Clomipramine is a tricyclic antidepressant (TCA) marketed under the brand name Anafranil.
It is used primarily for the treatment of obsessive-compulsive disorder (OCD) and major depressive disorder, and sometimes prescribed off-label for panic disorder and chronic pain.
Clomipramine works by inhibiting the presynaptic reuptake of serotonin and norepinephrine, increasing their levels in the synaptic cleft and enhancing neurotransmission in the central nervous system.
Clomipramine is metabolized in the liver by cytochrome P450 enzymes, primarily CYP2D6 and CYP2C19. CYP2D6 and CYP2C19 encode enzymes that oxidize and break down clomipramine into its active and inactive metabolites.
Genetic variations in these genes can alter enzyme activity: an ultrarapid metabolizer may clear the drug too quickly, reducing its efficacy, while a poor metabolizer may process it more slowly, leading to higher blood levels and increased risk of side effects.
Depending on genetic variation, individuals can be classified as ultrarapid, rapid, normal, intermediate, or poor metabolizers; these categories predict how quickly clomipramine is processed, influencing drug concentrations, therapeutic response, and risk of adverse effects.
The following dosing guidelines are based on the available guidelines for clomipramine and genetic variation in CYP2D6 and CYP2C19.
| Phenotype | Clinical Consequence | Guideline Recommendation |
|---|---|---|
| Ultrarapid Metabolizer | Increased metabolism leading to lower plasma concentrations and risk of inadequate response. | Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose and utilize therapeutic drug monitoring to guide dose adjustments. |
| Normal Metabolizer | Normal metabolism with expected therapeutic levels. | Initiate therapy with recommended starting dose. |
| Intermediate Metabolizer | Reduced metabolism leading to higher plasma concentrations and increased risk of side effects. | Consider a 25% reduction of the recommended starting dose and utilize therapeutic drug monitoring to guide dose adjustments. |
| Poor Metabolizer | Greatly reduced metabolism resulting in significantly elevated plasma concentrations. | Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of the recommended starting dose and utilize therapeutic drug monitoring to guide dose adjustments. |
| Indeterminate | No CPIC guidance for this phenotype. | Initiate therapy with recommended starting dose. |
| Not available | No CPIC guidance for this phenotype. | Initiate therapy with recommended starting dose. |
| Phenotype | Clinical Consequence | Guideline Recommendation |
|---|---|---|
| Ultrarapid Metabolizer | Increased metabolism resulting in greater conversion of tertiary to secondary amines; potential reduced efficacy. | Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments. |
| Rapid Metabolizer | Increased metabolism with greater formation of secondary amines; potential for altered response or side effects. | Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments. |
| Normal Metabolizer | Normal metabolism with expected therapeutic levels. | Initiate therapy with recommended starting dose. |
| Intermediate Metabolizer | Reduced metabolism leading to slower conversion of tertiary amines. | Initiate therapy with recommended starting dose. |
| Poor Metabolizer | Greatly reduced metabolism resulting in decreased conversion to secondary amines. | Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19 (e.g., nortriptyline, desipramine). For tertiary amines, consider a 50% reduction of the recommended starting dose and utilize therapeutic drug monitoring to guide dose adjustments. |
| Likely Intermediate Metabolizer | Reduced metabolism similar to intermediate metabolizer. | Initiate therapy with recommended starting dose. |
| Likely Poor Metabolizer | Significantly reduced metabolism similar to poor metabolizer. | Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. For tertiary amines, consider a 50% reduction of the recommended starting dose and utilize therapeutic drug monitoring to guide dose adjustments. |
| Indeterminate | No CPIC guidance for this phenotype. | Initiate therapy with recommended starting dose. |
| Not available | No CPIC guidance for this phenotype. | Initiate therapy with recommended starting dose. |
The CPIC guideline suggests considering alternative antidepressants not extensively metabolized by CYP2D6 or CYP2C19. Examples include secondary amines such as nortriptyline and desipramine, as well as non-TCA antidepressants (e.g., selective serotonin reuptake inhibitors).
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