RESEARCH MONOGRAPH · KDC-MN-220

Clomipramine

May 9, 2026 Kodiac biolabs Research Revised May 30, 2026 3 min read

Our opinion on this compound

75/100

The serotonergic outlier of the TCAs and still the OCD reference compound

Clomipramine is a weird member of the TCA family and thats exactly what makes it interesting. Most tricyclics lean noradrenergic. Clomipramine, by virtue of that chlorine on the dibenzazepine and the tertiary amine sidechain, tips hard the other way. Parent compound has SERT Ki in the low nanomolar range, and its desmethyl metabolite then swings back toward NET. So in plasma you get a serotonergic parent plus a noradrenergic active metabolite riding alongside. Thats unusual.

The historical importance is OCD. Before SSRIs landed, clomipramine was the first compound to show convincing effects on obsessive-compulsive symptomatology in controlled trials, going back to the Insel and Murphy work at NIMH in the eighties. Even now, in head-to-head trials, clomipramine often beats SSRIs on effect size in OCD populations, which is a finding people in psychopharm still argue about. Whether thats the serotonergic potency, the metabolite contribution, the sigma-1 affinity, or something else entirely is honestly not fully settled.

For research it's a useful comparator if you're doing serotonergic transporter work, particularly because it gives you a TCA scaffold rather than an SSRI scaffold. Different physicochemical behavior, different tissue distribution. We've also seen it used in veterinary behavior research, where it remains a frontline compound for canine compulsive disorders.

What we don't like is the safety margin. The sodium channel and cardiac effects are real, the anticholinergic load is heavy compared to desipramine or nortriptyline, and seizure threshold drops measurably at the high end of exposure. None of that matters for in vitro work but it does shape how the clinical signal is interpreted.

Sourcing is fine. Hydrochloride salt is widely available, the reference standard is well characterized, and CYP2D6 plus CYP1A2 handle the metabolism in case you need to think about that in pharmacokinetic studies.

Worth keeping around if you do compulsivity models, serotonergic biology, or want a genuine 5-HT-tilted TCA for pharmacological dissection. Not exciting, just useful.

Evidence: 86
Mechanism: 84
Reliability: 80
Safety: 55
Sourcing: 85
Value: 76
Signal: 65
Staying power: 70

Plain-language summary Intrigue 64 / 100

Clomipramine (Anafranil) is a tricyclic antidepressant with one chlorine atom added to imipramine, a small change that flips the selectivity sharply toward serotonin. It is in fact the most potent serotonin reuptake blocker in the entire tricyclic class, with affinity rivaling modern SSRIs. The active leftover after liver metabolism then shifts steady-state activity back toward norepinephrine, so the drug ends up doing both jobs over a 24-hour period. It is the only tricyclic with FDA approval for OCD and remains a third-line option for severe OCD when SSRIs fail. The usual tricyclic burdens (sedation, anticholinergic effects, cardiac risk in overdose) all apply. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Tricyclic antidepressant (chlorinated tertiary amine)

A chloro-substituted TCA with the most potent SERT inhibition in the class; the only TCA with FDA approval for OCD.

Abstract

Clomipramine (3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine; CAS 303-49-1; molecular formula C19H23ClN2; molecular weight 314.85) is a 3-chloro-substituted analog of imipramine developed at Geigy and approved by the FDA in 1989 under the trade name Anafranil. The chloro substitution shifts transporter selectivity sharply toward SERT (SERT Ki approximately 0.28 nM, the most potent in the TCA class; NET Ki approximately 38 nM). The active metabolite N-desmethylclomipramine (formed via CYP3A4/CYP2C19) is a NET-preferring secondary amine, producing balanced steady-state monoaminergic activity from a SERT-dominant parent. Off-target activity parallels other tertiary amine TCAs: muscarinic, H1, alpha-1, and sodium channel block. Plasma half-life is 19 to 37 hours. The compound is the only TCA with FDA approval for obsessive-compulsive disorder, an indication where the SSRI class typically requires higher doses; clomipramine remains a benchmark in treatment-resistant OCD. Used as the reference SERT-potent TCA in mechanism studies.

Mechanism of action

Most potent SERT inhibition in TCA class; active metabolite N-desmethylclomipramine shifts steady-state to NET. Anticholinergic, antihistaminergic, alpha-1, and sodium channel block.

Reported research dose ranges

Reported research dose ranges in the literature.

References

DeVeaugh-Geiss J, et al. Clomipramine hydrochloride in the treatment of obsessive compulsive disorder. Arch Gen Psychiatry 1989.
Trimble MR. Worldwide use of clomipramine. J Clin Psychiatry 1990.
Faravelli C, et al. Comparison of clomipramine with other TCAs and SSRIs. CNS Drugs 2003.

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KDC-MN-220

The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.

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Clomipramine

Abstract

Mechanism of action

Reported research dose ranges

References

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Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

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