Tricyclics PDF Print E-mail

Amitriptyline, Amoxapine, Clomipramine, Dosulepin, Doxepin, Imipramine, Lofepramine, Nortrityline, Trimipramine, Maprotiline, Mianserin, Trazodone

How the TCA’s interact with/affect the brain

The theory behind how TCA’s and other antidepressants elevate individuals mood is based around the assumption that individuals who are feeling depressed have reduced levels of neurotransmitters, particularly serotonin and noradrenaline in the brain. Neurotransmitters are released from neurons (cells found in the brain and other parts of the nervous system) and act as messengers, passing signals between neurons. For example, when a nerve impulse arrives at a serotonergic neuron (also known as a pre-synaptic neuron), serotonin is released from the cell and diffuses through a space between two neurons, called the synaptic cleft. Serotonin then binds to specific serotonin receptors on a different neuron (post-synaptic neuron) producing a specific signal, impulse or effect. Serotonin is then released from its receptors and ‘re-absorbed’ into the pre-synaptic neuron, or degraded by enzymes in the synaptic cleft.

It is a similar mechanism through which noradrenaline is released from a noradrenergic (noradrenaline releasing) pre-synaptic neuron, binds to noradrenaline receptors on the post-synaptic neuron and is then ‘re-absorbed’ into the neuron it was originally released from.

When a TCA is introduced into the body, it attaches itself to the ‘re-absorbing’ receptors for serotonin and noradrenaline on the pre-synaptic neuron, therefore enabling serotonin and noradrenaline to stay in the synaptic cleft for longer and they will have a greater chance of re-attaching to a serotonin or noradrenaline receptors on the post synaptic neuron and generating further impulses/signals. Tricyclic antidepressants however do not specifically interact solely with the serotonin and noradrenaline re-uptake receptors, they can also attach to receptors on the post-synaptic neuron which can lead to unwanted effects. When TCA binds to histamine H1 receptors it can make the individual feel sedated, binding to α adrenoceptors can lead to postural hypotension (a sudden drop in blood pressure upon standing, leading the individual to feel dizzy or faint) and binding to muscarinic acetylcholine receptors can produce blurred vision, dry mouth and constipation.

Potential adverse effects upon withdrawal of TCA’S

Tricyclic antidepressants rapidly bind to and block the action of noradrenaline re-uptake transporters (NARTs) and serotonin re-uptake transporters (SERTs). Chronic administration of these antidepressants leads to increases in NARTand SERT gene expression and more re-uptake transporters are produced. So when the TCA is removed from the body, there is an increased rate of re-uptake of serotonin and noradrenaline into the pre-synaptic neuron, leading to reduced levels of serotonin and noradrenaline in the synapse. 

BNF Doses

The doses listed below are the maximum safe amounts an individual theoretically could be prescribed daily. However, the usual ‘therapeutic’ doses will vary depending on the individual and the prescriber.

Amitriptyline: Adult max = 200mg daily 

Amoxapine: Adult max = 300mg daily (elderly max = 150mg daily)

Clomipramine: Adult max = 250mg daily (elderly max = 75mg)

Dosulepin: Adult max = 225mg

Doxepin: Adult max = 300mg daily

Imipramine: Adult max = 300mg daily (hospital patients)

Lofepramine: Adult max = 210mg daily

Nortrityline: Adult max = 150mg daily

Trimipramine: Adult max = 300mg

Maprotiline: Adult max = 150mg

Mianserin: Adult max = 90mg

Trazodone: Hospital patients max = 600mg daily, outpatients max = 300mg

Side effects of TCA’s

General; dry mouth, sedation, blurred vision, constipation, nausea, difficulty passing water. Sweating, tremor, rashes and hypersensitivity reactions, hypomania or mania, confusion, delirium, headache, interference with sexual function, blood sugar changes, increased appetite and weight gain.

Convulsions, movement disorders, change in speech pronunciation, spontaneously occurring tingling sensations, taste disturbances, ringing in the ears, fever, agranulocytosis (severe deficiency of certain white blood cells, can predispose to development of infections), decreased amounts of platelets in the blood, low body sodium.

Side effects affecting the heart and blood vessels include; arrhythmias, postural hypotension (low blood pressure upon standing, individuals can feel dizzy or faint), abnormal electrical conductivity in the heart, raised heart rate (>100 beats per minute), fainting.

Side effects affecting the hormonal system include; testicular enlargement, gynecomastia (enlargement of the breasts) and galactorrhoea (milk production and secretion from the breasts).

Other drug specific side-effects that have been noted:

Amoxapine- tardive dyskinesia (restlessness and involuntary rolling of the tongue or twitching of the face, trunk, or limbs), menstrual irregularities, breast enlargement

Clomipramine- Diarrhoea, hair loss

Lofepramine -liver disorders

Maprotiline - rashes, increased risk of seizures compared to other TCA's

Mianserin - leucopenia (decreased white blood cell concentration), agranulocytosis (loss of white blood cell production), anaemia, jaundice, arthritis, arthraligia (painful joints)

Trazodone- rarely priapism (continuous erection of the penis)