Precision Psychiatry Approach to Treat Depression and Anxiety Targeting the Stress Hormone System – V1b-antagonists as a Case in Point

Abstract

The future of depression pharmacotherapy lies in a precision medicine approach that recognizes that depression is a disease where different causalities drive symptoms. That approach calls for a departure from current diagnostic categories, which are broad enough to allow adherence to the “one-size-fits-all” paradigm, which is complementary to the routine use of “broad-spectrum” mono-amine antidepressants. Similar to oncology, narrowing the overinclusive diagnostic window by implementing laboratory tests, which guide specifically targeted treatments, will be a major step forward in overcoming the present drug discovery crisis.

A substantial subgroup of patients presents with signs and symptoms of hypothalamic-pituitary-adrenocortical (HPA) overactivity. Therefore, this stress hormone system was considered to offer worthwhile targets. Some promising results emerged, but in sum, the results achieved by targeting corticosteroid receptors were mixed.

More specific are non-peptidergic drugs that block stress-responsive neuropeptides, corticotropin-releasing hormone (CRH), and arginine vasopressin (AVP) in the brain by antagonizing their cognate CRHR1-and V1b-receptors. If a patientʼs depressive symptomatology is driven by overactive V1b-signaling then a V1b-receptor antagonist should be first-line treatment. To identify the patient having this V1b-receptor overactivity, a neuroendocrine test, the so-called dex/CRH-test, was developed, which indicates central AVP release but is too complicated to be routinely used. Therefore, this test was transformed into a gene-based “near-patient” test that allows immediate identification if a depressed patient’s symptomatology is driven by overactive V1b-receptor signaling. We believe that this precision medicine approach will be the next major innovation in the pharmacotherapy of depression.

Keywords

depression - anxiety disorders - precision psychiatry - HPA axis - V1b-receptor antagonists

Publication History

Received: 03 May 2024

Accepted after revision: 06 June 2024

Article published online:
19 August 2024

• References

• 1 Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: Toward combination strategies with curative potential. Cell 2015; 161: 205-214
• 2 Editorial Precision cardiology in the digital era. Nat Rev Cardiol 2019; 16: 637-637
• 3 Cohen PR, Kurzrock R. Dermatologic disease-directed targeted therapy (D(3)T(2)): The application of biomarker-based precision medicine for the personalized treatment of skin conditions-precision dermatology. Dermatol Ther (Heidelb) 2022; 12: 2249-2271
• 4 Holsboer F. How can we realize the promise of personalized antidepressant medicines?. Nat Rev Neurosci 2008; 9: 638-646
• 5 Kuhn R. Treatment of depressive states with an iminodibenzyl derivative (G 22355). Schweiz Med Wochenschr 1957; 87: 1135-1140
• 6 Angst J. A clinical analysis of the effects of tofranil in depression. Longitudinal and follow-up studies. Treatment of blood-relations. Psychopharmacologia 1961; 2: 381-407
• 7 Carhart-Harris R, Giribaldi B, Watts R. et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med 2021; 384: 1402-1411
• 8 Krystal JH, Karper LP, Seibyl JP. et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199-214
• 9 Nguyen TD, Kowalec K, Pasman J. et al. Genetic contribution to the heterogeneity of major depressive disorder: Evidence from a sibling-based design using Swedish National Registers. Am J Psychiatry 2023; 180: 714-722
• 10 Cipriani A, Furukawa TA, Salanti G. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet 2018; 391: 1357-1366
• 11 Rush AJ, Trivedi MH, Wisniewski SR. 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: 1905-1917
• 12 Kraft JB, Peters EJ, Slager SL. et al. Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry 2007; 61: 734-742
• 13 Serretti A, Benedetti F, Zanardi R. et al. The influence of serotonin transporter promoter polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1074-1084
• 14 Greden JF, Parikh SV, Rothschild AJ. et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res 2019; 111: 59-67
• 15 Zeier Z, Carpenter LL, Kalin NH. et al. Clinical implementation of pharmacogenetic decision support tools for antidepressant drug prescribing. Am J Psychiatry 2018; 175: 873-886
• 16 Uhr M, Tontsch A, Namendorf C. et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 2008; 57: 203-209
• 17 Breitenstein B, Scheuer S, Bruckl TM. et al. Association of ABCB1 gene variants, plasma antidepressant concentration, and treatment response: Results from a randomized clinical study. J Psychiatr Res 2016; 73: 86-95
• 18 Breitenstein B, Scheuer S, Pfister H. et al. The clinical application of ABCB1 genotyping in antidepressant treatment: A pilot study. CNS Spectr 2014; 19: 165-175
• 19 Silberbauer LR, Rischka L, Vraka C. et al. ABCB1 variants and sex affect serotonin transporter occupancy in the brain. Mol Psychiatry 2022; 27: 4502-4509
• 20 Menke A. Is the HPA axis as target for depression outdated, or is there a new hope?. Front Psychiatry 2019; 10: 101
• 21 McEwen BS. Physiology and neurobiology of stress and adaptation: Central role of the brain. Physiol Rev 2007; 87: 873-904
• 22 Beurel E, Nemeroff CB. Interaction of stress, corticotropin-releasing factor, arginine vasopressin and behaviour. Curr Top Behav Neurosci 2014; 18: 67-80
• 23 de Kloet ER, Joels M, Holsboer F. Stress and the brain: From adaptation to disease. Nat Rev Neurosci 2005; 6: 463-475
• 24 Trapp T, Rupprecht R, Castrén M. et al. Heterodimerization between mineralocorticoid and glucocorticoid receptor: A new principle of glucocorticoid action in the CNS. Neuron 1994; 13: 1457-1462
• 25 Echeverria PC, Picard D. Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility. Biochim Biophys Acta 2010; 1803: 641-649
• 26 Denny WB, Valentine DL, Reynolds PD. et al. Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology 2000; 141: 4107-4113
• 27 Galigniana NM, Ballmer LT, Toneatto J. et al. Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51. J Neurochem 2012; 122: 4-18
• 28 Baischew A, Engel S, Geiger TM. et al. Structural and biochemical insights into FKBP51 as a Hsp90 co-chaperone. J Cell Biochem DOI: 10.1002/jcb.30384.
• 29 Carroll BJ, Feinberg M, Greden JF. et al. A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. Arch Gen Psychiatry 1981; 38: 15-22
• 30 Holsboer F, Liebl R, Hofschuster E. Repeated dexamethasone suppression test during depressive illness. Normalisation of test result compared with clinical improvement. J Affect Disord 1982; 4: 93-101
• 31 Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000; 23: 477-501
• 32 Rybakowski JK, Twardowska K. The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness. J Psychiatr Res 1999; 33: 363-370
• 33 von Bardeleben U, Holsboer F. Cortisol response to a combined dexamethasone-human corticotrophin-releasing hormone challenge in patients with depression. J Neuroendocrinol 1989; 1: 485-488
• 34 von Bardeleben U, Holsboer F. Effect of age on the cortisol response to human corticotropin-releasing hormone in depressed patients pretreated with dexamethasone. Biol Psychiatry 1991; 29: 1042-1050
• 35 Heuser I, Yassouridis A, Holsboer F. The combined dexamethasone/CRH test: A refined laboratory test for psychiatric disorders. J Psychiatr Res 1994; 28: 341-356
• 36 Holsboer F, von Bardeleben U, Wiedemann K. et al. Serial assessment of corticotropin-releasing hormone response after dexamethasone in depression. Implications for pathophysiology of DST nonsuppression. Biol Psychiatry 1987; 22: 228-234
• 37 Holsboer-Trachsler E, Stohler R, Hatzinger M. Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression. Psychiatry Res 1991; 38: 163-171
• 38 Zobel AW, Yassouridis A, Frieboes RM. et al. Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remitted depression. Am J Psychiatry 1999; 156: 949-951
• 39 Ising M, Horstmann S, Kloiber S. et al. Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression-a potential biomarker?. Biol Psychiatry 2007; 62: 47-54
• 40 von Bardeleben U, Stalla GK, Müller OA. et al. Blunting of ACTH response to human CRH in depressed patients is avoided by metyrapone pretreatment. Biol Psychiatry 1988; 24: 782-786
• 41 Gold PW, Chrousos G, Kellner C. et al. Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry 1984; 141: 619-627
• 42 Holsboer F, von Bardeleben U, Gerken A. et al. Blunted corticotropin and normal cortisol response to human corticotropin-releasing factor in depression. N Engl J Med 1984; 311: 1127
• 43 von Bardeleben U, Holsboer F, Stalla GK. et al. Combined administration of human corticotropin-releasing factor and lysine vasopressin induces cortisol escape from dexamethasone suppression in healthy subjects. Life Sci 1985; 37: 1613-1618
• 44 Purba JS, Hoogendijk WJ, Hofman MA. et al. Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch Gen Psychiatry 1996; 53: 137-143
• 45 Modell S, Yassouridis A, Huber J. et al. Corticosteroid receptor function is decreased in depressed patients. Neuroendocrinology 1997; 65: 216-222
• 46 Stec I, Barden N, Reul JM. et al. Dexamethasone nonsuppression in transgenic mice expressing antisense RNA to the glucocorticoid receptor. J Psychiatr Res 1994; 28: 1-5
• 47 Arcego DM, Buschdorf JP, O'Toole N. et al. A glucocorticoid-sensitive hippocampal gene network moderates the impact of early-life adversity on mental health outcomes. Biol Psychiatry 2024; 95: 48-61
• 48 Reul JM, Labeur MS, Grigoriadis DE. et al. Hypothalamic-pituitary-adrenocortical axis changes in the rat after long-term treatment with the reversible monoamine oxidase-A inhibitor moclobemide. Neuroendocrinology 1994; 60: 509-519
• 49 Reul JM, Stec I, Söder M. et al. Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology 1993; 133: 312-320
• 50 Pepin MC, Govindan MV, Barden N. Increased glucocorticoid receptor gene promoter activity after antidepressant treatment. Mol Pharmacol 1992; 41: 1016-1022
• 51 Montkowski A, Barden N, Wotjak C. et al. Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. J Neuroendocrinol 1995; 7: 841-845
• 52 Carvalho LA, Pariante CM. In vitro modulation of the glucocorticoid receptor by antidepressants. Stress 2008; 11: 411-424
• 53 Ding Y, Wei Z, Yan H. et al. Efficacy of treatments targeting hypothalamic-pituitary-adrenal systems for major depressive disorder: A meta-analysis. Front Pharmacol 2021; 12: 732157
• 54 Schatzberg AF, Rothschild AJ, Langlais PJ. et al. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res 1985; 19: 57-64
• 55 Belanoff JK, Flores BH, Kalezhan M. et al. Rapid reversal of psychotic depression using mifepristone. J Clin Psychopharmacol 2001; 21: 516-521
• 56 Otte C, Hinkelmann K, Moritz S. et al. Modulation of the mineralocorticoid receptor as add-on treatment in depression: A randomized, double-blind, placebo-controlled proof-of-concept study. J Psychiatr Res 2010; 44: 339-346
• 57 Holsboer F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res 1999; 33: 181-214
• 58 Jahn H, Schick M, Kiefer F. et al. Metyrapone as additive treatment in major depression: A double-blind and placebo-controlled trial. Arch Gen Psychiatry 2004; 61: 1235-1244
• 59 Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992; 6: 2311-2322
• 60 Rupprecht R, Ströhle A, Hermann B. et al. Neuroactive steroid concentrations following metyrapone administration in depressed patients and healthy volunteers. Biol Psychiatry 1998; 44: 912-914
• 61 Vale W, Spiess J, Rivier C. et al. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981; 213: 1394-1397
• 62 Nemeroff CB. The corticotropin-releasing factor (CRF) hypothesis of depression: New findings and new directions. Mol Psychiatry 1996; 1: 336-342
• 63 Chalmers DT, Lovenberg TW, De Souza EB. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: Comparison with CRF1 receptor mRNA expression. J Neurosci 1995; 15: 6340-6350
• 64 Nemeroff CB, Widerlov E, Bissette G. et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984; 226: 1342-1344
• 65 Nemeroff CB, Owens MJ, Bissette G. et al. Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry 1988; 45: 577-579
• 66 Raadsheer FC, Hoogendijk WJ, Stam FC. et al. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994; 60: 436-444
• 67 Heuser I, Bissette G, Dettling M. et al. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: Response to amitriptyline treatment. Depress Anxiety 1998; 8: 71-79
• 68 Holsboer F, von Bardeleben U, Steiger A. Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man. Neuroendocrinology 1988; 48: 32-38
• 69 Schüssler P, Kluge M, Gamringer W. et al. Corticotropin-releasing hormone induces depression-like changes of sleep electroencephalogram in healthy women. Psychoneuroendocrinology 2016; 74: 302-307
• 70 Vgontzas AN, Bixler EO, Wittman AM. et al. Middle-aged men show higher sensitivity of sleep to the arousing effects of corticotropin-releasing hormone than young men: Clinical implications. J Clin Endocrinol Metab 2001; 86: 1489-1495
• 71 Held K, Kunzel H, Ising M. et al. Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression. J Psychiatr Res 2004; 38: 129-136
• 72 Lu A, Steiner MA, Whittle N. et al. Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. Mol Psychiatry 2008; 13: 1028-1042
• 73 Kimura M, Muller-Preuss P, Lu A. et al. Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep. Mol Psychiatry 2010; 15: 154-165
• 74 Zobel AW, Nickel T, Künzel HE. et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: The first 20 patients treated. J Psychiatr Res 2000; 34: 171-181
• 75 Spierling SR, Zorrilla EP. Don't stress about CRF: Assessing the translational failures of CRF(1)antagonists. Psychopharmacology (Berl) 2017; 234: 1467-1481
• 76 Griebel G, Holsboer F. Neuropeptide receptor ligands as drugs for psychiatric diseases: The end of the beginning?. Nat Rev Drug Discov 2012; 11: 462-478
• 77 Landgraf R. The involvement of the vasopressin system in stress-related disorders. CNS Neurol Disord Drug Targets 2006; 5: 167-179
• 78 Scott LV, Dinan TG. Vasopressin as a target for antidepressant development: An assessment of the available evidence. J Affect Disord 2002; 72: 113-124
• 79 Wotjak CT, Ganster J, Kohl G. et al. Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: New insights into the secretory capacities of peptidergic neurons. Neuroscience 1998; 85: 1209-1222
• 80 de Wied D. Peptides and behavior. Life Sci 1977; 20: 195-204
• 81 Gold PW, Goodwin FK, Reus VI. Vasopressin in affective illness. Lancet 1978; 1: 1233-1236
• 82 Landgraf R, Wigger A. High vs low anxiety-related behavior rats: An animal model of extremes in trait anxiety. Behav Genet 2002; 32: 301-314
• 83 Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: Implications for anxiety, depression, and social behaviors. Trends Neurosci 2012; 35: 649-659
• 84 Wigger A, Sánchez MM, Mathys KC. et al. Alterations in central neuropeptide expression, release, and receptor binding in rats bred for high anxiety: Critical role of vasopressin. Neuropsychopharmacology 2004; 29: 1-14
• 85 Keck ME, Welt T, Müller MB. et al. Reduction of hypothalamic vasopressinergic hyperdrive contributes to clinically relevant behavioral and neuroendocrine effects of chronic paroxetine treatment in a psychopathological rat model. Neuropsychopharmacology 2003; 28: 235-243
• 86 Bunck M, Czibere L, Horvath C. et al. A hypomorphic vasopressin allele prevents anxiety-related behavior. PLoS One 2009; 4: e5129
• 87 van West D, Del-Favero J, Aulchenko Y. et al. A major SNP haplotype of the arginine vasopressin 1B receptor protects against recurrent major depression. Mol Psychiatry 2004; 9: 287-292
• 88 Keck ME, Wigger A, Welt T. et al. Vasopressin mediates the response of the combined dexamethasone/CRH test in hyper-anxious rats: Implications for pathogenesis of affective disorders. Neuropsychopharmacology 2002; 26: 94-105
• 89 Corbani M, Marir R, Trueba M. et al. Neuroanatomical distribution and function of the vasopressin V(1B) receptor in the rat brain deciphered using specific fluorescent ligands. Gen Comp Endocrinol 2018; 258: 15-32
• 90 Chaki S. Vasopressin V1B receptor antagonists as potential antidepressants. Int J Neuropsychopharmacol 2021; 24: 450-463
• 91 Kanes SJ, Dennie L, Perera P. Targeting the arginine vasopressin V(1b) receptor system and stress response in depression and other neuropsychiatric disorders. Neuropsychiatr Dis Treat 2023; 19: 811-828
• 92 Serradeil-Le Gal C, Wagnon J, Simiand J. et al. Characterization of (2 S,4 R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), a selective and orally active vasopressin V1b receptor antagonist. J Pharmacol Exp Ther 2002; 300: 1122-1130
• 93 Griebel G, Simiand J, Serradeil-Le Gal C. et al. Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders. Proc Natl Acad Sci U S A 2002; 99: 6370-6375
• 94 Hodgson RA, Mullins D, Lu SX. et al. Characterization of a novel vasopressin V1b receptor antagonist, V1B-30N, in animal models of anxiety-like and depression-like behavior. Eur J Pharmacol 2014; 730: 157-163
• 95 Griebel G, Beeské S, Stahl SM. The vasopressin V(1b) receptor antagonist SSR149415 in the treatment of major depressive and generalized anxiety disorders: Results from 4 randomized, double-blind, placebo-controlled studies. J Clin Psychiatry 2012; 73: 1403-1411
• 96 Katz DA, Liu W, Locke C. et al. Clinical safety and hypothalamic-pituitary-adrenal axis effects of the arginine vasopressin type 1B receptor antagonist ABT-436. Psychopharmacology (Berl) 2016; 233: 71-81
• 97 Katz DA, Locke C, Greco N. et al. Hypothalamic-pituitary-adrenal axis and depression symptom effects of an arginine vasopressin type 1B receptor antagonist in a one-week randomized Phase 1b trial. Brain Behav 2017; 7: e00628
• 98 Kamiya M, Sabia HD, Marella J. et al. Efficacy and safety of TS-121, a novel vasopressin V(1B) receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study. J Psychiatr Res 2020; 128: 43-51
• 99 Koga K, Nagai Y, Hanyu M. et al. High-contrast PET imaging of vasopressin V(1B) receptors with a novel radioligand, (11)C-TASP699. J Nucl Med 2017; 58: 1652-1658
• 100 Gillies GE, Linton EA, Lowry PJ. Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 1982; 299: 355-357
• 101 Aguilera G, Subburaju S, Young S. et al. The parvocellular vasopressinergic system and responsiveness of the hypothalamic pituitary adrenal axis during chronic stress. Prog Brain Res 2008; 170: 29-39
• 102 Camp RM, Remus JL, Kalburgi SN. et al. Fear conditioning can contribute to behavioral changes observed in a repeated stress model. Behav Brain Res 2012; 233: 536-544
• 103 Lowrance SA, Ionadi A, McKay E. et al. Sympathetic nervous system contributes to enhanced corticosterone levels following chronic stress. Psychoneuroendocrinology 2016; 68: 163-170
• 104 Holsboer F, Müller-Myhsok B. Method for predicting a treatment response to a CRHR1 antagonist and/or a V1B antagonist in a patient with depressive and/or anxiety symptoms. In: Office USPaT ed. U.S.A.: Max-Planck-Gesellschaft zur Förderung der Wissenschaften E.V. 2019
• 105 de Leon J, Susce MT, Murray-Carmichael E. The AmpliChip CYP450 genotyping test: Integrating a new clinical tool. Mol Diagn Ther 2006; 10: 135-151
• 106 Colla M, Offenhammer B, Scheerer H. et al. Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation – Clinical and safety results. J Psychiatr Res 2024; 173: 124-130 DOI: 10.1016/j.jpsychires.2024.03.002.
• 107 AbbVie. Allergan Announces Phase 3 Results for Rapastinel as an Adjunctive Treatment of Major Depressive Disorder (MDD) 2019. https://news.abbvie.com/2019-03-06-Allergan-Announces-Phase-3-Results-for-Rapastinel-as-an-Adjunctive-Treatment-of-Major-Depressive-Disorder-MDD
• 108 Miller AH, Raison CL. Burning down the house: Reinventing drug discovery in psychiatry for the development of targeted therapies. Mol Psychiatry 2023; 28: 68-75
• 109 Chisholm D, Sweeny K, Sheehan P. et al. Scaling-up treatment of depression and anxiety: Aglobal return on investment analysis. Lancet Psychiatry 2016; 3: 415-424