An Introduction to Antidepressant Medications PDF

AN INTRODUCTION TO ANTIDEPRESSANT MEDICATIONS Dr Dylan Birk INTRODUCTION Antidepressants appear to exert antidepressant actions by increasing the availability of monoamine neurotransmitters (serotonin, noradrenaline and dopamine) in synapses. Although the net increase in monoamines occur shortly af...

AN INTRODUCTION TO ANTIDEPRESSANT MEDICATIONS Dr Dylan Birk INTRODUCTION Antidepressants appear to exert antidepressant actions by increasing the availability of monoamine neurotransmitters (serotonin, noradrenaline and dopamine) in synapses. Although the net increase in monoamines occur shortly after administration, the effects that these medications exert on mood take a while to see. It is therefore likely that other mechanisms may also be involved, such as changes in receptor regulation or changes in intracellular signalling. a b Figure 1: Illustration of the synapses of (a) serotonin and (b) noradrenaline synapses Figure 1 is an illustration of some monoamine synapses. Monoamines are released when the vesicles containing the neurotransmitters fuse with the presynaptic membrane. The neurotransmitters cross the synapse and bind to relevant receptors in the postsynaptic membranes to exert heir effect. Neurotransmitters in the synapse are then taken up again into the presynaptic neurone via transporters in the cell membrane. They can then either be repackaged into vesicles or broken down by an enzyme called monoamine oxidase (MAO). By understanding this process, we can begin to see how we might be able to increase the availability of monoamines. A few example mechanisms include: Enhancing presynaptic release of monoamines Blocking the reuptake transporters in the presynaptic membranes Blocking monoamine breakdown by inhibiting the function on MAO (monoamine oxidase) Through your reading you will find that not many antidepressants are specific or selective. They often bind to multiple receptors and lead to side-effects. STARTING ANTIDEPRESSANT MEDICATION Patients should be reviewed 1–2 weeks at the start of antidepressant treatment (1 week if aged 18-25 due to increased risk of suicide). Treatment should be continued for at least 4 weeks (6 weeks in the elderly) before considering whether to switch antidepressant due to lack of efficacy. In cases of partial response, continue for a further 2–4 weeks (elderly patients may take longer to respond). Following remission, antidepressant treatment should be continued at the same dose for at least 6 months (about 12 months in the elderly), or for at least 12 months in patients receiving treatment for generalised anxiety disorder (as the likelihood of relapse is high). In the first two weeks of treatment, patients may initially feel worse. This could mean an increase in suicidal ideation and increased risk of suicide. It is important to counsel patients on this. Cease treatment if this is noted. CHOOSING A MEDICATION Shared decision making with the patient is critical if an antidepressant is prescribed. The choice of antidepressant depends on: its efficacy for the indication tolerability – how do patients typically find the side-effects? the presentation – eg if presenting with significant insomnia or weight loss, mirtazapine could be considered since it also has a sedative effect drug interactions – always check the BNF past medical history – eg citalopram contraindicated in QT prolongation STOPPING ANTIDEPRESSANT TREATMENT Antidepressants should not be stopped suddenly. The dose should be reduced slowly over at least four weeks to minimise discontinuation symptoms (unless there is an urgent need to stop). Discontinuation symptoms are usually mild but occasionally are more severe. They typically start within 2-3 days of stopping treatment and resolve within 1-2 weeks. Possible symptoms include: Flu-like symptoms Insomnia Electric shock-like sensations Vivid dreams Irritability SWITCHING ANTIDEPRESSANTS Always check the guidelines (eg on BNF) to ensure the correct regime for swapping. Some can be directly switched, stopping the previous medication and starting the new one the next day. This is the case for switching between SSRIs and SNRIs (except fluoxetine due to the long half-life). Others need to be cross-tapered over several weeks (e.g., switching between an SSRI and mirtazapine), gradually reducing the dose of the existing drug while increasing the dose of the new one. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) SSRIs work by blocking the reuptake of serotonin in the presynaptic membrane. SSRIs are better tolerated and are safer in overdose than other classes of antidepressants. EXAMPLES Sertraline, citalopram, escitalopram, fluoxetine, paroxetine. Sertraline tends to have helpful anti-anxiety effects and is one of the safest in patients with heart disease (e.g., following myocardial infarction or heart failure). However, it is associated with a higher rate of diarrhoea. Citalopram can prolong the QT interval, although this effect is dose-dependent (a higher dose is more likely to cause a prolonged QT). QT prolongation can lead to torsades de pointes. Along with escitalopram, it is considered the least safe SSRI in patients with heart disease and arrhythmia. Perform an ECG before starting citalopram to check for QT interval. Fluoxetine is the usual first-line choice in children and adolescents. SIDE-EFFECTS Gastrointestinal symptoms (e.g., weight change, nausea and diarrhoea are common) Headaches Sexual dysfunction, such as loss of libido, erectile dysfunction and difficulty achieving an organism Hyponatraemia is associated with all antidepressants but reported more frequently with SSRIs. Consider hyponatraemia if patients develop drowsiness, confusion or convulsions after starting SSRI. Anxiety or agitation, typically in the first few weeks of use. Palpitations Increased risk of bleeding (e.g., gastrointestinal bleeding, intracranial haemorrhage and postpartum haemorrhage). This risk increases significantly with use of NSAIDs or anticoagulants Insomnia There are fewer anticholinergic side effects when compared to some of the other antidepressant medications. SEROTONIN AND NORADRENALINE REUPTAKE INHIBITORS (SNRIs) These work by blocking the reuptake of both sertraline and noradrenaline. EXAMPLES Examples include venlafaxine and duloxetine. Venlafaxine is often used when there is an inadequate response to other antidepressants. It is more likely to cause discontinuation symptoms when stopped. It has an increased risk of death from overdose. Duloxetine is also used to treat neuropathic pain, particularly diabetic neuropathy. SIDE-EFFECTS These are similar to the side-effects of SSRIs. They can increase the blood pressure and are contraindicated in uncontrolled hypertension. Take caution if a patient has hypertension. Duloxetine can also cause liver and kidney damage. It is therefore contraindicated in liver impairment and severe renal impairment (creatinine clearance less than 30ml/min). TRICYCLIC ANTIDEPRESSANTS (TCAs) These medications also block the reuptake of serotonin and noradrenaline. However, they also have action at M1 (antimuscarinic) and H1 (antihistaminergic) receptors. EXAMPLES Amitriptyline, nortriptyline, imipramine, lofepramine. Amitriptyline and nortriptyline are commonly used at low doses to treat neuropathic pain. The dose for neuropathic pain is too low to treat depression, so higher doses are given for mood disorders. CONTRAINDICATIONS Tricyclic antidepressants are particularly known to cause arrhythmias, including tachycardia, prolonged QT interval and bundle branch block. They block Na channels in the heart. The effects are dose dependent. They are contraindicated in arrhythmias and heart block. Caution is advised when prescribing with other cardiovascular diseases. They are also contraindicated in severe liver or kidney impairment. It is good practice to monitor cardiac, liver and kidney blood tests with long-term treatment. SIDE-EFFECTS H1 antagonism – drowsiness (so typically taken at night) and weight gain M1 – dry mouth, blurred vision, constipation, urinary retention, palpitations, confusion α1 antagonism – postural hypotension, dizziness, sexual dysfunction MONOAMINE OXIDASE INHIBITORS (MAOi) These irreversibly block the function of the enzyme monoamine oxidase (MAO). This prevents the breakdown of monoamines (serotonin, noradrenaline and dopamine) and increases their availability. Monoamine oxidase is also found in the gut, where is breaks down tyramine in our foods. Tyramine stimulates the release of catecholamines, so it important that it can be metabolised in our GI system. Since these medications don’t specifically block MAO in the brain, they are often used as a last line. EXAMPLES Isocarboxazid, moclobemide, phenelzine, tranylcypromine HYPERTENSIVE CRISIS Due to the block of GI MAO, tyramine can enter the bloodstream and stimulate the release of catecholamines such as adrenaline. This can lead to a hypertensive crisis. Patients must be counselled on avoiding foods that are high in tyramine. Examples include cheese, yeast extracts, alcohol, avocado and many more! WASHOUT PERIOD If monoamine oxidase inhibitors are to be switched to another antidepressant, you must not cross taper with the other medication. You must allow for all of the MAOi to be fully cleared from the body before starting another antidepressant. Other antidepressants should not be started for 2 weeks after treatment with MAOIs has been stopped. Do not start a MAOi until 7-14 days after a TCA has been stopped, or 7 days after a SSRI is stopped (5 weeks if fluoxetine due to longer half-life) ATYPICAL ANTIDEPRESSANTS There are other medications that also have antidepressant effects, but via different mechanisms to those already mentioned. An example is mirtazapine, which blocks presynaptic alpha receptors (therefore increasing availability of serotonin and noradrenaline) and postsynaptic serotonin receptors. Mirtazapine can cause sedation, increased appetite and weight gain. SIDE-EFFECTS CAN SOMETIMES BE USEFUL! The side effects of sedation and increased appetite may be beneficial, depending on the patient. In someone with a loss of appetite, weight loss, and poor sleep due to depression, these side effects can be very helpful. For this reason, it is commonly used in older patients. However, in someone else who is overweight and oversleeping already, these side effects would be a big problem.