Amitriptyline, Amoxapine, Clomipramine, Dosulepin, Doxepin, Imipramine, Lofepramine, Nortrityline, Trimipramine, Maprotiline, Mianserin, Trazodone
How the TCAs interact with/affect the brain
The theory behind how TCAs 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 ? 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 TCAs
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.
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 TCAs
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 TCAs
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)
When discussing coming off psychiatric drugs the terms withdrawal and discontinuation will be used interchangeably. Although the term withdrawal is usually associated with coming off drugs to which an individual is addicted to, when an individual comes off TCA's they are not addicted to the drug, they do not consciously crave the drug. The effects an individual may experience when withdrawing/discontinuing/reducing a TCA are not related to addiction but rather to the body struggling to adapt to the absence of a chemical it has become used to being present.
- Listed below are reported withdrawal effects from individuals who have discontinued a TCA.
- Coryza (inflammation of the mucous membranes of the nose)
- Anergy (lack of energy)
- Anorexia (loss of appetite)
- Muscle aches
- Profuse sweating
- Abdominal pains
- Vivid and terrifying dreams
- Movement disorders (akathisia (restlessness under the skin), bradykinesia (difficulty initiating movements and slowness in executing movements), rigidity
In a study by Kramer et al, the authors evaluated 45 individuals who discontinued imipramine. Of those who had been taking imipramine for more than 2 months 85% experienced withdrawal effects. Only 16% of the individuals who had taken imipramine for less than 2 months experienced withdrawal effects. This suggests that an individual is more likely to develop withdrawal effects if they have been on a TCA for longer than 2 months.
Of the individuals who had been on imipramine for longer than 2 months, those who tapered their doses over 2 weeks or longer only 17% experienced withdrawal effects compared to 62% of individuals who reduced their doses and withdrew in under 2 weeks. This suggests that the longer the period of time the individual reduces their medications over, the less likely they are to develop withdrawal effects. The most common withdrawal effects were nausea, headache and 'giddiness'.
Rates of withdrawal
We would recommend that at least two weeks should pass between each dose reduction.
As for how much to reduce the dose by, this is not a finite science. Some individuals are able to come off all at once without ay problems, whereas others develop severe withdrawal effects. Reducing in 10% steps would seem to be a sensible target, especially if the drug has been take consistently for over a year. A maximum of 25% reduction every 2 weeks is probably the fastest you could sensibly attempt to reduce, however, it should be bourn in mind that the more gradual the reductions the more time the brain has to adapt and fewer withdrawal effects experienced. But ultimately the choice as to how fast and how much to reduce by is the individuals.
If you are taking any medications other than your psychiatric drugs it is worthwhile speaking to your GP about what potential interactions your psychiatric medications may have with your other medications.