Joseph De Soto MD, PhD, FAIC Antidepressants Joseph De Soto MD, PhD, FAIC

Overview The symptoms of depression include feelings of sadness and hopelessness along with the inability to experience pleasure in one’s usual activities. The patient may also see changes in their sleep patterns, a loss of appetite, loss of energy and even have suicidal thoughts. Mania on the other hand is characterized by enthusiasm, rapid thought and speech patterns, extreme self confidence, irritability and impaired judgement. Severe cases of depression and mania can be associated with psychosis.

Mechanism for Depression and Mania The most useful theory but perhaps overly simplistic is that depression is caused by a lack of the following alone or in combination of these following neurotransmitters in certain areas of the brain: norepinephrine, dopamine, and serotonin. Conversely mania may be due to any of the following alone or in combination: norepinephrine, dopamine, and serotonin. Changes in receptor sensitivity for these bio-amines are also thought to have an important effect.

Serotonin Synthesis

Selective Serotonin Reuptake Inhibitors The selective serotonin reuptake inhibitors (SSRI’s) are antidepressants that specifically inhibit serotonin reuptake and have a 300 to 3000x greater selectivity for blocking the serotonin transporter , as compared to the norepinephrine transporter. These SSRI’s have replaced TCA’s as first line as they have a better safety profile. However, failures of SSRI’s in the treatment of depression are often treated with TCA’s/ The SSRI’s include: Fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine, and sertraline.

Therapeutics The primary indication for SSRI’s is depression. These however are also treated with SSRI’s. These medications take about 2 weeks to have a significant effect with a maximum effect occurring in about 6 weeks. Obsessive compulsive disorder, Panic disorder, Generalized anxiety disorder, Post-traumatic stress disorder, Social anxiety disorder, Premenstrual dysphoric disorder, and Bulimia nervosa

Adverse Effects SSRI’s have fewer and less significant side effects than TCA’s and MAOI’s . Some of the side effects are headache, sweating, anxiety, agitation, gastrointestinal upset, sexual dysfunction, changes in sleep patterns, and change of weight. Sleep disturbances: Paroxetine and Fluvoxamine are sedating. Sertraline and fluoxetine are activating. Sexual dysfunction: Loss of libido, delayed ejaculation, inability to orgasm.

Adverse Effects Children & Teenagers: Pediatric patients should be monitored for worsening depression and suicidal thinking with initiation of change of dosage of medication. Overdose: As a rule the SSRI’s lower the seizure threshold . These medications may also cause serotonin syndrome which include: hyperthermia, muscle rigidity, sweating, myoclonus, tachycardia, mydriasis and changes in mental status. Discontinuation syndrome: Abrupt discontinuation of these medications may cause headache, malaise, irritability , nervousness, change in sleep patterns, and agitation.

Serotonin/Norepinephrine Reuptake Inhibitors The serotonin/norepinephrine reuptake inhibitors (SNRI’s) include venlafaxine, desvenlafaxine, levomilnacipran, and duloxetine. These medications may be effective in patients who have failed SSRI’s. Depression that is associated with pain are often treated with these medications as SSRI’s are not effective in depression with pain symptoms. TCA’s can also be used in depression associated with pain. Among the pain syndromes are diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia and low back pain.

Serotonin/Norepinephrine Reuptake Inhibitors Venlafaxine and desvenlafaxine: Desvenlafaxine is the active metabolite of venlafaxine. At low levels these medications are effective inhibitors of serotonin reuptake. At higher doses these medications inhibit norepinephrine reuptake. The most common side effects of these drugs include nausea, headache, sexual dysfunction, dizziness, insomnia, sedation and constipation. These medications are also used in: general anxiety disorder, social phobia, and panic disorder.

Serotonin/Norepinephrine Reuptake Inhibitors Duloxetine: this medication inhibits serotonin and norepinephrine at all doses. This medication is extensively metabolized in the liver and should not be given to patients with liver dysfunction. This medication is used to treat depression, generalized anxiety disorder, fibromyalgia and neuropathic pain. Side effects include: nausea, dry mouth, constipation, increase in blood pressure, sweating and sexual dysfunction.

Atypical Antidepressants Bupropion: this medication is a weak dopamine and norepinephrine reuptake inhibitor that is used to alleviate the symptoms of depression. This medication has been shown to be useful for decreasing symptoms of nicotine in patients trying to quit smoking The side effects include dry mouth, sweating , nervousness, tremor, and an increased risk for seizures. Buproprion should be avoided in those patients at risk for seizure.

Atypical Antidepressents Mirtazapine: the medication enhances serotonin and norepinephrine neurotransmission by antagonizing the α2 receptor. This medication is also sedating due to its antihistaminic activity , but it does not cause the antimuscarinic side effects of TCA’s and it does not interfere with sexual function like SSRI’s. Side effects: increased weight gain, sedation, and increased appetite.

Atypical Antidepressants Trazadone/Nefazadone: These medications are weak inhibitors of serotonin reuptake and their benefit for depression seems to also be related to their ability to block 5-HT2A receptors. These agents are also potent H1 blocking agents which accounts for their sedating effects. This medication is useful for: Anxiety disorder, Unipolar depression, with or without anxiety and Insomnia. These medications are associated with priapism. Vortioxetine: This medication is a serotonin reuptake inhibitor and it has 5-HT1A agonism and 5HT3 and 5HT7 antagonism. This drug is used for major depressant disorder.

Tricyclic Antidepressants (TCA’s) The TCA’s block norepinephrine and serotonin reuptake into the presynaptic neuron. The TCA’s include the tertiary amines imipramine, amitryptyline, clomipramine, doxepin, and trimipramine. There are also the secondary amines, nortriptyline, and protriptyline. The tetracyclic maprotiline and amoxapine are related. Maprotiline and desiipramine are rather selctive for norepinephrine reuptake. TCA’s also block histamine, serotonin and alpha receptors.

Therapeutic Uses TCA’s are used when SSRI’s fail. They are useful in treating moderate to severe depression. The onset of mood elevation takes about 2 weeks. In major depression morbid preoccupation is reduced in 50-70% of patients. Imipramine can be used to control bed wetting in those over 6 years of age. Amitriptyline has been used to prevent migraine and to treat chronic pain syndrome.

Adverse Effects Blockade of muscarinic receptors causes blurred vision, xerostomia, urinary retention, sinus tachycardia, constipation and aggravation of glaucoma. TCA’s block the α receptor and may cause orthostatic hypotension, dizziness and reflex tachycardia. TCA’s can also cause cardiac arrhythmias and send a person who is bipolar into mania. TCA’s may worsen prostate hyperplasia, epilepsy and preexisting arrhythmias.

MAO I’s Monoamine oxidase is a mitochondrial enzyme that oxidatively deaminates and inactivates excess neurotransmitters such as norepinephrine, dopamine and serotonin. The MAO inhibitors available for depression include Phenelzine (nardil), tranylcypromine (parnate), isocarboxazid (marplan) and selegine (anipryl). Use of MAOIs is limited due to their dietary restrictions and there interactions with other medications.

MOAIs The MAOIs form stable complexes with the MAO enzyme causing irreversible inactivation. This results in increased stores of norepinephrine, serotonin and dopamine within the neuron and a subsequent release of excess neurotransmitter in the synaptic cleft. MAO in not only the neuron but the liver and gut are also inhibited thus, increasing the number of drug-food and drug-drug interaction. Even though these drugs fully inhibit the MAO enzyme within a few days these drugs also require a few weeks to have a clinical effect.

Therapeutic Uses The MAOIs are indicated for depressed patients who are unresponsive or do not respond to SSRI’s, SNRI’s, or TCA therapy. Atypical depression may respond preferentially to MAO therapy. Atypical depression: Significant weight gain or increase in appetite; Hypersomnia (sleeping too much, as opposed to the insomnia present in melancholic depression); Leaden paralysis (i.e., heavy, leaden feelings in arms or legs); Long-standing pattern of interpersonal rejection sensitivity

Pharmacokinetics MAOI are readily absorbed, because enzymes are inactivated several weeks must go by before the action of the drug is terminated. Therefore, when we switch to other antidepressants we must wait at least two weeks after we terminate the MAOI administration. MAOI are metabolically acted on in the liver and excreted in the urine.

Adverse Effects Those on MAOI’s cannot eat large amounts of tyramine. Tyramine will cause large amounts of stored catecholamines to be released by the nerve terminals. Hypertension, orthostatic hypotension, tachycardia, occipital headache, stiff neck, cardiac arrhythmias, seizures and stroke can occur. Phentolamine and prazosin can be used for tyramine induced hypertension.

Mania/Bipolar Lithium: these salts are used acutely and prophylactically for the management of bipolar patients. Lithium is effective in treating 60 – 80% of patients exhibiting mania or hypomania. The therapeutic index is very low. Adverse effects include headache, dry mouth, polydipsia, polyuria, polyphagia, GI distress, fine hand tremor, dizziness, sedation and dermatological issues. At higher doses ataxia, slurred speech, confusion and convulsions can occur. Antiepileptic drugs such as valproic acid, carbamazapine, and lamotrigine are also used as mood stabilizers.