Antidepressants consist of a number of different classes of drugs with different mechanisms of action. Only tricyclic antidepressants (TCAs) have proven efncacy in migraine; we cover the newer components for completeness and reader interest.
Mechanism of Action
TCAs, selective serotonin-reuptake inhibitors (SSRIs), and serotonin NE-reuptake inhibitors increase synaptic NE or serotonin (5-HT) by inhibiting high-affinity reuptake. Some are more potent inhibitors of NE, others of 5-HT reuptake. Bupropion is both a dopamine and NE-reuptake inhibitor. Monoamine oxidase inhibitors (MAOIs) block the degradation of catecholamines. The most consistent neurochemical finding with antidepressant treatment (including the TCAs, SSRIs, MAOIs, and electroconvulsive therapy) is a decrease in β-adrenergic receptor density and NE-stimulated cyclic adenosine monophosphate (cAMP) response. Increased arreceptor System sensitivity is not seen as consistently with antidepressant treatment. Long-term antidepressant treatment decreases 5-HT2-receptor binding and imipramine-binding sites (related to the 5-HT uptake System) but does not change 5-HT1-receptor binding. A strong interaction exists between the NE and 5-HT Systems. Antidepressant treatment β-receptor downregulation is dependent on an intact 5-HT System, whereas lesions of the NE System block the decrease in 5-HT2-receptor binding. The decrease in 5-HT2 receptor-binding sites does not correlate with a decrease in fonction; there may be enhanced physiologie responsiveness. In fact, long-term antidepressant treatment actually enhances the efficacy of 5-HT synaptic transmission. The mechanisms underlying this enhanced synaptic transmission differ according to the type of treatment administered. TCAs and electroconvulsive shocks (ECS) enhance 5-HT synaptic transmission by increasing the sensitivity of postsynaptic 5-HT1A receptors, whereas selective 5-HT reuptake blockers reduce the fonction of terminal 5-HT autoreceptors, thereby increasing the amount of 5-HT released per stimulation-triggered action potential.
TCAs upregulate the GABA-B receptor, downregulate the histamine receptor, and enhance the neuronal sensitivity to substance P. Some TCAs are 5-HT2-receptor antagonists. TCAs also interact with endogenous adenosine Systems. They inhibit adenosine and augment its electrophysiologic actions contributing to antinociception. Adenosine A! receptor activation results in antinociception mediated by inhibition of adenylate cyclase, whereas adenosine A2 receptor activation is pronociceptive due to stimulation of adenylate cyclase within the sensory nerve terminal. Adenosine A3 receptors facilitate pain due to release of histamine and 5-hydro-xytryptamine from mast cells.
Neurotrophic factors may also be candidates for mediating the long-term effects of antidepressants. The neurotrophins [a protein class comprising nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NTW), NT-4/5, and NT-6] positively modulate monoaminergic neurotransmission and CNS neuron survival, outgrowth, and neuroprotection. BDNF binds to and phosphorylates its high-affinity tyrosine kinase receptor and activates intracellular signaling pathways including microtubule-associated protein kinase and cAMP. BDNF promutes serotonin neuron development, augments serotonin synthesis and turnover, and increases serotonergic axon fiber density. Serotonergic axon densities are decreased in the prefrontal cortex of suicide patients with major depressive disorder. In the neocortex and hippocampus, BDNF mRNA and protein are highly expressed, and these regions are widely implicated in the pathophysiology of depressive disorders. Environmental stressors, such as immobilization, that produce learned helplessness in animais and precipitate depression in humans decrease BDNF mRNA. Intraventricular, dorsal raphe, or hippocampal infusions of BDNF in rats reduce learned helplessness behavior and reduce immobility in the forced swim and inescapable shock models, indicating an antidepressant-like effect. BDNF mRNA increases in animais treated with antidepressant drugs and following seizures. Antidepressants increase BDNF mRNA in the brain via 5-HT2A and β-adrenoceptor subtypes and prevent the stress-induced decreases in BDNF mRNA.
In the hippocampus of depressed patients treated with unspecified antidepressants, BDNF protein immunoreactivity was elevated compared with subjects who were not so treated at the time of death. Clinical trials are currently evaluating the antidepressant activity of small molecules that increase BDNF mRNA and protein release from cultured cells. BDNF protein levels were measured with a two-site enzyme-linked immunosorbent assay in six brain regions of adult male rats that received daily ECS or daily injections of antidepressant drugs. BDNF increased gradually in the hippocampus and frontal cortex, with a peak response by the fourth day of ECS. Increases peaked at 15 hours after the last ECS and lasted at least three days thereafter. Two weeks of daily injections with the MAO-A and MAO-B inhibitor tranylcypromine (8-10 mg/kg, IP) increased BDNF by 15% in the frontal cortex, and three weeks of treatment increased it by 18% in the frontal cortex and 29%o in the neostriatum. Tranylcypromine, fluoxetine, and desmethylimipramine did not elevate BDNF in the hippocampus. Elevations in BDNF protein in the brain are consistent with greater treatment efficacy of ECS and MAOIs in drug-resistant major depressive disorder and may be predictive for the antidepressant action of the more highly efficacious interventions.
The mechanism by which antidepressants work to prevent headache is un-certain but does not result from treating masked depression. Antidepressants are useful in treating many chronic pain states, including headache, independent of the presence of depression, and the response occurs sooner than the expected antidepressant effect. In animal pain models, antidepressants potentiate the effects of coad-ministered opioids. The antidepressants that are clinically effective in headache prevention either inhibit noradrenaline and 5-HT reuptake or are antagonists at the 5-HT2 receptors.
Clinical Trials and Use
A total of 16 controlled trials have investigated the efficacy of the TCAs amitriptyline and clomipramine and the SSRIs fluoxetine and fluvoxamine. Amitriptyline has been more frequently studied than the other agents, and is the only antidepressant with fairly consistent support for efficacy in migraine prevention. Three placebo-controlled trials found amitriptyline significantly better than placebo at reducing headache index or frequency. One trial found no significant difference between amitriptyline and propranolol. Another trial reported that amitriptyline was significantly more efficacious than propranolol for patients with mixed migraine and tension-type headache, whereas propranolol was significantly better for patients with migraine alone. Similarly, a trial conducted in a group of patients with mixed migraine and tension-type headache found that amitriptyline was significantly better than timed-released dihydroergotamine (TR-DHE) at reducing headache index. However, an analysis of the data on headache duration, stratified by severity, showed that amitriptyline was significantly better than TR-DHE at reducing the number of hours of moderate and mild tension-type headache-like pain. In contrast, TR-DHE was significantly better than amitriptyline at reducing the number of hours of extremely severe and severe migraine-like pain. The evidence was insufficient to support the efficacy of clomipramine and fluvoxamine for migraine prevention. Fluoxetine was significantly better than placebo in one but not a second migraine prevention trial.
Pharmacology of the TCAs. There is wide individual variation in the absorption, distribution, and excretion of the TCAs, with a 10- to 30-fold variation in individuals’ drug metabolism. There may exist a therapeutic window above which the TCAs are ineffective, but this has been evaluated only for nortriptyline for treatment of depression. TCAs are lipid soluble, have a high volume of distribution, and avidly bind to plasma proteins. The antihistamine and antimuscarinic activity of the TCAs account for many of their side effects. A useful rule of thumb is to start low and aim for a dose of 1 to 1.5mg/kg body weight.
The TCAs most commonly used for headache prophylaxis include amitriptyline, nortriptyline, doxepin, and protriptyline. Imipramine and desipramine have been used at times. With the exception of amitriptyline, the TCAs have not been vigorously evaluated; their use is based on anecdotal or uncontrolled reports. None have been approved for migraine.
Principles of TCA Use. The following principles are useful when using a TCA.
• The TCA dose range is wide and must be individualized.
• With the exception of protriptyline, TCAs are sedating. Treatment should be started with a low dose of the chosen TCA taken at bedtime, except in the case of protriptyline, which should be administered in the morning.
• If the TCA is too sedating, the tertiary TCA (amitriptyline and doxepin) should be switched over to a secondary TCA (nortriptyline and protriptyline). If a patient develops insomnia or nightmares, TCA should be given in the morning.
• SSRIs can be given as a single dose in the morning, although rigorous evidence for activity in migraine is lacking. They are less sedating than the TCAs and some patients may require a hypnotic for sleep induction.
• Bipolar patients can become manic on antidepressants.
AEs are common with TCA use. The AEs of TCA are due to its interaction with multiple neurotransmitters and their receptors. The antimuscarinic AEs are most common; they include dry mouth, a metallic taste, epigastric distress, constipation, dizziness, mental confusion, tachycardia, palpitations, blurred vision, and urinary retention. Antihistaminic activity may be responsible for carbohydrate cravings, which contributes to weight gain. Adrenergic activity is responsible for the orthostatic hypotension, reflex tachycardia, and palpitations that patients may experience. Amitriptyline and other TCAs rarely cause inappropriate secretion of antidiuretic hormone. Any antidepressant treatment may change depression to hypomania or frank mania (particularly in bipolar patients). Ten percent of patients develop tremors, and confusion or delirium may occur, particularly in older patients who are more vulnerable to the muscarinic side effects. Antidepressant treatments may also reduce the seizure threshold, although this is not generally a problem in antimigraine treatment.
Tertiary Amines. Amitriptyline is a tertiary amine tricyclic that is sedating and has antimuscarinic activity. Patients with coexistent depression are more tolerant and require higher doses of amitriptyline. Administration of the drug should be started at a dose of 10 to 25 mg at bedtime. The dose ranges from 10 to 400 mg/day ().
Doxepin is a sedating tertiary amine TCA. The drug should be started at a dose of 10 mg at bedtime. The dose ranges from 10 to 300 mg/day.
Secondary Amines. Nortriptyline is a secondary amine that is less sedating than amitriptyline. Nortriptyline is a major metabolite of amitriptyline. If insomnia develops, the drug must be given earlier in the day or in divided doses. The drug is started at a dose of 10 to 25 mg at bedtime. The dose ranges from 10 to 150 mg/day.
Protriptyline is a secondary amine similar to nortriptyline. The dosage should be started at 5 mg/day. The dose ranges from 5 to 60 mg/day.
Selective Serotonin-Reuptake Inhibitors. Evidence for the use of SSRIs is poor. They are helpful for patients with comorbid depression because their tolerability profile is superior to tricyclics. Fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram are specifie SSRIs that have minimal antihistaminic and antimuscarinic activity. These drugs produce less weight gain (and in some cases produce weight loss) and have fewer cardiovascular side effects than the TCAs. The most common AEs include anxiety, nervousness, insomnia, drowsiness, fatigue, tremor, sweating, anorexia, nausea, vomiting, and dizziness or lightheadedness. Headache was noted in 20.3% of patients on fluoxetine; however, it was also noted in 19.9% of patients on placebo. The combination of an SSRI and a TCA can be beneficial in treating refractory depression and, in our experience, resistant cases of migraine. The combination may require dose adjustment of the TCA because levels may significantly increase.
The efficacy analysis summarized in the AHCPR Evidence Report did not indicate a clear benefit of the racemic mixture of fluoxetine over placebo. In contrast, a recent randomized controlled trial of S-fluoxetine indicated a possible clinical benefit in migraine prevention, as measured by a reduction in migraine frequency, as early as one month after initiation of therapy. Anecdotal reports and our experience seem to indicate its benefit in migraine prophylaxis where coexistent depression is a prominent issue. Some researchers have reported that fluoxetine does not improve or may worsen headache. A recent single-center, randomized, double-blind, parallel study of fluoxetine showed a significant reduction (p < 0.W) beginning from the third month of treatment in the fluoxetine group and no significant reduction in the placebo group.
Fluoxetine should be administered starting at a dose of 10 mg in the morning. The dose ranges from 10 to 80 mg/day.
Monoamine Oxidase Inhibitors
MAOIs exist in two subtypes: MAO-A, which preferentially deaminates NE and 5-HT, and MAO-B, which preferentially deaminates dopamine. Phenelzine is a nonspecific inhibitor of MAO-A and MAO-B. L-Deprenyl is a selective MAO-B inhibitor that may be effective in the treatment of Parkinson’s disease.
The MAOI phenelzine at a dose of 15mg TID was effective in an open study, but no placebo-controlled, double-blind trials exist. The dose of phenelzine ranges from 30 to 90 mg/day in divided doses. Ail patients on MAOI-A must be on a restricted diet and avoid certain medications to prevent hypertensive crisis. Meperidine, sympathomimetics (including Midrin), alcohol, and foods with a high tyramine content (cheddar cheese, fava beans, banana peel, tap beers, Marmite and Veggie-Mite concentrated, yeast extract, sauerkraut, soy sauce, and other soybean condiments) must be avoided.
The most common AEs of MAOIs include insomnia, orthostatic hypotension, constipation, increased perspiration, weight gain, peripheral edema, and, less commonly, inhibition of ejaculation or reduced libido. Insomnia can be reduced by giving most of the medication early in the day. The risk of hypertensive crisis may be reduced by having the patient take the MAOI three to four hours before or after eating or taking the entire dose at bedtime, as gut MAO activity rapidly returns to normal. Sublingual nifedipine has been used to treat hypertensive crisis when it occurs in MAOI users.