Changes

==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.  

Tricyclic group of antidepressants (TCA) are chemically similar to phenothiazines. Amitriptyline and clomipramine are examples of drugs of this type, with clomipramine also being classed as a serotonin re-uptake inhibitor due to its modest serotonergic selectivity.  

TCAs have three important effects which alter in degree depending on the specific drug used. These are:  

TCAs have three major effects which vary 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 <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>.

#Inhibnition of the presynaptic re-uptake mechanisms of neurotransmitters such as noradrenaline and serotonin (5-HT), leading to raised intrasynaptic concentrations of these neurotransmitters<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>.

The main target of action for these drugs are structures in the brain that depend upon nor-adrenaline and serotonin as major neurotransmitters, including:

The main target of action for these drugs are structures in the brain that depend upon nor-adrenaline and serotonin as major neurotransmitters, including:

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.

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.

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, Ca²⁺, cGMP, IP₃), 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-HT₁ receptor is the most relevant.

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 altered receptor expression. This is dependent on secondary messenger systems (cAMP, Ca²⁺, cGMP, IP₃), 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-HT₁ receptor is the most relevant.

For example, in states of anxiety and depression the following presynaptic changes are thought to occur:

For example, in states of anxiety and depression the following presynaptic changes are thought to occur: