Anafranil: Clinical Profile & Pharmacology

Anafranil, known generically as clomipramine hydrochloride, stands as a cornerstone in neuropsychopharmacology, fundamentally transforming the therapeutic landscape for severe obsessive-compulsive disorder and refractory mood disorders. Developed initially as a chlorinated derivative of the dibenzazepine class, the compound bridges classic tricyclic antidepressant mechanisms with potent serotonergic reuptake inhibition, establishing an empirical paradigm for neurobiological interventions. This comprehensive monograph explores its pharmacodynamic profile, historical emergence, clinical indications, diagnostic metrics, and enduring pharmacological relevance.

Anafranil (Clomipramine)

1. Concise Definition

Anafranil is the proprietary trade name for clomipramine hydrochloride, a tricyclic pharmacological agent belonging to the dibenzazepine chemical class that functions as a potent inhibitor of presynaptic serotonin and norepinephrine reuptake transporters. Clinically recognized as a gold-standard pharmacotherapy for obsessive-compulsive disorder (OCD), it is also deployed internationally for major depressive disorder, cataplexy associated with narcolepsy, and select chronic neuropathic pain conditions.

Biochemically, Anafranil acts as a dual-action monoamine reuptake inhibitor with distinctive selectivity; the parent molecule exerts an exceptionally high affinity for the serotonin transporter (SERT), while its primary active hepatic metabolite, desmethylclomipramine, primarily inhibits the norepinephrine transporter (NET). This bifunctional profile generates a profound modulation of central monoaminergic neurotransmission, producing therapeutic neuroplastic alterations across cortico-striato-thalamo-cortical (CSTC) circuits alongside peripheral antimuscarinic, antihistaminic, and antiadrenergic physiological effects.

2. Etymology & Linguistic Origin

The trade name Anafranil was coined by the Swiss pharmaceutical manufacturer Geigy (later Ciba-Geigy, and currently Novartis) during the mid-20th century. The prefix Ana- derives from the Greek root ana- (ἀνά), denoting upward movement, renewal, or elevation, metaphorically referencing the elevation of clinical mood and restoration of psychic equilibrium. The medial syllable -fran- is historically linked to early nomenclature stems used by Geigy for imipramine-derived psychotropics (as seen in its predecessor, Tofranil), while the terminal -il reflects standard mid-century pharmaceutical naming conventions for dibenzazepine-type psychoactive compounds.

The generic international nonproprietary name (INN), clomipramine, is a systematic chemical portmanteau. It denotes the incorporation of a chlorine substituent (chlor- / clo-) into the existing dibenzazepine backbone of imipramine (which itself derives from the chemical descriptor 5-(3-dimethylaminopropyl)-10,11-dihydro-5H-dibenz[b,f]azepine). This single chloro-substitution at the 3-position of the ring system markedly amplifies serotonergic affinity relative to other classical tricyclics.

3. Pronunciation & Grammatical Form

In standard English nomenclature, Anafranil is phonetically transcribed as /ˌæn.əˈfræn.ɪl/ (AN-uh-FRAN-il). The generic designation clomipramine is pronounced /kloʊˈmɪp.rəˌmiːn/ or /kləˈmɪp.rəˌmiːn/ (kloh-MIP-ruh-meen). Chemically, its full systematic salt name is 3-chloro-10,11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine hydrochloride.

Grammatically, the term functions as a proper noun when designating the commercial formulation manufactured by Novartis or licensed distributors, and as a common noun when referring generally to the medication or its dosage forms (e.g., “the patient was stabilized on oral clomipramine”). It can also function adjectivally in clinical phrases such as “clomipramine-induced anticholinergic syndrome” or “Anafranil challenge paradigm.”

4. Detailed Conceptual Explanation

To fully understand Anafranil, one must appreciate its unique pharmacological footprint at the intersection of tricyclic chemistry and selective monoaminergic modulation. Structurally composed of a central cycloheptadiene-like azepine ring fused between two benzene rings, Anafranil exhibits a three-dimensional conformation that sterically mimics the biogenic monoamines. Unlike second-generation selective serotonin reuptake inhibitors (SSRIs), Anafranil maintains substantial cross-reactivity across multiple postsynaptic G-protein-coupled receptors and ion channels, which accounts for both its robust clinical efficacy and its prominent side-effect profile.

The primary mechanism of action relies upon competitive inhibition of the solute carrier family 6 member 4 (SLC6A4, or SERT). By preventing the clearance of 5-hydroxytryptamine (serotonin) from the synaptic cleft, Anafranil dramatically enhances downstream serotonergic neurotransmission. Over sustained therapeutic windows lasting between six to twelve weeks, this synaptic surplus induces profound down-regulation of inhibitory somatodendritic 5-HT_1A autoreceptors and terminal 5-HT_1D autoreceptors, uncoupling the endogenous negative feedback loop and facilitating persistent, tonic serotonergic firing throughout limbic and prefrontal projections.

Concurrently, hepatic biotransformation through the cytochrome P450 enzyme system converts clomipramine into its active N-demethylated metabolite, desmethylclomipramine (norclomipramine). This metabolite shifts pharmacological targets, exhibiting steep selectivity for the norepinephrine transporter (NET, SLC6A2). Consequently, the overall in vivo profile of Anafranil is that of a balanced, dual serotonin-norepinephrine reuptake inhibitor. This dual mechanistic action exerts downstream effects on brain-derived neurotrophic factor (BDNF), cyclic AMP response element-binding protein (CREB) phosphorylation, and dendritic remodeling across the hippocampus and striatum.

Beyond monoamine transporters, Anafranil exhibits notable antagonist affinity for histamine H₁ receptors, muscarinic acetylcholine receptors (M₁ through M₅), alpha-1 adrenergic receptors, and voltage-gated sodium/potassium channels. Blockade of H₁ receptors produces pronounced sedation and metabolic weight gain; antimuscarinic activity yields peripheral dry mouth, visual accommodation impairment, urinary retention, and constipation; and alpha-1 antagonism precipitates peripheral vasodilation and orthostatic hypotension. Crucially, cardiac myocyte sodium channel inhibition (quinidine-like class Ia antiarrhythmic action) prolongs intraventricular conduction and the corrected QT (QTc) interval, necessitating careful therapeutic drug monitoring.

5. Historical Development

The origins of Anafranil trace back to the revolutionary psychopharmacological epoch of the 1950s and 1960s. Following Roland Kuhn’s historic discovery of the antidepressant properties of imipramine in 1957 at Münsterlingen Psychiatric Hospital in Switzerland, chemists at J.R. Geigy S.A. engaged in rational drug design to modify the tricyclic core. In 1961, synthetic chemists synthesized clomipramine by introducing an electronegative chlorine atom at position 3 of the dibenzazepine tricyclic nucleus. Early preclinical screenings quickly demonstrated that this substitution enhanced serotonergic transport blockade far beyond that observed in imipramine, amitriptyline, or nortriptyline.

During the late 1960s, European and Latin American clinicians began using clomipramine for affective disorders, noting its marked effectiveness in melancholy with prominent psychomotor agitation. However, its pivotal breakthrough occurred in the clinical recognition of obsessive-compulsive neurosis—a condition previously considered largely untreatable by somatic psychotropics and predominantly consigned to psychoanalytic interventions or ablative neurosurgery. In 1967, Spanish psychiatrist Juan López-Ibor published groundbreaking clinical observations showing that intravenous infusions of clomipramine could remit severe, obsessional states.

Throughout the 1970s and 1980s, rigorous double-blind, placebo-controlled trials led by pioneering researchers—including Joseph Zohar, Dennis Murphy, and Judith Rapoport at the United States National Institute of Mental Health (NIMH)—conclusively established the unique anti-obsessional efficacy of Anafranil. In 1989, the United States Food and Drug Administration (FDA) formally approved Anafranil for the treatment of pediatric and adult OCD. This landmark approval made it the first drug cleared by the regulatory agency specifically for obsessive-compulsive disorder, serving as the empirical foundation for modern serotonergic hypotheses of OCD pathophysiology.

6. Theoretical Foundations

The clinical efficacy of Anafranil is grounded in several major theoretical models of neuropsychiatric illness, most notably the Serotonergic Hypothesis of OCD and the Cortico-Striato-Thalamo-Cortical (CSTC) Dysregulation Model. Before clomipramine’s systematic deployment, biological psychiatry struggled to explain the mechanistic divergence between generalized affective disorders and ego-dystonic repetitive cognitive processes. Because standard noradrenergic tricyclics (such as desipramine) systematically failed to ameliorate obsessions and compulsions, the distinct, rapid anti-obsessional response to clomipramine provided the first pharmacodynamic evidence that central serotonergic pathway pathology is a primary driver of compulsive phenomena.

From a neurocircuitry perspective, obsessive-compulsive symptomatology arises from an imbalance in parallel processing loops running from the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) through the ventral striatum, globus pallidus, and thalamus back to the cortex. Overactivity in the direct striatal pathway results in failure to gate intrusive thoughts and stereotyped behavioral programs. Clomipramine is theorized to recalibrate this circuit by enhancing 5-HT signaling at inhibitory postsynaptic 5-HT_2A and 5-HT_2C receptors within the striatum, which suppresses aberrant metabolic hyperactivity in the orbitofrontal cortex and caudate nucleus.

A complementary framework, the Neuroplasticity and Epigenetic Hypothesis of Depression, underpins Anafranil’s efficacy in major affective disorders. Sustained clomipramine administration activates intracellular signaling cascades, notably the mitogen-activated protein kinase (MAPK) and protein kinase A (PKA) pathways. This promotes neurogenesis in the subgranular zone of the dentate gyrus and reverses stress-induced dendritic atrophy in CA3 pyramidal neurons, addressing core neurobiological deficits seen in severe and melancholic depression.

7. Key Components, Types & Dimensions

Understanding Anafranil requires examining its pharmacokinetics, formulations, active entities, and metabolic transformations:

• Parent Drug (Clomipramine): A tertiary amine tricyclic characterized by an elimination half-life of 19 to 37 hours. It exhibits an exceptionally high SERT:NET inhibition ratio of approximately 100:1, functioning as the driving force behind the acute serotonergic actions of the medication.
• Primary Active Metabolite (Desmethylclomipramine): Generated via hepatic demethylation primarily mediated by CYP2C19, CYP1A2, and CYP3A4. Desmethylclomipramine has a significantly longer half-life (ranging from 54 to 77 hours) and acts as an exceptionally potent inhibitor of norepinephrine reuptake with low serotonergic activity.
• Secondary Metabolites (8-Hydroxy Derivatives): Produced through aromatic ring hydroxylation catalyzed by CYP2D6. 8-hydroxyclomipramine and 8-hydroxydesmethylclomipramine retain partial biological activity and clear largely through renal pathways; their accumulation is implicated in cardiotoxic side effects.
• Oral Formulations: Commercially distributed in standard immediate-release oral capsules containing 25 mg, 50 mg, or 75 mg of clomipramine hydrochloride, formulated alongside pharmaceutical excipients such as lactose, magnesium stearate, and titanium dioxide.
• Controlled-Release / Retard Formulations: Available in select non-US markets (e.g., Anafranil SR 75 mg), providing slow mucosal absorption that flattens peak plasma concentrations ($C_{\max}$) to mitigate acute anticholinergic surges and postural orthostasis.
• Parenteral Preparations: Intravenous and intramuscular ampoules (typically 25 mg/2 mL) utilized historically or in specialized inpatient centers for rapid dose titration, gastrointestinal bypass, or treatment-refractory depressive crises.

8. Examples & Illustrative Cases

The following anonymized clinical vignettes illustrate typical trajectories, monitoring paradigms, and challenges encountered during Anafranil pharmacotherapy.

Case 1: Treatment-Resistant Obsessive-Compulsive Disorder
A 32-year-old software engineer presented with a 12-year history of debilitating contamination obsessions and mental cleaning rituals occupying upwards of six hours daily. The patient had previously completed adequate, high-dose trials of sertraline (200 mg/day for 16 weeks) and escitalopram (30 mg/day for 20 weeks), each augmented with exposure and response prevention (ERP) therapy, but achieved less than a 15% reduction in symptoms. Baseline baseline electrocardiography (ECG) revealed a normal corrected QT interval of 408 ms.

The clinician initiated Anafranil at 25 mg at bedtime, titrating upward by 25 mg every four to five days until reaching 150 mg/day, with subsequent titration to 225 mg/day guided by clinical response. At week ten, the patient noted a substantial reduction in obsessive intrusive distress, with compulsive engagement dropping to under 45 minutes daily. Serum therapeutic drug monitoring confirmed combined clomipramine and desmethylclomipramine concentrations of 340 ng/mL, while follow-up ECG revealed a QTc prolongation to 438 ms, which remained well within clinically acceptable parameters.

Case 2: Cataplexy Secondary to Narcolepsy Type 1
A 24-year-old female diagnosed with narcolepsy type 1 experienced severe, emotionally triggered cataplectic attacks, suffering bilateral knee buckling and falls several times per week, primarily evoked by laughter. Modafinil successfully treated her daytime hypersomnolence but left her cataplexy unmanaged. Low-dose Anafranil was initiated at 10 mg nocturnally and titrated to 25 mg daily. The potent noradrenergic reuptake inhibition provided by the active metabolite rapidly suppressed REM-sleep motor disinhibition, resolving the cataplectic collapses within 72 hours, with mild xerostomia as the only documented adverse effect.

9. Measurement & Assessment

Assessing the indications, efficacy, and safety profile of Anafranil requires standardized psychometric evaluation and rigorous physiological monitoring:

• Yale-Brown Obsessive Compulsive Scale (Y-BOCS): The gold-standard, 10-item clinician-administered rating scale quantifying the severity of obsessions and compulsions independent of specific thematic content. A baseline score $ge 24$ typically reflects severe disease indicating tricyclic pharmacotherapy, with a $ge 35%$ reduction denoting robust clinical response.
• Montgomery-Åsberg Depression Rating Scale (MADRS) & HAM-D: Standardized multi-item inventories used to quantify affective severity and monitor symptom changes when clomipramine is prescribed for major depressive episodes.
• Therapeutic Drug Monitoring (TDM): Laboratory quantification of steady-state trough plasma levels of parent clomipramine plus its active metabolite desmethylclomipramine via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The consensus therapeutic reference range is defined as 200 to 450 ng/mL; concentrations exceeding 500 ng/mL markedly elevate seizure and cardiotoxicity risks.
• Baseline and Serial Electrocardiography (ECG): Pre-treatment and post-titration assessment of intraventricular conduction velocities, primarily monitoring the PR interval, QRS complex duration (alert threshold: $> 120$ ms), and Bazett-corrected QTc interval (alert threshold: $> 460$ ms in biological males, $> 470$ ms in biological females).
• Orthostatic Vital Signs: Measurement of supine and standing blood pressure and pulse rate to detect subclinical alpha-1 adrenergic blockade and orthostatic drops greater than 20 mmHg systolic or 10 mmHg diastolic.
• CYP2D6 and CYP2C19 Pharmacogenomic Profiling: Molecular testing to identify poor, intermediate, extensive, or ultra-rapid metabolizer phenotypes, guiding personalized dosing to avoid unexpected toxicity or therapeutic failure.

10. Applications & Practical Significance

The practical application of Anafranil spans psychiatric, neurological, and somatic disciplines, highlighting its versatile clinical utility:

Obsessive-Compulsive Disorder: Anafranil remains an FDA-approved first-line therapeutic benchmark for adult and pediatric patients aged 10 years and older. Although contemporary treatment guidelines often initiate therapy with SSRIs due to their wider tolerability profiles, meta-analyses consistently confirm that Anafranil demonstrates higher absolute effect sizes than SSRIs in severe or refractory cohorts, positioning it as the premier second-line agent following standard SSRI failure.

Severe Affective Disorders: In unipolar major depressive episodes with melancholic, psychotic, or vegetative features, Anafranil delivers rapid and potent monoaminergic restoration. Its dual SERT-NET actions make it particularly effective in hospital-based inpatient psychiatry, where rapid symptom relief is paramount.

Related Obsessive-Compulsive and Impulse Spectrum Conditions: The medication is frequently applied off-label to manage body dysmorphic disorder (BDD), trichotillomania (hair-pulling disorder), excoriation (skin-picking) disorder, and severe compulsive gaming or hoarding behaviors unresponsive to frontline treatments.

Cataplexy and Sleep Architecture Disorders: Because desmethylclomipramine strongly suppresses rapid eye movement (REM) sleep, micro-doses of clomipramine (10–75 mg daily) provide rapid, sustained relief from cataplexy, hypnagogic hallucinations, and sleep paralysis in patients with narcolepsy.

Neuropathic Pain and Migraine Prophylaxis: By augmenting descending noradrenergic and serotonergic inhibitory pain pathways within the spinal dorsal horn, clomipramine serves as an effective analgesic adjunct in diabetic peripheral neuropathy, post-herpetic neuralgia, and refractory chronic tension-type headaches.

11. Research & Empirical Evidence

The academic literature on clomipramine spans over five decades, featuring seminal randomized controlled trials (RCTs) and extensive network meta-analyses. The foundational multicenter trial conducted by the Clomipramine Collaborative Study Group (1991), involving 520 patients across two parallel 10-week clinical trials, established that clomipramine achieved statistically and clinically superior reductions in Y-BOCS scores relative to placebo (mean reduction exceeding 40% vs. 8% on placebo), solidifying its place in academic neuropsychiatry.

Subsequent landmark comparative trials rigorously contrasted Anafranil with modern selective serotonin reuptake inhibitors. A seminal meta-analysis published by Eddy and colleagues (2004) in the Journal of Clinical Psychiatry analyzed 34 clinical trials and demonstrated that clomipramine possessed a significantly larger mean effect size ($d = 1.13$) compared to fluoxetine ($d = 0.52$), fluvoxamine ($d = 0.60$), and sertraline ($d = 0.69$). While methodological heterogeneity and variable study designs contributed to these differences, these findings established clomipramine’s unmatched pharmacological potency.

Modern network meta-analyses, such as the comprehensive study by Skapinakis et al. (2016) in Lancet Psychiatry, reaffirmed that while modern SSRIs exhibit superior drop-out rates secondary to side-effect tolerability, clomipramine consistently ranked highest or near the top in absolute efficacy endpoints for treatment-resistant OCD. Neuroimaging investigations, particularly positron emission tomography (PET) and functional MRI studies led by researchers such as Baxter, Saxena, and Rauch, showed that successful clomipramine treatment directly normalizes hypermetabolic activity in the right caudate nucleus and orbital frontal cortex, visually confirming its disease-modifying neurobiological effects.

12. Cultural & Cross-Cultural Considerations

The cross-cultural utilization, accessibility, and perception of Anafranil vary significantly between global healthcare ecosystems. In many low- and middle-income countries (LMICs), Anafranil remains on the World Health Organization (WHO) Model List of Essential Medicines because of its low cost, well-characterized chemical synthesis, and generic availability. In these regions, it often serves as a frontline treatment for both severe depression and OCD, whereas high-income countries often reserve it as a second- or third-line alternative behind more expensive branded or second-generation SSRIs and SNRIs.

Prescribing conventions also demonstrate clear regional divergence. In parts of Europe and Latin America, intravenous clomipramine pulse therapy remains an accepted clinical method for acute, inpatient management of severe catatonic depression and treatment-resistant obsessions. In contrast, this approach is virtually absent in North American psychiatric practice due to medicolegal concerns regarding intravenous arrhythmia risks. Furthermore, cultural beliefs surrounding psychiatric somatic side effects shape treatment adherence: in cultures where medication-induced weight gain, sexual dysfunction, or xerostomia are heavily stigmatized, premature discontinuation rates are markedly elevated, highlighting the necessity of culturally sensitive psychoeducation.

13. Criticisms, Debates & Limitations

Despite its proven efficacy, Anafranil has faced significant criticism and ongoing clinical debate, centered largely around its adverse-effect profile, narrow therapeutic index, and overdose lethality.

The principal critique focuses on its prominent anticholinergic, antihistaminic, and antiadrenergic side effects. Patients often report severe xerostomia, persistent constipation, blurred vision, sinus tachycardia, urinary hesitancy, sedation, and significant sexual dysfunction (including anorgasmia and erectile failure). These effects lead to high discontinuation rates in naturalistic clinical settings, with attrition often exceeding 30% in real-world cohorts.

The most pressing clinical concern is the risk of cardiotoxicity and lethal overdose. Unlike modern SSRIs, which are relatively safe in overdose, tricyclic antidepressants such as clomipramine exhibit substantial lethality when taken in toxic amounts. The ingestion of a two-week supply (1.5 to 2.5 grams) can prove fatal, inducing refractory ventricular arrhythmias (e.g., torsades de pointes, ventricular tachycardia), profound refractory hypotension, and intractable status epilepticus via GABA_A antagonism and myocardial fast sodium channel blockade. This profile creates a persistent clinical dilemma when prescribing the drug to severely depressed patients with active suicidal ideation.

Another area of debate concerns the dose-dependent elevation of seizure risk. At daily doses up to 250 mg, the incidence of unprovoked seizures remains approximately 0.5%; however, exceeding this ceiling spikes the cumulative seizure incidence to nearly 2.1%. Consequently, modern guidelines strictly mandate capping out-of-hospital oral dosing at 250 mg daily, while recommending careful titration protocols that some clinicians view as limiting optimal therapeutic dosing.

14. Related Terms & Distinctions

Understanding Anafranil requires distinguishing it from other psychotropic compounds across several drug classes:

• Imipramine (Tofranil): The unchlorinated parent tricyclic. While imipramine is structurally nearly identical, it acts primarily as a balanced dual reuptake inhibitor with slightly higher noradrenergic leaning, lacking clomipramine’s potent, sub-nanomolar affinity for the serotonin transporter.
• Fluoxetine (Prozac): A selective serotonin reuptake inhibitor. Unlike Anafranil, fluoxetine lacks significant anticholinergic, antihistaminic, or alpha-adrenergic receptor antagonism, and possesses virtually no affinity for the norepinephrine transporter, resulting in a significantly milder adverse effect profile alongside lower acute overdose lethality.
• Venlafaxine (Effexor): A serotonin-norepinephrine reuptake inhibitor (SNRI). While venlafaxine functionally reproduces the dual monoaminergic inhibition of clomipramine and desmethylclomipramine, it achieves this without blocking post-synaptic muscarinic, histaminergic, or alpha-1 receptors, avoiding classical tricyclic adverse effects.
• Fluvoxamine (Luvox): An SSRI with potent sigma-1 receptor agonist activity approved for OCD. Fluvoxamine shares Anafranil’s anti-obsessional utility, but presents a fundamentally distinct pharmacodynamic profile that lacks cardiotoxic sodium channel blockade.
• Amitriptyline (Elavil): A classical tertiary amine tricyclic antidepressant. Amitriptyline exhibits much stronger sedative and anticholinergic profiles while failing to match the specific, high-potency anti-obsessional clinical efficacy characteristic of clomipramine.

15. Summary & Key Takeaways

Anafranil (clomipramine hydrochloride) represents a landmark development in biological psychiatry and neuropsychopharmacology. It established the first definitive evidence that pharmacologically modulating central serotonergic pathways can treat the obsessions and compulsions of OCD. Through its parent drug and active metabolite desmethylclomipramine, Anafranil delivers dual serotonergic and noradrenergic reuptake inhibition, promoting lasting neuroplastic recovery across cortico-striato-thalamo-cortical pathways.

While newer SSRIs and SNRIs have largely supplanted Anafranil as initial therapies due to their wider therapeutic indices and lower overdose cardiotoxicity, clomipramine remains a crucial gold-standard intervention for treatment-resistant OCD, severe melancholic depression, and narcolepsy-associated cataplexy. When managed with careful clinical oversight—including therapeutic drug monitoring, baseline electrocardiography, and deliberate dose titration—Anafranil remains an indispensable psychiatric medication with proven efficacy.

References

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• Clomipramine Collaborative Study Group. (1991). Clomipramine in the treatment of patients with obsessive-compulsive disorder. Archives of General Psychiatry, 48(8), 730–738. https://doi.org/10.1001/archpsyc.1991.01810320054008
• Eddy, K. T., Dutra, L., Bradley, R., & Westen, D. (2004). A multidimensional meta-analysis of pharmacotherapy for obsessive-compulsive disorder. The Journal of Clinical Psychiatry, 65(8), 1018–1027. https://doi.org/10.4088/jcp.v65n0801
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• Skapinakis, P., Caldwell, D. M., Hollingworth, W., Bryden, P., Fineberg, N. A., Salkovskis, P., Welton, N. J., Baxter, H., Kessler, D., Churchill, R., & Lewis, G. (2016). Pharmacological and psychotherapeutic interventions for management of obsessive-compulsive disorder in adults: A systematic review and network meta-analysis. The Lancet Psychiatry, 3(8), 730–739. https://doi.org/10.1016/S2215-0366(16)30069-4