Depression

Clinical picture (children and adolescents)

• In children and adolescents, irritability, bodily complaints, falling school performance and social withdrawal may be more prominent than low mood. A
• Prevalence: point prevalence of major depression in adolescents is about 8% and lifetime prevalence 19%; elevated self-reported depressive symptoms 34% (not a diagnosis). More common in girls (Shorey et al., 2022). A
• After puberty, rates rise markedly in girls; depression beginning in adolescence carries a risk of recurrence. A
• Co-occurring conditions: anxiety disorders, ADHD, substance use; suicidal thoughts and behavior must always be asked about. A

Circuits and networks

• Anterior Cingulate Cortex (especially the subgenual part): negative emotion and self-evaluation; a stimulation target in treatment-resistant depression. B
• Orbitofrontal Cortex and Medial & Frontopolar Prefrontal Cortex: reward appraisal and self-referential thinking; in ENIGMA, adults had thinner orbitofrontal, cingulate, insular and temporal cortex (Schmaal et al., 2017). A
• Hippocampus: linked to stress and cortisol; smaller volume, especially in recurrent depression and depression beginning before age 21 (Schmaal et al., 2016). A
• Amygdala: increased response to negative stimuli. B
• Nucleus Accumbens and Ventral Tegmental Area: reward anticipation and motivation; the response to reward is reduced in anhedonia. B
• Habenula (habenula): the "expected reward did not arrive" signal; it suppresses the dopamine and serotonin nuclei and is linked to depression in animal models. B
• Hypothalamus & Pituitary: the hypothalamic-pituitary-adrenal (HPA) axis; the stress response. A
• Dorsolateral Prefrontal Cortex: cognitive control; the target of repetitive transcranial magnetic stimulation (rTMS). A
• Networks: increased connectivity within the Default mode network (DMN) and rumination (going over negative thoughts), reduced control by the Frontoparietal control network. B

Neurotransmitter systems

• Serotonin (serotonin): SSRIs are effective; but the simple "serotonin deficiency" explanation is inadequate, and the effect emerges over weeks through neuroplasticity. B
• Dopamine (dopamine): reward and motivation; linked to anhedonia. B
• Noradrenaline (noradrenaline): energy and arousal; the target of SNRIs and some antidepressants. B
• Glutamate: the rapid antidepressant effect of ketamine works through this system; esketamine is approved in adults, evidence in adolescents is limited. B

Imaging and neurobiological findings

• ENIGMA-MDD subcortical: smaller hippocampal volume; the difference is clear in recurrent depression and early onset (≤ 21 years) (Schmaal et al., 2016). A
• ENIGMA-MDD cortex (2,148 patients, 7,957 controls): in adults, thinner orbitofrontal, anterior and posterior cingulate, insular and temporal cortex; in adolescents no thickness difference but smaller total surface area (frontal and sensorimotor regions), most in recurrent cases (Schmaal et al., 2017). A
• These are group-level differences; imaging cannot diagnose an individual. A

Developmental course

• Brain findings in adolescent-onset depression differ from adult-onset depression (surface area rather than thickness), suggesting a different effect on the developing brain (Schmaal et al., 2017). B
• Early-life stress and adverse childhood experiences raise the risk of depression through the HPA axis and the hippocampus. B

Treatment and the systems it targets

• In adolescents (ages 12–17, 439 patients), response at 12 weeks: fluoxetine + CBT 71.0%, fluoxetine alone 60.6%, CBT alone 43.2%, placebo 34.8%; combined treatment had the best benefit-risk balance (TADS, 2004). By week 36, CBT alone and fluoxetine alone had also approached combined treatment. A
• In mild depression, psychotherapy (CBT, interpersonal therapy) and support first; in moderate and severe depression, medication in addition to psychotherapy. A
• Medication: FDA-approved drugs for children and adolescents are fluoxetine (age 8 and up) and escitalopram (age 12 and up). Antidepressants may increase the risk of suicidal thoughts under age 25 (boxed warning); close monitoring is needed. A
• In resistant depression, rTMS (left DLPFC) and electroconvulsive therapy are options; in adolescents they are used in specialist centers. B

Link to the book (The Green Walnut on the Couch)

• In the book (translated from the Turkish original):
  • SEEKING system, clinical: "anhedonia, depression, addiction, ADHD, mania, and excessive attribution of meaning in psychosis".
  • PANIC/GRIEF system, clinical: "separation anxiety, panic, depression, complicated grief".
  • PLAY system, clinical: "ADHD, social play in autism, traumatic play, depression".
  • CARE system, clinical: "parenting difficulties, postpartum depression, attachment problems".
  • VTA and accumbens, clinical: "Depression (anhedonia), ADHD, addiction, mania"; where it appears in the book: "the extinguishing of SEEKING and anhedonia in depression (Chapter 8)".
  • PAG, clinical: "PTSD and dissociation, selective mutism, exhaustion in depression, the EMDR hypothesis".

In the atlas

Regions

Core structures in bold.

Networks

Neurotransmitter pathways

Panksepp systems

References

1. Schmaal L et al. (2016). Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group. Molecular Psychiatry, 21(6), 806–812. Search PubMed
2. Schmaal L et al. (2017). Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Molecular Psychiatry, 22(6), 900–909. Search PubMed
3. Shorey S, Ng ED, Wong CHJ (2022). Global prevalence of depression and elevated depressive symptoms among adolescents: a systematic review and meta-analysis. British Journal of Clinical Psychology, 61(2), 287–305. Search PubMed
4. Treatment for Adolescents With Depression Study (TADS) Team (2004). Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. JAMA, 292(7), 807–820. Search PubMed
5. Watt DF, Panksepp J (2009). Depression: an evolutionarily conserved mechanism to terminate separation distress? A review of aminergic, peptidergic, and neural network perspectives. Neuropsychoanalysis, 11(1), 7–51. Search PubMed