Selective Serotonin Reuptake Inhibitors (Clomipramine, Fluoxetine)

Also known as: SSRI — SRI — Serotonine Reuptake Inhibitors

Mechanism of Action

The 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 (SRI) due to its modest serotonergic selectivity.

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

1. Sedation
2. Central and peripheral anticholinergic action.
3. Inhibnition of the presynaptic re-uptake mechanisms of neurotransmitters such as noradrenaline and serotonin (5-HT), leading to raised intrasynaptic concentrations of these neurotransmitters.

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

• Noradrenaline: Locus Coeruleus (LC)
• Serotonin: Raphe nuclei

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 and 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:

	α2-Adrenergic-autoreceptor	α2-Adrenergic-heteroreceptor	5-HT1A-autoreceptor
	Nor-adrenergic neuron	serotonergic neuron	serotonergic neuron
Depression/Anxiety	↑	↑	?
Clomipramine	↓	↓	↓

↓=Downregulation of receptor ↑=Upregulation of receptor

These receptors normally inhibit noradrenaline or serotonin release so down regulation of the receptors increases the release of the neurotransmitters. Postsynaptic changes also occur:

	α1 Ad-R	5-HT2A, 2C-R	5-HT1A-R	β1,2,3-R	5-HT4,6,7-R
Depression/Anxiety	↓	↑	?	↑	?
Clomipramine	↑	↓	?	↓	?

↓=Downregulation of receptor ↑=Upregulation of receptor

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:

• Increase in serotonin in the synaptic cleft.
• Increase in stimulation of postsynaptic 5-HT_1A receptors, leading to an elevation of mood (mechanism unknown).
• Increase in CREB and BDNF, leading to normally CNS adaptation to external events.

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. 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.

Clomipramine and TCAs are far more safely and commonly used in behavioural pharmacology in comparison to benzodiazepines, phenothiazines, barbiturates and sympathomimetic agents.

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are a group of drugs that all have a greater effect on serotonin reuptake than noradrenaline reuptake. Unlike TCAs, which are named on the basis of chemical structure, the SSRIs are named according to their primary effect on serotonin reuptake. The ratio of serotonin reuptake selectivity in favour varies from around 15:1 (fluoxetine) to more than 150:1 (sertraline). Along with increasing serotonergic selectivity, SSRI drugs also show fewer effects on other neurotransmitter systems. In particular, they are less anticholinergic than TCAs.

Effects on Anxiety and Panic

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.

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 include:

• Approach-avoidance conflict (stretched approach posture test).
• Separation distress vocalisation (guinea pig isolation calls, rat pup isolation ultrasonic vocalisation).
• 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.

Adverse Effects

Adverse effects of these drugs include:

• Decreased appetite
• Depression/lethargy
• Shaking/shivering/tremor
• Vomiting and diarrhoea
• Restlessness and anxiety
• Seizures
• Aggression
• Mydriasis
• Vocalisation
• Weight loss
• Panting
• Confusion
• Incoordination
• Hypersalivation

However, the level and incidence of adverse effects varies considerably between drugs, with more selective drugs generally producing fewer adverse effects.

The main adverse effects of this group of drugs are mediated through their effect on histamine (H1) and muscarinic (M1) acetylcholine receptors, as summarised in the table below.

H1 Blockade	Ach (Muscarinic) Blockade
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

Amitriptyline also antagonises α2-adrenoceptors, which can 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 that predominantly alter noradrenaline re-uptake inhibition may predispose patients to sudden and violent emotional reactions including aggression and should be used with care in aggression cases.

There are large differences in selectivity of re-uptake inhibitor drugs, as can be seen in the following table.

Drug	Class	5-HT:NorAdrenaline Blocking ratio	H1 Blockade	Ach (Muscarinic) Blockade
Amitriptyline	TCA	1:4	+++	+++
Clomipramine	TCA	5:1	++	++
Fluoxetine	SSRI	15:1		+
Fluvoxamine	SSRI	150:1		+
Sertraline	SSRI	150:1		+

The blocking ratio indicates the relative effect of the agent on reuptake of serotonin vs. noradrenaline. Fluoxetine is 3 times more selective for serotonin than clomipramine. Clomipramine was the first TCA whose ratio favours serotonin reuptake inhibition, hence its title of non-selective serotonin reuptake inhibitor (SRI). The level of anticholinergic effect is usually also decreased with increasing serotonergic selectivity.

Medical Cautions

Caution should be taken if the animal suffers from any of the following pre-existing medical conditions:

• Heart disease, especially heart block and arrythmias
• Diabetes: increases hyperglycaemia
• Epilepsy (reduction of seizure threshold)
• Glaucoma (closed angle type)
• Impaired liver function (TCAs metabolised by liver)
• Hyperthyroidism (enhanced response to TCAs)
• Urinary retention .

Interactions

Care should be taken if used in conjunction with any of the following drugs, which may interact and cause severe adverse effects:

• Opioids (e.g. morphine): enhanced analgesia and respiratory depression.
• 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.
• Thyroid medications: if used simultaneously patients must be carefully monitored
• Inhibitors of cytochrome p450, including other SSRI drugs, ketoconazole and cimetidine.
• Drugs which lower seizure threshold (eg. phenothiazines such as acepromazine or chlorpromazine).
• Fibre rich diets reduce availability of TCAs.
• Amitraz

Serotonin syndrome

If an SRI, SSRI or TCA is overdosed or combined with another serotonergic drug (see above) an increased level of sedation and adverse effects will be observed. There is also the possibility of serotonin syndrome, especially if one of these drugs is given with an MAOI (e.g. selegiline). Signs include:

• Gastrointestinal distress
• Head pain
• Agitation
• Increased heart rate, body temperature, respiratory rate
• Muscular rigidity
• Convulsions
• Coma
• Death

Any adverse reaction should be reported via the NOAH reporting system.

Drug Withdrawal

In humans, sudden withdrawal of SRI/SSRI/TCA drugs is associated with dysphoria, agitation, increased anxiety, relapse of psychiatric symptoms and, in some cases discontinuation syndrome. It is recommended that, unless otherwise indicated by drug monographs, withdrawal should be gradual. Typically a period of 1 week per month of treatment is allowed for withdrawal. This is divided into three periods of equal length with three dose decreases to 75% of original dose, followed by 50% of original dose and finally 25% of original dose.

Clomipramine

• Licensed preparation: Clomicalm (dog).

• License indication: Separation anxiety

• Unlicensed/off-label uses

• Anxiety related problems, especially those involving panic.
• Stereotypy/compulsive disorders such as acral lick dermatitis (ALD), compulsive grooming .
• Aggression where anxious apprehension is an obstacle to treatment.
• Feline indoor spray marking where anxiety, especially chronic, is a factor (if problem is longstanding or refractory to behavioural treatment).

For dose, consult appropriate data sheets and references. Onset of action is 4 or more weeks. The dose of clomipramine may need to be increased if the 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.

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.

Fluoxetine

Fluoxetine is largely metabolised in the liver by the cytochrome P450 enzyme system to norfluoxetine, also an SSRI.

• Licensed preparation: Reconcile (dog). Currently unavailable in Europe.

• License indication: Treatment of canine separation anxiety in conjunction with behaviour modification in dogs over 6 months old.

• Unlicensed/off-label uses

• Compulsive disorders
• Aggression (involving impulsivity)
• Panic and anxiety disorders
• Feline Urine Marking

As with other drugs used to treat behavioural problems it is recommended that fluoxetine be used in conjunction with behavioural modification techniques . Although effects are generally seen within 4-6 weeks, 6-8 weeks should be allowed before making an assessment of efficaciousness. The long half-life of fluoxetine and its metabolites also mean that a period of at least 6 weeks should be allowed to pass before administration of any drugs which may interact adversely.

References

The creation of this content was made possible by Ceva Santé Animale as part of the feline behaviour project.

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