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| − | ==Mechanism of Action==
| + | #redirect[[Selective Serotonin Reuptake Inhibitors (Clomipramine, Fluoxetine)]] |
| − | 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.
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| − | TCAs have three important effects which alter in degree depending on the specific drug used. These are:
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| − | #Sedation
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| − | #Central and peripheral anticholinergic action
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| − | #Presynaptic blocking of CNS biogenic amines such as noradrenaline and serotonin (5-HT) and therefore their potentiation <ref name="Overall1">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>. | |
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| − | Clomipramine blocks the reuptake of serotonin and nor-adrenaline from the synaptic cleft, thus causing a build up of these neurotransmitters in the synapse.
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| − | The effect of clomipramine is to elevate mood, reduce anxiety and block the development of panic reactions.
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| − | The main target of action for these drugs are structures in the brain that depend upon nor-adrenaline and serotonin as major neurotransmitters, including:
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| − | :*Noradrenaline: Locus Coeruleus (LC)
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| − | :*Serotonin: Raphe nuclei
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| − | Together the LC and Raphe nuclei form parts of the ascending reticular activating system that has projections throughout the CNS and is involved in mood, wakefulness, sleep cycles and arousal as well as pain modulation and a host of other maintenance functions such as meal patterning.
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| − | The effect on neurotransmitter levels is quite rapid, but therapeutic effects take 3 weeks or more to become apparent. This is because although clomipramine and many other serotonergic antidepressants (SRI, selective serotonin reuptake inhibitor (SSRI), TCA, atypical) have immediate effects on synaptic neurotransmission, the lasting changes in emotional response are the result of intracellular changes and in receptor numbers. This is dependent on secondary messenger systems (cAMP, Ca<sup>2+</sup>, cGMP, IP<sub>3</sub>), gene expression and protein synthesis that take time to occur. Receptors for nor-adrenaline and serotonin are linked to metabotropic G-proteins that can induce changes in protein synthesis such as the up- and down-regulation of receptors. There are 14 known classes of 5-HT receptors, of these, in anxiety problems the 5-HT<sub>1</sub> receptor is the most relevant.
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| − | For example, in states of anxiety and depression the following presynaptic changes are thought to occur:
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| − | {| class="wikitable"
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| − | ! !! α2-Adrenergic-autoreceptor !! α2-Adrenergic-heteroreceptor !! 5-HT<sub>1A</sub>-autoreceptor
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| − | | || Nor-adrenergic neuron || serotonergic neuron || serotonergic neuron
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| − | | Depression/Anxiety || ↑ || ↑ || ?
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| − | | Clomipramine || ↓ || ↓ || ↓
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| − | |}
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| − | ↓=Downregulation of receptor ↑=Upregulation of receptor
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| − | These receptors normally inhibit noradrenaline or serotonin release so down regulation of the receptors increases the release of the neurotransmitters. Postsynaptic changes also occur:
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| − | {| class="wikitable"
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| − | ! !! α1 Ad-R !! 5-HT2A, 2C-R !! 5-HT1A-R !! β1,2,3-R !! 5-HT4,6,7-R
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| − | | Depression/Anxiety || ↓ || ↑ || ? || ↑ || ?
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| − | | Clomipramine || ↑ || ↓ || ? || ↓ || ?
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| − | ↓=Downregulation of receptor ↑=Upregulation of receptor
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| − | Significant changes in receptor numbers take several weeks to occur. The effect of these postsynaptic receptor number changes is an increase in the levels of two crucial compounds, C-amp Response Element Binding Protein (CREB) and Brain Derived Neurotropic Factor (BDNF). The end results of these presynaptic and postsynaptic changes are:
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| − | *Increase in serotonin in the synaptic cleft.
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| − | *Increase in stimulation of postsynaptic 5-HT<sub>1A</sub>1A-receptors, leading to an elevation of mood (mechanism unknown)
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| − | *Increase in CREB and BDNF, leading to normally CNS adaptation to external events
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| − | The exact reason why CREB, BDNF and other neurotropic factors are central to resolving depression and anxiety is to date unclear but it is thought to relate to adaptability of the CNS to external events.
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| − | These factors affect the rate of protein synthesis and a host of other intracellular processes that take even longer to become active, hence the long delay in efficacy of these drugs. All typical antidepressant drugs work through the common pathway of increasing BDNF.
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| − | Clomipramine and TCAs are far more safely and commonly used in behavioural pharmacology in comparison to benzodiazepines, phenothiazines, barbiturates and sympathomimetic agents.
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| − | ==Specific Effects on Anxiety and Panic==
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| − | Panic is a specific manifestation of anxiety and the mechanism of action of drugs that reduce panic share a common factor. Only drugs that reduce the firing rate of neurons in the Locus Coeruleus (LC) effectively reduce panic. For those drugs that do affect the firing rate of the LC, this is thought to be a key to their mode of action in reducing anxiety.
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| − | 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:
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| − | *Approach-avoidance conflict (Stretched approach posture test).
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| − | *Separation distress vocalisation (guinea pig isolation calls, rat pup isolation ultrasonic vocalisation).
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| − | *Defensive burying in rodents (only some 5-HT reuptake inhibitors)
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| − | Interestingly no effect has been found in those tests (so far performed) that involve conditioned fear potentiated startle responses.
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| − | ==Use==
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| − | *Licensed (dog)
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| − | :*Separation anxiety<ref>Clomipramine hydrochloride [http://www.clomicalm.novartis.us/pdf/Clomicalm-product-info.pdf data sheet]</ref>
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| − | *Unlicensed
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| − | :*Anxiety related problems, especially those involving panic.
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| − | :*Stereotypy/compulsive disorders such as [[Acral Lick Dermatitis|acral lick dermatitis (ALD)]], [[Feline Grooming Disorders|compulsive grooming]] <ref>Thoren, P., Asberg, M. & Cronholm, B. (1980). Clomipramine treatment of obsessive-compulsive disorder. Archives of General Psychiatry 37, 1281–5.</ref><ref>Flament, M. F., Rappoport, J. L. & Berg, C. J. (1985). Clomipramine treatment of childhood obsessive compulsive disorder. A double-blind controlled study. Archives of General Psychiatry 42, 977–83.</ref><ref>Ananth, J. (1986). Clomipramine: an anti-obsessive drug. Canadian Journal of Psychiatry 31, 253–8.</ref><ref>Perse, T. (1988). Obsessive-compulsive disorder: A treatment review. Journal of Clinical Psychiatry 49, 48–55.</ref><ref>McTavish, D. & Benfield, P. (1990). Clomipramine: an overview of its pharmacological properties and a review of its therapeutic use in obsessive-compulsive behavior and panic attack. Drug 39, 136–53.</ref><ref>Overall, K. L. (1994). Use of clomipramine to treat ritualistic motor behavior in dogs. Journal of the American Veterinary Medical Association 205, 1733–41.</ref><ref>Hewson, C. J., Luescher, A., Parent, J. M., Conlon, P. D. & Ball, R. O. (1998b). Efficacy of clomipramine in the treatment of canine compulsive disorder. Journal of the American Veterinary Medical Association 213, 1760–6.</ref><ref>Moon-Fanelli, A. A. & Dodman, N. H. (1998). Description and development of compulsive tail chasing in terriers and response to clomipramine treatment. Journal of the American Veterinary Medical Association 212, 1252–7.</ref><ref>Dodman, N. H., Donnelly, R., Shuster, L., Mertens, P. & Miczek, K. (1996). Use of fluoxetine to treat dominance aggression in dogs. Journal of the American Veterinary Medical Association 209, 1585–7.</ref><ref>Seksel, K. & Lindeman, M. J. (1998). Use of clomipramine in the treatment of anxiety-related and obsessive-compulsive disorders in cats. Australian Veterinary Journal 76, 317–21.</ref>
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| − | :*Aggression where anxious apprehension is an obstacle to treatment
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| − | :*[[Indoor Marking - Cat|Feline indoor spray marking]] where anxiety, especially chronic, is a factor (if problem is longstanding or refractory to behavioural treatment)
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| − | Onset of action is 4 or more weeks. The dose of Clomipramine may need to be increased from an initial dose rate once daily, to a higher dose rate if initial response is insufficient after 6-8 weeks. Higher doses are associated with increased adverse effects such as sedation and it is important that genuine response to therapy is not confused with undesirable profound sedative effects which will suppress all sorts of behaviour. Sensitivity of cats to TCAs is generally higher than in dogs as they use glucuronidation to metabolise them<ref>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>.
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| − | Once the condition being treated is deemed under control, drug therapy can be gradually phased out over a period of 1 week per month of treatment. Sudden withdrawal of medication can lead to relapse, withdrawal effects or discontinuation syndrome, especially with short half-life SRI/SSRI drugs. Successful drug therapy should produce around 70% reduction in the behaviour and an increase in normal activity as a substitute.
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| − | ==Adverse Effects<ref>Wiersma, J., Honig, A. & Peters, F. P. J. (2000). Clomipramine-induced allergic hepatitis: a case report. International Journal of Psychiatry in Clinical Practice 4, 69–71.</ref>==
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| − | The main adverse effects of this class of drugs is mediated through their effect on histamine and Ach receptors.
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| − | {| class="wikitable"
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| − | ! H<sub>1</sub> Blockade !! Ach (Muscarinic) Blockade
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| − | | Sedation, hypotension, increased appetite, weight gain, anti-allergic activity || Delirium, hyperthermia, insomnia, seizure induction, tachycardia, constipation, decreased bronchial secretion, blurred vision, narrow angle glaucoma (exacerbation), photophobia, dry mouth
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| − | Amitriptyline also antagonises α2-adrenoceptors, which can lead to agitation and tachycardia.
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| − | TCAs can also cause loss of libido (breeding animals) and mild corneal drying. They can cause galactorrhea through increased prolactin secretion (especially in cats).
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| − | 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.
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| − | There are large differences in selectivity of re-uptakje inhibitor drugs, as can be seen in the following table.
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| − | {| class="wikitable"
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| − | ! Drug !! Class !! 5-HT:NorAdrenaline Blocking ratio !! H<sub>1</sub> Blockade !! Ach (Muscarinic) Blockade
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| − | | Amitriptyline || TCA || 1:4 || +++ || +++
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| − | | Clomipramine || TCA || 5:1 || ++ || ++
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| − | | Fluoxetine || SSRI || 15:1 || || +
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| − | | Fluvoxamine || SSRI || 150:1 || || +
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| − | | Sertraline || SSRI || 150:1 || || +
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| − | 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 was the first TCA whose ratio favours 5-HT reuptake inhibition, and hence its title of non-selective serotonin reuptake inhibitor (SRI). The level of anticholinergic effect is usually also decreased with increasing serotonergic selectivity.
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| − | '''Caution should be taken if the animal suffers from any of the following pre-existing medical conditions:'''
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| − | *Heart disease, especially heart block and arrythmias <ref>Pouchelon, J. L., Martel, E., Champeroux, P., Richard, S. & King, J. N. (2000). Effect of clomipramine hydrochloride on the electrocardiogram and heart rate of dogs. American Journal of Veterinary Research, in press.</ref><ref>Reich, M. R., Ohad, D. G., Overall, K. L. & Dunham, A. E. (2000). Electrocardiographic assessment of antianxiety medication in dogs and correlation with drug serum concentration. Journal of the American Veterinary Medical Association 216, 1571–5.</ref>
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| − | *Diabetes: increases hyperglycaemia
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| − | *Glaucoma (closed angle type)
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| − | *Impaired liver function (TCAs metabolised by liver)
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| − | *Hyperthyroidism (enhanced response to TCAs)
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| − | *Urinary retention <ref>Overall, K.L. 2001. Pharmacological Treatment in Behavioural Medicine: The Importance of Neurochemistry, Molecular Biology and Mechanistic Hypotheses. The Veterinary Journal, 162, 9-23</ref>.
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| − | '''Care should be taken if used in conjunction with any of the following drugs, which may interact and cause adverse effects:'''
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| − | *Morphine: enhanced analgesia and respiratory depression.
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| − | *MAOIs: risk of serotonin syndrome, advise washout period of 2-3 weeks between treatment with these drugs.
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| − | *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.
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| − | *SSRIs: Fluoxetine inhibits Cytochrome p450, leading to toxic levels of TCA. Cimetidine also has this effect.
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| − | *Fibre rich diets reduce availability of TCAs.
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| − | *Thyroid medications: can interfere, therefore if simultaneously used must be carefully monitored <ref>Gullikers, K.P., Panciera, D.L., 2002. Influence of various medications on canine thyroid function. Compendium of Continuing Education for the Practicing Veterinarian 24, 511-521</ref>
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| − | 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:
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| − | *Gastrointestinal distress
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| − | *Head pain
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| − | *Agitation
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| − | *Increased heart rate, body temperature, respiratory rate
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| − | *Muscular rigidity
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| − | *Convulsions
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| − | *Coma
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| − | *Death
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| − | ==References==
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| − | <references/>
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| − | {{unfinished}}
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| − | [[Category:To Do - Behaviour GGP]]
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| − | [[Category:Pharmacological Approach to Problem Behaviour]]
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| − | [[Category:JBowen prereview]]
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