psychological trauma. Psychol Med. 2016;46(8):1749–1759.

32.

Kaar

, Ferris

, Waldron

, Devaney

, Ramsey

, Winstock

. Up: the rise of nitrous oxide abuse. An international survey of contemporary nitrous oxide use. J Psychopharmacol. 2016 Apr;30(4):395–401.

33.

Nunn

. Clinical aspects of the interaction between nitrous oxide and vitamin B12. Br J Anaesth. 1987;59(1):3–13.

34.

McGain

, Muret

, Lawson

, Sherman

. Environmental sustainability in anaesthesia and critical care. Br J Anaesth. 2020 Nov 1;125(5):680–692.

35.

Adams

, Hunt

, Clark

. Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. I. J Am Chem Soc. 1940 Jan;62(1):196–200.

36.

Cheng

, Spiro

, Jenner

, Garner

, Karl

. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice. J Alzheimers Dis. 2014 Jan 1;42(4):1383–1396.

37.

Devinsky

, Marsh

, Friedman

, Thiele

, Laux

, Sullivan

, Miller

, Flamini

, Wilfong

, Filloux

, Wong

. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar 1;15(3):270–278.

38.

Mecha

, Torrao

, Mestre

, Carrillo-Salinas

, Mechoulam

, Guaza

. Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress. Cell Death dis. 2012 Jun;3(6):e331.

39.

Mecha

, Feliú

, Iñigo

, Mestre

, Carrillo-Salinas

, Guaza

. Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol Dis. 2013 Nov 1;59:141–150.

40.

Marinho

, Vila-Verde

, Fogaça

, Guimarães

. Effects of intra-infralimbic prefrontal cortex injections of cannabidiol in the modulation of emotional behaviors in rats: contribution of 5HT1A receptors and stressful experiences. Behav Brain Res. 2015 Jun 1;286:49–56.

41.

Shoval

, Shbiro

, Hershkovitz

, Hazut

, Zalsman

, Mechoulam

, Weller

. Prohedonic effect of cannabidiol in a rat model of depression. Neuropsychobiology. 2016;73(2):123–129.

42.

Gomes

, Llorente

, Del Bel

, Viveros

, López-Gallardo

, Guimarães

. Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr Res. 2015 May 1;164(1-3):155–163.

43.

Karniol

, Shirakawa

, Kasinski

, Pfeferman

, Carlini

. Cannabidiol interferes with the effects of Δ9-tetrahydrocannabinol in man. Eur J Pharmacol. 1974 Sep 1;28(1):172–177.

44.

Crippa

, Derenusson

, Ferrari

, . Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011 Jan;25(1):121–130.

45.

Kwee

, van Gerven

, Bongaerts

, Cath

, Jacobs

, Baas

, Groenink

. Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool. J Psychopharmacol. 2022 Dec;36(12):1299–1314.

46.

Elms

, Shannon

, Hughes

, Lewis

. Cannabidiol in the treatment of post-traumatic stress disorder: a case series. J Altern Complement Med. 2019 Apr 1;25(4):392–397.

47.

Pinto

, Saraf

, Frysch

, . Cannabidiol as a Treatment for Mood Disorders: A Systematic Review: Le cannabidiol comme traitement des troubles de l’humeur: une revue systématique. Can J Psychiatry. 2020 Apr;65(4):213–227.

48.

Gomes

, Llorente

, Del Bel

, Viveros

, López-Gallardo

, Guimarães

. Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr Res. 2015 May 1;164(1–3):155-163.

49.

Allsop

, Copeland

, Lintzeris

, . Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry. 2014 Mar 1;71(3):281–291.

50.

Trigo

, Lagzdins

, Rehm

, Selby

, Gamaleddin

, Fischer

, Barnes

, Huestis

, Le Foll

. Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. Drug Alcohol Depend. 2016 Apr 1;161:298–306.

51.

Laczkovics

, Kothgassner

, Felnhofer

, Klier

. Cannabidiol treatment in an adolescent with multiple substance abuse, social anxiety and depression. Neuropsychiatrie. 2021;35(1):31.

52.

Berger

, Li

, Rice

, . Cannabidiol for treatment-resistant anxiety disorders in young people: an open-label trial. J Clin Psychiatry. 2022 Aug 3;83(5):42111.

53.

Campos

, Moreira

, Gomes

, Del Bel

, Guimaraes

. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci, 2012 Dec 5;367(1607):3364–3378.

54.

De Leon

. AmpliChip CYP450 test: personalized medicine has arrived in psychiatry. Expert Rev Mol Diagn. 2006 May 1;6(3):277–286.

55.

Hicks

, Bishop

, Sangkuhl

, Müller

, Ji

, Leckband

, Leeder

, Graham

, Chiulli

, LLerena

, Skaar

. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clinical Pharmacology & Therapeutics. 2015 Aug;98(2):127–134.

56.

Namerow

, Walker

, Loftus

, Bishop

, Ruaño

, Malik

. Pharmacogenomics: an update for child and adolescent psychiatry. Curr Psychiatry Rep. 2020 May;22:1–1.

57.

Claudio-Campos

, Padrón

, Jerkins

, . Acceptability, feasibility, and utility of integrating pharmacogenetic testing into a child psychiatry clinic. Clin Transl Sci. 2021 Mar;14(2):589–598.

58.

Voort

, Orth

, Shekunov

, . A randomized controlled trial of combinatorial pharmacogenetics testing in adolescent depression. J Am Acad Child Adolesc Psychiatry. 2022 Jan 1;61(1):46–55.

59.

Phillips

, Veenstra

, Oren

, Lee

, Sadee

. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA. 2001 Nov 14;286(18):2270–2279.

60.

Cook

, Espinoza

, Leuchter

. Neuromodulation for depression: invasive and noninvasive (deep brain stimulation, transcranial magnetic stimulation, trigeminal nerve stimulation). Neurosurg Clin. 2014 Jan 1;25(1):103–116.

61.

McGough

, Sturm

, Cowen

, Tung

, Salgari

, Leuchter

, Cook

, Sugar

, Loo

. Double-blind, sham-controlled, pilot study of trigeminal nerve stimulation for attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2019 Apr 1;58(4):403–411.

62.

Loo

, Salgari

, Ellis

, Cowen

, Dillon

, McGough

. Trigeminal nerve stimulation for attention-deficit/hyperactivity disorder: cognitive and electroencephalographic predictors of treatment response. J Am Acad Child Adolesc Psychiatry. 2021 Jul 1;60(7):856–864.

63.

Baziar

, Aqamolaei

, Khadem

, . Crocus sativus L. versus methylphenidate in treatment of children with attention-deficit/hyperactivity disorder: A randomized, double-blind pilot study. J Child Adolesc Psychopharmacol. 2019 Apr 1;29(3):205–212.

64.

Rutter

. Child psychiatry: looking 30 years ahead. J Child Psychol Psychiatry. 1986 Nov;27(6):803–840.

Newer Modalities in Psychopharmacology in Children and Adolescents: A Selective Narrative Review of the Literature

Abstract

Keywords

Introduction

Methodology

Ketamine

Nitrous Oxide

Cannabidiol and Cannabis Derivates

Pharmacogenomics

Other Recent Updates

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References