Depression and Antidepressant Drugs PDF

Depression and Antidepressant Drugs Dr Rima Atallah Hijazeen  Depression Overview * Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest. * Major depressive disorder (MDD) has significant potential morbidity and mortality, Contributing to suicide...

Depression and Antidepressant Drugs Dr Rima Atallah Hijazeen  Depression Overview * Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest. * Major depressive disorder (MDD) has significant potential morbidity and mortality, Contributing to suicide. * With appropriate treatment, 70-80% of individuals with major depressive disorder can achieve a significant reduction in symptoms.  Major types of Depression Unipolar: Major depressive disorder (most common) Bipolar: Manic depression (least common)  1. Major depressive disorder (MDD) (Unipolar or clinical depression) - Sad for a long period of time (2 weeks or longer) →Unipolar. - Hate himself and hopelessness (despair). - Loss of appetite (weight loss) or overeating (weight gain). - Insomnia or hypersomnia. - Reduction in libido (reduced sex drive). - Fatigue (loss of energy). - Thoughts of suicide (thoughts of death).  2. Bipolar Depression (Manic depression or Mania). - Mood swings from extremes of high energy with an "up" mood to low "depressive" periods----→Bipolar. - Extremely elevated mood (Mania). - During mania an individual feels or acts abnormally happy, energetic or irritable (abnormally elevated energy levels). - The need for sleep is usually reduced. - During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life.  3. Persistent Depressive Disorder or Dysthymia (Chronic Depression). - Symptoms are milder than of major depression, but for a long period of time often two years or longer. - Major depressive disorder may occur before or during persistent depressive disorder: This is sometimes called double depression. - It is often begins early: in childhood, the teen years or young adult life.  4. Seasonal Affective disorder (SAD). - It is related to changes in seasons: begins and ends at about the same times every year. - It is due to reduced level of sunlight in fall and winter may cause winter onset- SAD - Light therapy is a common treatment for seasonal affective disorder. - When the depression season ends, they get well and function normally again.  5. Atypical Depression (AD) - A typical depression or depression with atypical features. - Characterized by over eating and over sleeping (Hypersomnia). - This type of depression is mild and can easily by cured compared to OTHER types. - Have a hard time maintaining romantic relationships and are especially afraid of rejection by others (is two to three times more common in women than in men).  6. Psychotic major Depression (PMD) - Severe form of major depression. - Characterized by hallucinations, hears voices and delusional. - It is a person with untreated major depression, may suffer from a psychotic depression. - It can be difficult to distinguish from schizoaffective disorder. - Most patients with psychotic depression report having an initial episode between the ages of 20 and 40.  7. Postpartum Depression (PPD). - Usually begins in the first few months after childbirth and can affect both sexes. - Characterized by feelings of extreme sadness, fatigue, loneliness. hopelessness fears about hurting the baby. - Rarely and extreme mood disorder called postpartum psychosis also may develop after childbirth. 8. Premenstrual dysphoric disorder (PMDD). - Premenstrual dysphoric disorder is a condition in which a woman has severe depression symptoms, irritability and tension before menstruation. 9. Situational depression - It is a short term form of depression that can occur in the aftermath of various traumatic changes in the normal life, including divorce, retirement, loss of a job and the death of a relative or close friend.  Pathophysiology of MDD (Biology of Depression) * The underlying pathophysiology of major depressive disorder has not been clearly defined. The older idea that a deficit in function1 or amount2 of monoamines (monoamine hypothesis), there is evidence that neurotrophic3 and endocrine factors4 play a major role (neurotrophic hypothesis).  Monoamine Hypothesis - The Monoamine hypothesis of depression suggests that depression is related to a "deficiency in the amount or function of cortical and limbic serotonin (5- HT), norepinephrine (NE) and dopamine (DA). - Up regulation of 5HT-A2 and 5HT-C2 - Many antidepressant drugs increase synaptic levels of the monoamine neurotransmitter. The observation of this efficacy led to the monoamine hypothesis of depression. Neurotrophic Factor - Brain derived neurotrophic factor (BDNF) (nerve growth factor) one of the major neurotrophic factors, plays an important role in neuroprotection, neurogenesis and synaptic connection. - In the brain, BDNT is active in the hippocampus, cortex and basal forebrain, areas vital to learning. Memory and higher thinking. ❑Exposure to stress and the stress hormones (glucocorticoids)-→decrease BDNF synthesis-→depressant effects. Decreasing levels of BDNF in specific areas of the brain, such as the hippocampus, leads to depression and suicide. Increase mononmines levels-→increase BDNF synthesis-→antidepressant effects. Time required for synthesize of neurotrophnic factors takes 2 weeks or longer (explains antidepressant effects). Biology of Depression  Hypothalamic pituitary adrenal (HPA) Axis - Depression is known to be associated with a number of hormonal abnormalities. - The significance of these HPA abnormalities is unclear, but they are thought to indicate a dysregulation of the stress hormone axis. - More severe types of depression, such as psychotic depression, tend to be associated with HPA abnormalities. - Exogenous glucocorticoids and endogenous elevation of cortisol are associated with mood symptoms and cognitive deficits similar to those seen in MDD. - Thyroid dysregulation has also been reported in depressed patients (up to 25%). - Estrogen deficiency states, which occur in the postpartum and postmenopausal periods, are thought to play role in the etiology of depression in some women. - Severe testosterone deficiency in men in sometimes associated with depressive symptoms. - Hormone replacement therapy in hypogonadal men and women may be associated with an improvement in mood and depressive symptoms. ❑HPA and steroids abnormalities may contribute to suppression of transcription of the BDN gene. ❑Glucorticoids receptors are found in high density in the hippocampus.  Major depressive disorder (MDD) DSM-5 criteria for MDD: Symptoms….Emotional due to low level of 5HT…..Biological due to low level of NE It is diagnosed when a patient exhibits at least 5 of the following symptoms nearly every day for at least 2 weeks: 1. Depressed mood most of the day, nearly every day (e. g., feels sad, empty and hopeless). Note: Children and adolescents can have irritable moods. 2. Diminished pleasure in all or almost all activities most of the day. Nearly every day. 3. Significant weight loss or weight gain (change: > 5% of body weight in a month) or decrease or increase in appetite nearly every day. Note: In children consider failure to make expected weight gain. DSM:Diagnostic Statistical Manual  DSM-5 criteria for MDD: 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day) observable by others). 6. Fatigue or loss of energy nearly every day. 7. Feelings of guilt or worthlessness nearly every day. 8. Diminished ability to think or concentrate or indecisiveness, nearly every day. 9. Recurrently thoughts of death, recurrent suicidal ideation without a specific plan.  MDD complications: * Depression is a serious disorder that can take a terrible to toll on individuals and families. * Untreated, can result in emotional, behavioral & health problems. Examples of complications associated with depression include: - Excess weight or obesity. - Pain and physical illness. - Alcohol or substance abuse. - Anxiety, panic disorder or social phobia. - Family conflicts, relationship difficulties. - Social isolation. - Suicidal feelings, suicide attempts or suicide. Causes of MDD The exact cause of depression are complex and unknown. * Some cases have a number of causes are: * Genetics: (4 genes) Genetic factors play an important role in the development of major depression. * Life events. Such as grief, neglect and unequal parental treatment of siblings in childhood can contribute to depression in adulthood. * Medications; such as sedative hypnotics (such as benzodiazepines), high blood pressure (such as beta-blockers, methyldopa, reserpine) and corticosteroids. * Substance abuse; such as alcohol and opioids. * Situations and environmental factors. * Poor sleep; may cause major depression. * Diet deficiencies in certain vitamins, such as Folic acid, Vita. B12, and Omega-3 fatty acids may cause depression. Diagnosis: History: history of symptoms is compared with the diagnostic criteria, (DSM-5 criteria). * Clinician rating scales: these are psychometric instruments used to identify depression and assess its severity. Common examples are: Scales completed by researchers: - Hamilton rating scale for depression (HAM-D): - It is a multiple item questionnaire (MCQ) used to provide an indication of depression and as a guide to evaluate recovery. - HAM-D is a standard instrument used to show efficacy in clinical trails for U. S. FDA approval. - A score of 0-7 is considered to be normal. - Scores of 20 or higher indicate moderate severe or very severe depression. - clinical global impression scale and Montgomery Asberg depression rating scale. Scales completed by patients (Patient rating Scales): - It is a question self report inventory that converts symptoms such as irritability, fatigue, weight loss, lack of interest in sex, and feelings of guilt, hopelessness. Example: Beck Depression inventory and quick inventory of depressive symptoms self- rated. Physical examination and laboratory tests; e. g. thyroid function test, vitamin deficiencies that may mimic symptoms of depression. Therapeutic options: * Psychotherapy and exercise: * Pharmacotherapy (Antidepressant drugs). * Electroconvulsive therapy (ECT). * Medical devices therapy.  Psychotherapy and Exercise: * Cognitive behavioral therapy for depression (CBT-D): * CTB alone takes longer to observe effectiveness, but when combined with pharmacotherapy it is effective. * Psychotherapy is recommended as monotherapy as initial treatment in patients with mild to moderate MDD. * The therapist will encourage patient to talk about his thoughts and feelings. - Cognitive behavioral therapy typically includes these steps: - Identify troubling situations or problems. - Identify negative or inaccurate thinking. - Challenge negative or inaccurate thinking. * Cognitive behavioral therapy is generally considered about 10 to 20 sessions. * Interpersonal therapy (IPT): * Interpersonal therapy (IPT) for depression is a form of psychotherapy that focuses on the relationships between a person and significant others. * IPT is a short term treatment option that typically consists of 12-16 one – hour weekly sessions. * Exercise: * It has long been known regular exercise is good for physical health. * In recent years, studies have shown that regular physical activity also has benefits for mental health. * Exercise can help people with depression and prevent them becoming depressed in the first place.  Psychotherapy and Exercise: Cognitive behavior therapy appear to be as affective as antidepressant treatment for mild to moderate forms of depression. Psychotherapy is often combined with antidepressant treatment, and the combination appears more effective than either strategy alone.  Pharmacological therapy: Pharmacotherapy may lead to a more rapid response than psychotherapy, but when it is discontinued there is a risk of relapse and adverse effects. There are several classes of antidepressant drugs: * Monoamine oxidase inhibitors (MAOIs). E. g. Phenelzine. * Tricyclic antidepressants (TCAs), e. g. Imipramine and Amitriptyline. * Selective serotonin reuptake inhibitors (SSRIs) e. g. Fluoxetine. * A typical antidepressants (heterocyclic): e. g. Bupropion and Mirtazapine. * Serotonin norepinephrine reuptake inhibitors (SNRIs), e. g. Venalafaxine. * Norepinephrine reuptake inhibitors (NRIs) e. g. Reboxetine.  Antidepressant Drugs - Most clinically useful antidepressant drugs potentiate, either directly or indirectly, the act of norepinephrine and or serotonin (5-HT) in the brain. - All antidepressants are considered to be equally efficacious. - First line medications include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), Bupropion and Mirtazapine. - In general it takes 4-6 weeks to see the full effect of antidepressants, given the correct drug, dose and adherence, but it may take as long as 8 weeks to see a response. Remission may take up to 12 weeks.  1. Monoamine Oxidase Inhibitors (MAOIs) - Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve and other tissues, such as the gut and liver. - In the neuron, MAO functions as a "safety valve" to oxidative deaminate and inactivate any excess neurotransmitters (for example: Norepinephrine, dopamine and Serotonin). - In human there are two types of MAO: MAO-A (brain and peripheral tissues (gut and liver) and MAO-B (brain only): - Serotonin and Norepinephrine are mainly broken by MAO-A. - Dopamine broken by both MAO-A and MAO-B equally. - The Monoamine oxidase inhibitors (MAOIs) may irreversibly or reversibly inactivate the enzyme, therefore accumulate neurotransmitters within the presynaptic neuron and leak into the synaptic space. - MAOIs were introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially lethal food and drug interactions.  Non-selective (MAO-A & MAO-B) inhibitors (Irreversible) Phenelzine (Nardil®) Isocarboxazid (Marplan®) Tranylcypromine (Parnate®) Selective MAO-A inhibitors (Reversible) Moclabemide (Aurorix®) - Phenelzine (FEN-el-zeen) isocarboxazid (eye-soe-car-BOX-ih-zid) tranylcypromine (tran-il-SIP-roe-meen) are non selective (MAO-A & MAO-B) inhibitors (irreversible). - Moclobemide (moe-KLOE-be-mide) is a selective MAO-A inhibitors (reversible). Pharmacokinetics: - MAOIs are well absorbed from the GIT. - MOIs have extensive first pass effects that may substantially decrease bioavailability (Selegiline is available in both transdermal and sublingual). Therapeutic Uses: Their primary use now is in the treatment of depression unresponsive to other antidepressant. They also been used historically to treat anxiety disorder. Two selective MAO-B inhibitor drugs, Selegiline and Rasagiline have been approved by the FDA for the treatment of Parkinson's disease (see later). They are effective antidepressants and may be especially useful for atypical depression (hypersomnia, hyperphagia, and mood reactivity). The use of MAOIs with other antidepressants is contraindicated. (May lead to Seretonin Syndrom) Drug Switching: - From another antidepressants to an MAOI, wait for 2 weeks after the antidepressants is discontinued before initiating the MAOI (except for Fluoxetine, waiting for 5-6 weeks). - From an MAOI to another antidepressant, wait for 2 weeks. Side effects: severe and unpredictable side effects, due to drug food and drug- drug interactions limit the widespread use of MAOLs. Most common side effects: orthostatic hypotension, sexual dysfunction, serotonin syndrome (not to be taken with TCA and SSRI), CNS stimulation (insomnia, tremor, hyperthermia and irritability).  Drug food interaction (cheese reaction) Tyramine is a naturally monoamine found in foods, such as aged (or ripe) cheeses, meats, chicken liver, pickled or smoked fish and red wines. - Tryamine :indirect sympathomimetic acts as a catecholamine releasing agent and normally inactivated by MAO in the gut. - Patients taking MAOI are unable to degrade tyramine obtained from diet-→release of large amount of catecholamines from nerve terminals -→hypertensive crisis (headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures and stroke). - Patients taking MAOIs must be educated and monitored to avoid foods high in tyramine. - Phentolamine & Parazosin (α-blocker) are used in tryramine induced hypertension.  2. Tricyclic antidepressants (TCAs) Imipramine (Toframil®) Amitriptyline (Tryptizol® Clomiramine (Anaframil®) Trimipramine (Surmontial® Doxepin (silenor® Secondary Amines Desipramine (Norpramine®) Nortriptyline (Pamelor®) Protriptyline (Vivactil®) Tetracyclic Antidepressant Maprotiline (ludiomil®) Amoxapine (Amokisan®) - Tricylic antidepessants (TCAs) were the first antidepressants available. - also in the 1950s the first tricylcic antidepressants (Imipramine) were discovered. These agents also called cyclic antidepressants. - They are used for depression, buy they have several off-label uses such as treatment for pain syndromes, migraine prophylaxis and anxiety disorders. - The TCAs were the dominant class of antidepressants until the introduction of selective serotonin reuptake inhibitors (SSRIs) in the 1980s and 1990s. The TCAs includes: - Tertiary amines: impiramine (ee-MIP-ra-men) (the prototype drug), Amitriptyline (amee-TRIP- ti-leen), clompiramine (kole-MIP-ra-meen), doxepin (DOXe-pin) and Trimpiramine (trye-MIP-ra-meen). - Secondary amines Desipramine (dess-IP-ra-meen) (the metabolites of impiramine), Nortriptyline (nor-TRIP-ti-leen) (The metabolites of amitriptyline) and protriptyline (proe- TRIP-ti-leen). - Tetracyclic antidepressants: Maprotiline (ma-PROE-ti-leen) and Amoxapine (a-MOX-a-peen) are commonly included in the general class of TCAs. Pharmacokinetics All TCAs are rapidly absorbed after oral administration and bind strongly to plasma albumin. ❑- TCAs have long half-lives, as a result, most are dosed once daily at night because of their sedating effects. ❑- TCAs have a narrow therapeutic index (five- to six-fold the maximal daily dose of impiramine can be lethal), increasing their probability for toxicity, monitoring serum concentration during therapy may needed. ❑- TCAs are lipophilic, they are widely distributed and readily penetrate into the CNS. ❑- These drugs are metabolized by the hepatic microsomal system (CYP 450 isoenzymes) and conjugated with glucuronic acid. ❑- TCAs are excreted as inactive metabolites by the kidney.  Mechanism of Action - TCAs are inhibitors of neuronal reuptake of NE and 5-HT into presynaptic nerve terminal→increase concentration of monoamine in synaptic cleft. - Maprotiline and desipramine are relatively selective inhibitors of NE reuptake. - TCAs also block serotonergic, a-adrenergic- histaminic and muscarinic receptors. Amoxapine also blocks 5-HT2 and D2 receptors  Pharmacological action - TCAs elevate mood, improve mental alertness and increase physical activity. - The onset of the mood elevation is slow, requiring 2 weeks or longer. - After a therapeutic response, the dosage can be gradually reduced to improve tolerability, unless relapse occurs.  Therapeutic Uses Management of moderate to serve depression Panic disorder, some patients with panic disorder also respond to TCAs. Imparamine has been used to control bed wetting in children older than 6 years of age, but now it has largely been replaced by desmopressin (vasopressin analogue). Amitrptyline, have been used to help prevent migraine headache and chronic pain in depression (fibromyalgia) Doxepin, low doses of doxepin can be used to treat insomnia. Clomipramine, has been used to delay ejaculation in premature ejaculation, but now, it has largely been replaced by SSRIs.  Side Effects - Muscarinic receptors blocking side effects (Atropine like action). - Blurred vision, xerostomia (dry mouth), urinary retention, sinus tachycardia, constipation and aggravation of angle – closure glaucoma. - Amitroptyline is the most potent & desipramine is the least potent - α-adrengergic receptors blocking side effects: - Orthostatic hypotension, dizziness and reflex tachycardia. - Impiaramine is the most potent & Nortriptyline is the least potent. - Histaminic (H1) receptors blocking side effects: - Sedation, especially during the first several weeks of treatment. - Doxepin is the most potent & Desipramine is the least potent.  Side Effects - Serotonergic receptors blocking side effects: - Weight gain and sexual dysfunction (delay ejaculation). - Clompiramine is the most potent. - Quinidine like effects (Sodium channel blockers): - TCAs affect cardiac conduction similarly to quinidine and may precipitate life threatening arrhythmias in an overdose. Antidepressants should be used with caution in patients with bipolar disorder, even during their depressed state, because antidepressants may cause a switch to manic behavior. - These drugs must be used cautiously in patients with cardiac disease or seizure disorders.  Toxicity - Antidepressants were the eighth and seventh leading cause of toxic exposures in 2007 and 2008, respectively, according to the American association of poison control centers. - Approximately 70% death before reaching to the hospital. - TCAs have a narrow therapeutic index (five to six fold the maximal, daily dose of impiramine can be lethal), 10-20 mg per/kg of body weight are a risk for moderate to severe poisoning. - The toxic effect due to multiple action, antihistaminic, anticholinergic α- adrenoceptor blocker effect, sodium channel blocker, GABA receptor blocker effect and potassium channel blocker effect. - Atropine-like action (dry mouth, blurred vision and urine retention) - Metabolic acidosis - Cardiac Arrhythmia (tacchycardia, long QT interval and wide QRS) - Symptoms, tachycardia, drowsiness, a dry mouth, nausea and vomiting, urinary retention, confusion, agitation, headache hypotension, cardiac rhythm disturbances, hallucination and seizures. Toxicity Treatment: No specific antidote. - Supportive therapy: O2, BP and ECG monitoring. - GI decontamination: gastric lavage and activated charcoal (within 1 to 2 hours of ingestion). Dialysis doesn’t work bec. it has large Vd - Treatment of specific complications: Seizers, Benzodiazepine or other anticonvulsant. Arrhythmias, IV sodium bicarbonate (first thing to do)used for patients with severe or life threatening toxicity to resolving the metabolic acidosis and cardiovascular complications. Or IV Lidocain Hypotension: Hypertonic saline or Norepinephrine or dopamine can be used. The US FDA requires all antidepressants, to carry a black box warning with a generic warning about a possible suicide risk.  3. Selective serotonin reuptake inhibitors (SSRIs). - The FDA has approved six SSRIs for the treatment of depression: Fluoxetine (PRrozac®) Sertraline (Lustral®) Paroxetine (Seroxat®) Fluvoxamine (Faverin®) Citalopram (cipram®) Escitalopram (cipralex®) Flouxetine (floo-XE-e-teen) (the prototypic drug) sertraline (SER-tra-leen), Paroxetine (pa-ROX-teen), Fluvoxamine (floo-VOX-e-meen), Citalopram (sye- TAL-oh-pram) and Escitalopram (es-sye-TAL-ophram). Escitalopram is the pure S-enantiomer of Citalopram. Fluvoxamine is indicated only for obsessive – compulsive disorder (OCD) but is an effective antidepressant. (OCD, see anxiety disorders). - SSRIs selectively inhibit the reuptake of serotonin into the presynaptic neuron (300-3000 fold greater selectivity for the serotonin transporter, as compared to the norepinephrine transporter). - Advantage, SSRIs have little blocking acvtivity at muscarinic, a-arenergic, and histaminic H1 receptors, therefore, common side effects associated with TCAs, are not commonly seen with the SSRIs. - Therefore SSRIs have largely replaced TCAs and as the drugs of choice in depression. Pharmacokinetics - All SSRIs are well absorbed after oral administration. - Food has little effect on absorption (except, Sertraline,  absorption). - Fluoxetine differs from the other SSRIs: it having a much long half life, due to it active metabolite Norfluxetine, The elimination half life of Norfluoxetine is about three times longer than fluoxetine. - Fluoxetine has to be discontinued 4 weeks or longer before an MAOI can be administered to decrease the risk of serotonin syndrome. Pharmacokinetics - Extended formulations: Fluoxetine 90mg can be taken once weekly. - - Metabolism by cytochrome P450 enzymes. - Fluoxetine and paroxetine are potent inhibitors of the CYP2 D6. - Fluvoxamine is an inhibitor of CYP3A4. - Citalopram, Escitalopram & Sertraline: Modest CYP interactions. Half life Active Usual dose Maximal daily metabolite (mg/day) dose (mg) Fluoxetine 1-4 days Norfluoxetine 20-60 80 Sertraline 26 hours No 50-200 200 Paroxetine 21 hours No 10-60 50-60 Fluvoxamine 15 hours No 50-300 300 Citalopram 32 hours No 20-40 40 Escitalopram 27-32 hours No 10-20 20  Mechanism of Action The SSRIs block the reuptake of serotonin. Leading to increased concentrations of the neurotransmitter in the synaptic cleft. - Blockade of serotonin reuptake leads to an increase in serotonin overall and may influence all subtypes of serotonin receptors. The Efficacy of SSRIs is equal for treatment of depression. Onset & duration: - SSRIs (other antidepressants), typically take at least 2 weeks to produce significant improvement in mood and maximum benefit may require up to 12 weeks or more. Therapeutic Uses - Depression: All SSRIs except fluvoxamine (but it is effective). - Generalized anxiety disorder (GAD): all SSRIs except fluvoxamine. - Obsessive-compulsive disorder: All SSRIs. - Eating disorders (Bulimia Nervosa): Only fluoxetine. - Stroke recovery: all SSRIs except fluvoxamine. - Premature ejaculation: All SSRIs (include, Dapoxetine), Fluvoxamine. Side Effects - SSRIs are considered to have fewer or less severe adverse effects than the TCAs and MAOIs, but not without adverse effects. - In general, side effects of SSRI: GI side effects (nausea, vomiting, and diarrhea), headache, anxiety, agitation, fatigue, sexual dysfunction, changes in weight and sleep disturbances. GI side effects: - SSRIs enhance serotonergic tone, not just in the brain but throughout the body. - Increased serotonergic activity in the gut is commonly associated with nausea, GI upset, diarrhea, and other GI symptoms. Sleep disturbances: - Paroxetine and Fluvoxamine are the most sedating SSRIs. May be useful in patients who have difficulty sleeping. - Fluoxetine and Sertraline are the most activating SSRIs, May be useful in patients who have excessive somnolence. Side Effects Sexual Dysfunction: - Which may include loss of libido and delayed ejaculation. - Treatment of SSRI induced sexual dysfunction; 1. Adding Bupropion or, 2. Lowering the dose of the SSRI, or 3. Adding an agent such as sildenafil or cyproheptadine or 4. Changing to a drug less likely to cause this problem. Citalopram 40mg increase the risk of QT interval prolongation. SSRIs appear to increase the risk of bleeding. Serotonin Syndrome - Because these drugs have potent serotonergic activity, combination with other drugs affecting serotonin can lead to serotonin syndrome. - Combination of SSRI with Other drugs, for examples: MAOIs, TCAs, SNRIs, dextromethorphan, meperidine, sympathomimetics, triptans and lithium. Serotonin syndrome includes: 1. Neuromuscular hyperactivity: - Muscle rigidity, tremors, and incoordination. 2. Altered mental status: -Agitation, confusion and hypomania. 3. Autonomic instability: - Hyperthermia and diaphoresis. Treatments: - Discontinuing the offending agent. Supportive treatments such as cooling blankets and respiratory assistance and providing clonazepam for seizures and Nifedipine for hypertension. Withdrawal Symptoms Sudden discontinuation of short half life SSRIs such as paroxetine and sertraline is associated with a discontinuation syndrome in some patients characterized by: Dizziness, malaise, and flu-like symptoms, agitation and irritability, nervousness and changes in sleep patterns. Symptoms beginning 1 or 2 days after stopping the drug and persisting for 1 week or longer. - So a gradual dose reduction (e. g, over 2-4 weeks) may be indicated. - Fluoxetine has the lowest risk of causing SSRI withdrawal syndrome. Pregnancy: most antidepressants are category C (Paroxetine is a category D). Children: Antidepressants should be used cautiously in children: - Fluoxetine, sertraline and fluvoxamine are approved for use in children to treat obsessive compulsive disorder. - Fluoxetine and Escitalopram are approved to treat childhood depression. 4. Atypical antidepressants (Tetracyclic and unicyclic antidepressants) - The atypical antidepressants are a mixed group of agents that have actions at several different sites. - Each drug in this category has a unique mechanism of action. Bupropion (Wellbutrin®) - Bupropion (byoo-PROE-pee-on) is a weak norepinephrine dopamine reuptake inhibitor (NDRI), the exact mechanism of action remains unknown. It is indicated for: - Major depressive disorder and seasonal affective disorder. - Smoking cessation, it reduces the severity of nicotine withdrawal symptom, but somewhat less effective than Varenicline (Chantix®) - Sexual dysfunction: it is the drug of choice for the treatment of SSRI induced dysfunction. - Attention deficit hyperactivity disorder (ADHD), it is not very common to use it. - Obesity; FDA approves Bupropion /Naltrexone (Contrave®). - Usual Adult dosage: 200-450mg/day (in 2 or 3 divided doses). Most common side effects, increased risk of seizures, insomnia, anxiety, irritability, headache, and decreased appetite. Warning: Bupropion should not be prescribed to individuals with epilepsy or other condition that lower the seizure threshold. The risk of seizures can be minimized by the following: 1. Avoid use in susceptible patients (history of seizure disorder and eating disorders). 2. Do not give more than 150mg/dose or 450mg/day. 3. Avoid dosage titration any more frequently than every 3 days. Mirtazapine (Remeron®) Mirtazapine (mir-TAZ-a-peen) has a complex pharmacology. 1. Block presynaptic α2- receptors -→ enhances the release norepinephrine and serotonin.. 2. Block 5-HT2 and 5-HT3 receptors. 3. Potent H1 antagonist. Advantages: It does not cause the antimuscarinic side effects like TCAs, or interfere with sexual function like SSRIs. - It is used primarily in the treatment of depression. It is also off- label used as an anxiolytic, hypnotic and appetite stimulant. - Mirtazapine may be an advantage in depressed patients having difficulty sleeping. - Usual adult dosage; 15-45 day. Most common effects: Marked sedation, increased appetite, weight gain and constipation. - Mirtazapine and other antidepressants may cause a withdrawal syndrome upon discontinuation.  5-HT2 Receptor Modulators Trazodone (Trittico®) Nefazodone (serzone®) - Trazodone (TRAZ-oh-done) and Nefazodone (ne-FAZ-oh-done) are a 5-HT2 serotonin receptor antagonist and serotonin reuptake inhibitors. - Trazodone causes marked sedation, priapism (painful erect penis) and orthostatic hypotension. - Trazodone in low doses is commonly used off- label for the management of insomnia. - Nefazodone unlike trazodone, it causes minimal effects on sexual function and is less likely to cause hypotension. - Trazodone has been associated with a risk for hepatotoxicity. - Usual adult dosage: - Trazodone 150-300mg/d. - Nefazodone 300-500mg/d. Vilazodone (Viibryd®) - Vilazodone (vil-AZ-oh-done) is a serotonin reuptake inhibitor and a 5-HT1A partial agonist. - It was approved by the U. S. FDA for treatment major depressive disorder in 2011. - Usual adult dosage, initial dose, 10mg/day with food. Maintenance dose, 20- 40mg/d with food. - The side effect of vilazodone is similar to the SSRIs, including a risk for withdrawal syndrome. Vortioxetine (Brintellix®) - Vortioxetine (vor-TEE-ox-e-teen) is serotonin reuptake inhibitor, 5-HT1A agonist, 5-HT1B partial agonist and 5-HT1D, 5-HT3, 5-HT7 antagonist. - The clinical significance of Vortioxetine effects on the serotonin receptors is currently unknown, but it also appears antidepressant effects. - It is metabolized by CYP2D6. - It is used for treatment major depressive disorder. - Usual adult dosage, initial dose, 10mg/day. Maximum dose: 20mg/d. - Most common side effects: nausea, vomiting and constipation. 5. Serotonin/Norepinephrine Reuptake inhibitors (SNRIs) - SNRIs inhibit the reuptake of serotonin and norepinephrine into the presynaptic neuron. - Unlike TCAs, they have negligible effects at other receptors that cause anticholine or histaminic adverse effects, with the possible exception of Duloxetine, which appears to have a slightly higher incidence of anticholinergic symptoms. - SNRIs, may be effective in depression in patients in whom SSRIs are infective. - SNRIs, may be effective in depression is often accompanied by chronic painful symptoms such as backache and muscle aches (this pain is in part modulated by serotonin and norepinephrine pathway in the CNS). - Both SNRIs and TCAs, are effective in relieving pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, fibromyalgia and low back pain. - The SNRIs have relatively fewer CYP450 interactions than the SSRIs. - The SNRIs may produce serotonin syndrome. - SNRIs may produce a withdrawal syndrome if treatment is abruptly stopped. - Both Duloxetine and Venlafaxine have been associated with higher rate of suicide compared with SSRIs. ****The risk of suicide with SNRIs is still lower than with TCAs.  Venlafaxine (Effexor®) Desvenlafaxine (Pristiq®) - Venlafaxine (VEN-la-fax-een) is a potent inhibitor of serotonin reuptake and at medium to higher doses, is an inhibitor of norepinephrine reuptake (at doses less than 150mg/day, it has primarily a serotonin effect). - Desvenlfaxine (dez-VEN-la-fax-een) is the active metabolite of venlafaxine. - Venlafaxine is substrate but not an inhibitor of CYP2D6. - Venlafaxine is a minor substrate for CYP3A4. - Adult dosage:- Venlafaxine 74-375mg/d. – Desvenlafaxine 50-200mg/d. Side effects: similar to that of the SSRIs (GI effects are common), they are can cause increases in blood pressure, which are usually mild and not clinically significant unless the patient already has hypertension that is not well controlled.  Duloxetine (Cymbalta®) - Duloxetine (doo-LOX-e-teen) is an inhibitor of serotonin and norephinephrine reuptake at all doses. - It is moderate inhibitor of CYP2D6. It is indicated for the treatment of: 1. Major depressive disorder. 2. Generalized anxiety disorder. 3. diabetic peripheral neuropathy. 4. Fibromyalgia. 5. Chronic musculoskeletal pain caused by chronic lower back pain or osteoarthritis pain. - Usual adult dosage: 40-120mg/d. Side Effects: similar to that of the SSRI, increased blood pressure tachycardia (monitor blood pressure) dry mouth and constipation. Duloxetine can cause liver toxicity and should not be used in patients with hepatic insufficiency, severe renal impairment.  Levomilnacipran (Fetzima®) - Levomilnacipran (leevo-mil-Na-si-pran) is a newly approved SNRI, it is the enantiomer Milnacipran (an older SNRI). - It is the most noradrenergically active of the SNRI class. - It is primarily metabolized by CYP3A4. - It is indicated for the treatment of major depressive disorder in adults. It is not approved for the management of fibromyalgia. - Usual adult dosage: 40-120mg.day. Side effects: similar to that of the SSRI, increase blood pressure, tachycardia (monitor blood pressure) and constipation. 6. Norepinephrine reptuake inhibitors (NRIs) Reboxetine (Edronex®) - NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and in obesity due to their appetite suppressant effects. They are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder. - NRIs may produce a withdrawal syndrome if treatment is abruptly stopped. - Reboxetine is primarily metabolized by the CYP3A4 isozyme. - Reboxetine is indicated for the treatment of depression. - Most common side effects of reboxetine: insomnia, nausea, sweating, dry mouth and constipation. - Contraindications: Reboxetine is contraindicated in narrow angle glaucoma, cardiovascular disease, epilepsy, bipolar disorder, patients concomitantly on MAOIs. - N. B. Atomoxetine (Stratera®) is another norepinephrine reuptake inhibitor approved treatment of attention deficit hyperactivity disorder (ADHD). Phases of Therapy 1. Initiation (acute phase treatment) the goal of this phase is remission, which may take 12 weeks. Remission is defined as at least 3 weeks with no symptoms of depressed mood and no more than 3 remaining symptoms of depression. 2. Continuation phase: to reduce the high risk of relapse. continue the medication for 4-9 months, generally at the same dose used during the acute phase to achieve remission. 3. Maintenance phase, recurrence is common, occurring in 20% of patients within 6 months following remission. Long term therapy at full doses may be required in patients at high risk of relapse, which would include prior episodes of depression or a strong family history of relapse. The duration of this phase is determined on an individual basis. - N. B. if there is no response at least 6-12 weeks, the drug can be considered a failure, and another drug from another class is often tried. - Treatment resistance can usually be considered when two or more drugs from different classes have been tried, at this point, augmentation therapy, combination therapy or electroconvulsive therapy (ECT) can be used.  Augmentation therapy Augmentation regimens include the following: 1. Lithium: adding lithium appears to help in treatment resistant depression. The dosing ranging from full doses to small doses (the drug discussed in bipolar disorder). 2. Thyroid: Adding thyroid is also effective for treatment resistant depression. Thyroid hormones thyroxine (T4 and T3) play an important role in cognitive function, mood ability to concentrate, memory, attention span and emotions. The usual dose is 25mcg/day. 3. Buspirone; has also been used as in augmenting agent. 4. Second generation antipsychotics (SGAs or atypical antipsychotics) are also being used as adjustments to antidepressant therapy. Almost all of them have been used, but only aripiprazole and quetiapine have FDA approval for treatment resistant depression. (This drug discussed in schizophrenia disorder). 5. Omega-3 fatty acids and/or folate and/or vitamin B, may play a role in certain cases of depression.  Combination therapy Advantages: - Overcome one or more adverse effects of another drug. - Use lower doses of each may lead to fewer adverse effects. For example: 1. Adding Trazodone to SSRI therapy to treat SSRI induced insomnia. 2. Adding Bupropion to SSRI therapy for patients who do not fully respond to the SSRI alone.  Electroconvulsive therapy (ECT) - ECT has the highest rates of response and remission of any form of antidepressant treatment with 70-90% of patients treated showing improvement. - Indication: Option for refractory depression, depression in pregnancy, psychotic depression. And drug resistant depression. - Treatments course usually administered two or three times per week. An Acute course of ECT typically consists of 6-12 treatments, until symptoms have remitted or clearly reached a plateau. -Procedure: - ECT: is a procedure, done under general anesthesia, in which small electric currents are passed through the brain. - The exact mechanism of ECT remains elusive (unknown). - CV side effects; managed by optimizing blood pressure and monitor ECG during procedure. - Confusion that generally lasts 30-60 minutes after treatments.  Medical devices therapy Deep brain stimulation (DBS): - DBS: is a neurosurgical procedure introduced in 1987, implantation of a medical device called a neurostimulator or brain pacemaker, which sends electrical impulses to specific parts of the brain (mechanism unknown). - It is used in treatment resistant movement and affective disorders such as Parkinson's disease, essential tremor, chronic pain, major depression and obsessive- compulsive disorder (OCD). Vagus nerve stimulation (VNS) - VNS: is a surgical procedure that can be used in treatment resistant depression. - Pacemaker- like device that is implanted in the body. - The device is attached to a stimulating wire that is threaded along a vagus nerve. - The vagus nerve travels up the neck to the brain where it connects to areas believed to be involved in regulating mood. - Once implanted, this device delivers regular electrical impulses to the vagus nerve. - Uses an implanted electrode and generator to deliver electrical pulses to vagus nerve. * Transcranial- magnetic stimulation (TMS): - TMS is a non invasive procedure that uses magnetic fields to stimulate nerve cells in the b rain to improve symptoms of depression. TMS is typically used to treat treatment resistant depression * Cranial electrotherapy stimulation (CES): - CES: is a non invasive procedure that applies a small, pulsed electric current across a person's head to treat anxiety, depression, insomnia and chronic pain. - Electrodes are placed on the ear lobes.