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==Mechanism of Action==
==Mechanism of Action==
Clomipramine is a non-selective serotonin reuptake inhibitor [SRI], and a member of the tricyclic group of antidepressants [TCA]. It is chemically similar to phenothiazines and has similar adverse effects.
Clomipramine is a non-selective serotonin reuptake inhibitor (SRI), and a member of the tricyclic group of antidepressants (TCA). It is chemically similar to phenothiazines and has similar adverse effects.
TCAs have three important effects which alter in degree depending on the specific drug used. These are:
TCAs have three important effects which alter in degree depending on the specific drug used. These are:
#Sedation
#Sedation
#Central and peripheral anticholinergic action
#Central and peripheral anticholinergic action
#Presynaptic blocking of CNS biogenic amines such as noradrenaline and serotonin (5-HT) and therefore their potentiation
#Presynaptic blocking of CNS biogenic amines such as noradrenaline and serotonin (5-HT) and therefore their potentiation <ref name="Overall">Overall, K.L., 2004. Paradigms for pharmacologic use as a treatment component in feline behavioral medicine. Journal of Feline Medicine and Surgery 6, 29-42.</ref>.
Numerous models of anxiety have been tested in animals. Many are not apparently reliable detectors of anxiolytic effect, and have not been applied to more modern anxiolytic/antidepressant drugs like SSRIs/SRIs. Those in which there is a response to TCA/SRI and SSRI drugs are:
Numerous models of anxiety have been tested in animals. Many are not apparently reliable detectors of anxiolytic effect, and have not been applied to more modern anxiolytic/antidepressant drugs like SSRIs/SRIs. Those in which there is a response to TCA/SRI and SSRI drugs are:
*Approach-avoidance conflict [Stretched approach posture test].
*Approach-avoidance conflict (Stretched approach posture test).
*Separation distress vocalisation [guinea pig isolation calls, rat pup isolation ultrasonic vocalisation].
*Separation distress vocalisation (guinea pig isolation calls, rat pup isolation ultrasonic vocalisation).
*Defensive burying in rodents [only some 5-HT reuptake inhibitors]
*Defensive burying in rodents (only some 5-HT reuptake inhibitors)
Interestingly no effect has been found in those tests [so far performed] that involve conditioned fear potentiated startle responses.
Interestingly no effect has been found in those tests (so far performed) that involve conditioned fear potentiated startle responses.
==Comparison of Effects and Adverse Effects for Clomipramine and Related Drugs==
==Comparison of Effects and Adverse Effects for Clomipramine and Related Drugs==
The blocking ratio indicates the relative effect of the agent on reuptake of 5-HT vs. noradrenaline. Fluoxetine is 3 times more selective for 5-HT than clomipramine. Clomipramine is the only TCA that whose ratio favours 5-HT reuptake inhibition, and hence its title of non-selective serotonin reuptake inhibitor (SRI).
The blocking ratio indicates the relative effect of the agent on reuptake of 5-HT vs. noradrenaline. Fluoxetine is 3 times more selective for 5-HT than clomipramine. Clomipramine is the only TCA that whose ratio favours 5-HT reuptake inhibition, and hence its title of non-selective serotonin reuptake inhibitor (SRI).
In cases where animals experience sedation or other unwanted side effects awareness of the intermediate metabolites can be essential. This is because when treated with the intermediate compound on its own animals may respond better, with fewer adverse side effects.
In cases where animals experience sedation or other unwanted side effects awareness of the intermediate metabolites can be essential. This is because when treated with the intermediate compound on its own animals may respond better, with fewer adverse side effects. <ref name="Overall"/ >
==Use==
==Use==
*Licensed [dog]
*Licensed (dog)
:*Separation anxiety
:*Separation anxiety
*Unlicensed
*Unlicensed
:*Stereotypy/compulsive disorders such as acral lick dermatitis (ALD), compulsive grooming
:*Stereotypy/compulsive disorders such as acral lick dermatitis (ALD), compulsive grooming
:*Aggression where anxious apprehension is an obstacle to treatment
:*Aggression where anxious apprehension is an obstacle to treatment
:*Spraying where anxiety, especially chronic, is a factor [if problem is longstanding or refractory to behavioural treatment]
:*Spraying where anxiety, especially chronic, is a factor (if problem is longstanding or refractory to behavioural treatment)
:*Some narcopleptic disorders
:*Some narcopleptic disorders
Amitriptyline also antagonises α2-adrenoceptors, which can also lead to agitation and tachycardia.
Amitriptyline also antagonises α2-adrenoceptors, which can also lead to agitation and tachycardia.
TCAs can also cause loss of libido [breeding animals] and mild corneal drying. They can cause galactorrhea through increased prolactin secretion [especially in cats].
TCAs can also cause loss of libido (breeding animals) and mild corneal drying. They can cause galactorrhea through increased prolactin secretion (especially in cats).
Finally, those TCAs that depend upon NorAdrenaline reuptake inhibition for a part of their effect are sometimes associated with explosive emotional reactions including aggression. They should be used with some care.
Finally, those TCAs that depend upon NorAdrenaline reuptake inhibition for a part of their effect are sometimes associated with explosive emotional reactions including aggression. They should be used with some care.
*Heart disease, especially heart block and arrythmias
*Heart disease, especially heart block and arrythmias
*Diabetes: increases hyperglycaemia
*Diabetes: increases hyperglycaemia
*Glaucoma [closed angle type]
*Glaucoma (closed angle type)
*Impaired liver function [TCAs metabolised by liver]
*Impaired liver function (TCAs metabolised by liver)
*Hyperthyroidism [enhanced response to TCAs]
*Hyperthyroidism (enhanced response to TCAs)
'''Care should be taken if used in conjunction with any of the following drugs, which may interact and cause adverse effects:'''
'''Care should be taken if used in conjunction with any of the following drugs, which may interact and cause adverse effects:'''
*Morphine: enhanced analgesia and respiratory depression.
*Morphine: enhanced analgesia and respiratory depression.
*MAOIs: risk of serotonin syndrome, advise washout period of 2-3 weeks between treatment with these drugs.
*MAOIs: risk of serotonin syndrome, advise washout period of 2-3 weeks between treatment with these drugs.
*Phenothiazines: increased shared adverse effects [CVS, etc], mutual increase in serum levels due to competition for cytochrome p450. Definite risk of severe adverse affects and toxicity.
*Phenothiazines: increased shared adverse effects (CVS, etc), mutual increase in serum levels due to competition for cytochrome p450. Definite risk of severe adverse affects and toxicity.
*SSRIs: Fluoxetine inhibits Cytochrome p450, leading to toxic levels of TCA. Cimetidine also has this effect.
*SSRIs: Fluoxetine inhibits Cytochrome p450, leading to toxic levels of TCA. Cimetidine also has this effect.
*Fibre rich diets reduce availability of TCAs.
*Fibre rich diets reduce availability of TCAs.
If the drug is overdosed/combined with an inappropriate drug [see above] an increased sedation and degree of adverse effects as listed will be seen. If the drug dose is persistently high or the drug is combined with an MAOI, serotonin syndrome is a possible consequence:
If the drug is overdosed/combined with an inappropriate drug (see above) an increased sedation and degree of adverse effects as listed will be seen. If the drug dose is persistently high or the drug is combined with an MAOI, serotonin syndrome is a possible consequence:
*Gastrointestinal distress
*Gastrointestinal distress
*Head pain
*Head pain