723 Study Guide PDF

Week 1 Chapter 7: Depression Depressive disorders Depression: -key symptoms of depression: 1. Depressed mood, 2. Loss of interest of pleasure -depression can be perceived as a physical illness (exhaustion, lack of motivation) -classic presentation of a depressed patient: stooped posture, decreased m...

Week 1 Chapter 7: Depression Depressive disorders Depression: -key symptoms of depression: 1. Depressed mood, 2. Loss of interest of pleasure -depression can be perceived as a physical illness (exhaustion, lack of motivation) -classic presentation of a depressed patient: stooped posture, decreased movement, downward averted gaze -Observable signs of depression: generalized psychomotor retardation (most often described) -neurovegetative symptoms of depression: (somatic or physical symptoms) -most common complaint: reduced energy -reversed neurovegetative symptoms of atypical features ​ -increased appetite ​ -weight gain ​ -sleeping longer than usual ​ -younger age of onset ​ -more severe psychological slowing ​ -more likely to have comorbid disorders including anxiety, SUD, or somatic symptom disorder -dysphoria: another word for depressed -anhedonia: lack of pleasure or unable to enjoy things that you used to enjoy -those with a higher lifetime risk of successful suicide include those hospitalized with a suicide attempt or suicidal ideatin -cognitive symptoms: subjective reports of an inability to concentrate and impairments in thinking -can assess judgement by reviewing patients actions in the recent past and their behavior during the interview -common clinical mistake: to unquestioningly believe a depressed patient who states that a previous trial of antidepressants did not work- requires confirmation from another source Diagnosis: Major Depressive Disorder: ​ Look at chart 7-2 in book ​ Episodic ​ Euthymia: spontaneously entering normal mood after depressive episode (6-12 months) ​ According to dsm 5 ○​ For a duration of two weeks, 5 symptoms including dysphoria have to be present ○​ Anhedonia ○​ Depressed mood + SIGECAPS ​ Sleep, interest, guilt, energy (low), concentration (difficulty), appetite (decreased), psychomotor retardation (slow movement/speech→severe sign), suicide ​ Having 5 out of 9 symptoms persisting for 2+ weeks is diagnostic according to DSM V ○​ Altered sleep: difficulty sleeping & early morning awakening ○​ Altered activity ○​ Altered energy ○​ Decreased concentration ○​ SI/plan ○​ Depressing thoughts ​ With psychotic features ○​ Mood congruent/ mood correlates with bad thoughts ○​ Mood incongruent/more likely to have a comorbid primary psychotic disorder ○​ Characterized by paranoia, delusions, and hallucinations ​ With melancholic features ○​ Aka endogenous depression ○​ Associated with changes in the autonomic nervous system and endocrine functions ○​ Arising in the absents of external life structures ​ With atypical features ○​ Reverse of the neurovegetative symptoms: increased appetite & sleep ○​ Younger age of onset ○​ More severe psychomotor slowing  ○​ More likely to have comorbid disorders ○​ Notably mood remains reactive ○​ Often experience interpersonal rejection sensitivity ○​ MOAIs typically effective for this subtype ​ With catatonic features ○​ Hallmark symptoms of catatonia are stupor, blunted affect, extreme withdraw negativisim ○​ Marked psychomotor retardation ​ Postpartum onset ○​ Within 4 weeks postpartum ​ Seasonal pattern ○​ Depressive episodes during a particular season ○​ Tx: bright light therapy at least 30 min/day ​ COURSE ○​ Onset ​ About 50 percent of patients having their first episode of major depressive disorder exhibited significant depressive symptoms before the first identified episode ​ Later onset is associated with absence of family history of mood disorders, antisocial personality disorder, and alcohol abuse ○​ Duration ​ Untreated depessive episode last 6 to 13 months treated can last 3 months ​ Withdrawal of antidepressant before 3 months results in the return of symptoms ​ Course of disorder progesses patients tend to have more frequent episodes that last longer ​ PROGNOSIS ○​ Tends to be chronic patients tend to relapse ○​ Prognostic indicators ​ table7-9 Dysthymic disorder/ persistent depressive disorder ​ Table 7-3 ​ Chronic but milder than MDD ​ Course: 50 percent of patients with dysthymia experience an insidious onsent of symptoms ​ HES2SAD ○​ Hopelessness ○​ Energy  ○​ Self-esteem ○​ 2+ (Symptoms persist w/o break) ○​ Sleep ○​ Appetite ○​ Decision making ​ Less than 5/9 symptoms ​ Tx. = therapy and medication Other diagnoses ​ Minor depressive disorder ○​ Depressive symptoms less severe than those seen in major depressive ○​ Episodic nature of symptoms ○​ Between episodes euthymic mood ​ Recurrent brief depressive disorder ○​ Brief periods less than 2 weeks depressive episodes are present ○​ Episodic disorder symptoms are more severe ​ ***Double depression*** ○​ Patients with depressive disorders also meet the criteria for dysthymia ○​ Pts spend life mostly in chronic sub-syndromal state of dysthymia w/ discrete episodes of severe depression Differential diagnosis ​ General medical disorders ○​ Have depressive adolescents tested for mononucleosis ○​ Test patenties markedly overweight of underweight for adrenal and thyroid dysfunctions ○​ Substance-induced mood disorder ○​ Reasonable rule of thumb any drug a depressed patient is taking should be a factor in the mood disorder ​ Neurologic conditions ○​ Most common neurological problems that manifest depressive symptoms are parkinsons dementing illness epilepsy cerebrovascular diseases tumors ○​ Dementia ​ Major depressive disorder ​ Can occasionally be confused with a neurodegenerative illness ​ Cognitive symptoms in major depressive disorder have a sudden onset  ​ Depressed patients do not try to answer questions patients with dementia confabulate ​ Depressed patients can sometimes be coached and encourage into remembering an ability that demented patients lack Other mood disorders ​ Should determine whether patient has had episodes of mania like symptoms ​ Substance related disorders psychotic disorders eating disorders, adjustment disorders, and somatoform disorders ​ Commonly associated with depressive symptoms and should be considerd in the differential diagnosis of a patient with depressive symtoms Comorbidity ​ Anxiety ​ Substance use disorder ○​ Alcohol dependence frequently coexisit with mood disorders ○​ Abuse of substances may be involed in precipitating an episode of illness may represnets patients attemps to treat illness ○​ Depressed patients often use stimulents to relive depression ​ Medical conditions ○​ Clinicians must try to determine weather the underlying medical conditions is pathophysiologically realted to the depression ○​ Any drug that the patient is taking for the medical condition are causing depression Treatment approach ​ First patient safety must be guaranteed ​ Second a complete diagnostic evaluation of the patient is necessary ​ Third we should initiate a treatment plan that addresses not only the immediate symptoms but patients prospective well being ​ Should address the number of the severity of the stressors in patients lives ​ Hospitalization ○​ Definite indications for hospitalization are risk of homicide or suicide, grossly reduced ability to get food and shelter, and the need for diagnostic procedures ○​ A history of rapidly progressing symptoms ○​ Rupture of the patients natural support system ○​ A patient may safely treat dysthymia and other forms of milder depression in the office ○​ Changes in the patients symptoms of behavior or the attiude of the patients support system may warrent hospitalization ​ Choosing a treatment ○​ Combined treatments may offer the best option ​ A combination of pharmacotherapy and physchothrapy for chronically depressed outpatients have shown a higher response and higher remission rates for the combination ​ Somatic treatments ○​ Pharmacotherapy ​ Objective of the pharmacological treatment symptom remission not just reduction ​ All currently available antidepressants may take up to three to four weeks to exert significant therapeutic effects ​ May begin to show effects earlier ​ Choice of antidepressant depends of the side effect profile that is least objectionable to giving patients lifestyle ○​ Phases of treatment (table 7-10) ​ General clinical guidelines ○​ Most common clinical mistake leading to an unsuccessful trail of an antidepressant drug is the use of too low dosage for too short time ○​ Dosage of antidepressant should be raised to the maximum recommended level and mantied at the level for at least 4 to 5 weeks before a drug trial is considered unsuccessful ○​ If a patient is improving on the low dosage of the drug dosage should not be raised unless clinical improvement stops before obtaining maximum benefit ○​ Does not being to respond to appropriate dosage of a drug after 2 or 3 weeks, clinicals may decide to obtain a plasma concentration of the drug if such test is available ​ Initial medication selection ○​ Start with second and third-generation antidepressants ○​ Selection of the initial treatment depends on the chronicity of the condition course of the illness, family history of illness and treatment response, symptom severity, concurrent general medical or other psychiatric response, prior treatment response to other acute phase treatments, potential drug-drug interactions, and patient preference ​ Duration and prophylaxis ○​ Maintain antidepressant treatment for at least 6 months or the length of previous episodes whichever is greater ○​ When discontinuing and antidepressant treatment the drug should be tapered gradually over 1-2 weeks  ○​ Prophylactic treatment with antidepressants is effective in reducing the number and severity of recurrences ○​ Prevention of the new mood episodes aim of the maintenance phase of treatment ​ Treatment of specific depressive disorders ○​ Seasonal winter depression light therapy ○​ Major depressive episodes with psychotic features combination of an antidepressant and an atypical antipsychotic ○​ Ect is useful for this indication ○​ MAOIs SSRI and and bupropion can also be used in atypical depression ​ Comorbid disorders ○​ Simultaneous presence of another disorder can affect initial treatment selection ○​ The non-mood disorder dictates the choice of treatment in comorbid states ​ Therapeutic use of side effects ○​ Adjunctive medications such as hypnotics or anxiolytics combined with antidepressants ​ to provide more immediate symptom relief or to cover those side effects to which most patients ultimately adapt ​ Acute treatment failures ○​ Patients may not respond to medication because they ​ Cannot tolerate side effects ​ Individual adverse events may occur ​ Clinical response is not adequate ​ Wrong diagnosis has been made ○​ Medication trials should last 4-6 weeks to allow for adequate time for meaningful symptom reduction ○​ Those who will respond respond fully should show at least a partial response by the fourth week ​ Partial response- 20-25% reduction in pretreatment symptom severity ​ Those who dont even have a partial response likely need a change in treatment ​ Selecting second treatment options ○​ If initial treatment is unsuccessful ​ Switch to an alternative treatment or augment the current treatment  ○​ Choice between switching from a single treatment to a new single treatment vs augmenting current therapy rests on ​ Patients prior treatment history ​ Degree of benefit acheived with the initial treatment ​ Patient preference ○​ Switching rather than augmenting is preferred after an initial medication failure ○​ Augmentation is helpful with patients who have gained some benefit from the initial treatment but who have not acheived remission ○​ When switching from one monotherapy to another, usual suggestion is to pick a medication from a different class ​ Phases of treatment ○​ Acute and continuation (8-12 weeks) ​ Goals: achieve symptomatic remission, monitor side effects, restore function ○​ Maintenance: 6-24 months ​ Goals: return to full function and quality of life, prevention of recurrence Novel pharmacologic agents ​ Ketamine ○​ Anesthetic agent effective in treatment-resistant depression ○​ Mechanism of action: “inhibits the postsynaptic glutamate-binding protein N-methyl-D-aspartate (NMDA) receptor.” ○​ Available IV or in nasal spray formulation (esketamine) → to be administered in clinic for supervision ○​ Common SE: dizziness, headache, and poor coordination, which are transitory ​ Brexanolone: ○​ Neurosteroid agent ○​ IV form of allopregnanolone ○​ Treatment for postpartum depression ○​ Most common adverse SE: sleepiness, dry mouth, loss of consciousness, and flushing” Somatic Treatments: ​ Vagal Nerve Stimulation ○​ Initially explored for epilepsy, VNS improved mood in patients. ○​ Involves an implanted device similar to a pacemaker to stimulate the left vagus nerve. ○​ Shown to help some patients with chronic, recurrent major depressive disorder achieve remission.  ○​ Mechanism is unclear but may involve neurotransmitter release from the vagus nerve's connection to the enteric nervous system. ​ Transcranial Magnetic Stimulation (TMS): ○​ Uses magnetic pulses to stimulate brain nerve cells, approved for depression resistant to one prior antidepressant. ○​ Repetitive TMS (rTMS) is nonconvulsive, requires no anesthesia, and has minimal side effects. ○​ Treatment involves 40-minute outpatient sessions daily for 4–6 weeks, with scalp discomfort as the most common side effect. ○​ Contraindicated for patients with implanted metallic devices near the head. ​ Phototherapy: ○​ Effective for seasonal affective disorder (SAD) and other conditions like sleep disorders, jet lag, and possibly OCD with seasonal variation. ○​ Involves exposure to bright light (1,500–10,000 lux) for 1–2 hours, usually before dawn. ○​ Generally well-tolerated but may rarely induce mania or hypomania. ○​ Also used to improve sleep in older adults and reduce shift work irritability. ​ Sleep Deprivation: ○​ Many patients with unipolar depression experience transient relief from total sleep deprivation, but symptoms return after resuming normal sleep. ○​ Strategies for Sustained Benefits: 1.​ Serial Total Sleep Deprivation: Alternates total sleep deprivation with normal sleep days but often fails due to relapse during sleep days. 2.​ Partial Sleep Deprivation: Patients stay awake from 2 AM to 10 PM, with up to 50% experiencing same-day relief. Benefits tend to diminish over time but can treat insomnia linked to depression. 3.​ Combination Therapy: Pairing sleep deprivation with antidepressants or lithium helps sustain effects and may accelerate antidepressant response. ​ Psychosocial Therapy: 1.​ Cognitive therapy: a.​ Developed by Aaron Beck b.​ Help patients identify and challenge negative thoughts. c.​ Develop more flexible and positive thinking patterns.  d.​ Practice new cognitive and behavioral responses. e.​ Proven to be effective in treating major depressive disorder. f.​ Comparable in efficacy to pharmacotherapy, with fewer adverse effects and better long-term outcomes. g.​ Combining cognitive therapy with pharmacotherapy may enhance effectiveness, though evidence on this additive benefit is mixed. 2.​ Interpersonal therapy: a.​ Developed by Gerald Klerman b.​ Addresses: i.​ Interpersonal issues often stem from early dysfunctional relationships. ii.​ These issues contribute to or sustain depressive symptoms. c.​ Proven effective for major depressive disorder, especially for severe episodes when psychotherapy is used alone. d.​ Particularly helpful for resolving interpersonal problems. e.​ Involves 12–16 weekly sessions with an active therapeutic approach. f.​ Focuses on behaviors (e.g., lack of assertiveness, impaired social skills) in the context of interpersonal relationships rather than internal conflicts or defense mechanisms. 3.​ Behavior Therapy: a.​ Based on the idea that maladaptive behaviors reduce positive reinforcement and may lead to social rejection. b.​ Therapy aims to modify these behaviors, enabling patients to function in ways that elicit positive feedback. c.​ Effective for MDD 4.​ Psychoanalytically Oriented Therapy: a.​ Aims to change the patient’s personality structure or character, not just alleviate symptoms. b.​ Goal: Enhance interpersonal trust, emotional capacity, coping mechanisms, and ability to grieve and facilitate broader emotional experiences. c.​ Often involves long-term therapy with periods of heightened distress or anxiety. d.​ Differs from short-term therapies in its less-directive role for the therapist and long-term, less-defined endpoints. 5.​ Family Therapy: a.​ Helpful when mood disorders affect marriage or family functioning.  b.​ Examines the family’s role in maintaining or mitigating the patient’s symptoms and the impact of the patient’s disorder on the family. c.​ Improve family dynamics and reduce stress to lower relapse risk. d.​ Address relational issues, as patients with mood disorders often face marital and familial challenges (e.g., high divorce rates). The Epidemiology of Depression ​ Gender: ○​ More common in women than men ​ Age: ○​ Mean age of onset for MDD is 40 yr but increasing in younger population ​ Marital status: ○​ Occurs common in people w/o close interpersonal relationships, divorced/separated ​ Socioeconomic/Cultural Factors; ○​ Most common in rural than urban areas ○​ Highest prevalence in White and Native American populations Neurobiology of Depression Depression and the Hypothalamic–Pituitary–Adrenal Axis ​ Overactive HPA Axis: ○​ Depressed patients often show elevated cortisol levels over 24 hours, with 20–40% of outpatients and 40–60% of inpatients exhibiting increased HPA activity. ○​ Hypercortisolemia results from increased corticotropin-releasing hormone (CRH) secretion and decreased feedback inhibition. ○​ The dexamethasone suppression test (DST) can identify impaired feedback inhibition. Depressed patients show an initial cortisol decrease but then escape suppression, returning to high cortisol levels. ○​ Hypercortisolemia is associated with disturbances such as reduced serotonin inhibition, increased norepinephrine or CRH activity, and impaired hippocampal feedback inhibition. ○​ Chronic stress and early trauma are linked to heightened HPA activity and structural brain changes (e.g., cortical atrophy or decreased volume). ​ Thyroid Axis Activity:  ○​ Thyroid Dysfunction: About 5–10% of people with depression have undiagnosed thyroid issues, often showing abnormal thyroid-stimulating hormone (TSH) levels. ○​ Impact: Thyroid problems, if untreated, can interfere with depression treatment. ○​ Blunted TSH Response: Around 20–30% of depressed people have a weak TSH response to a thyroid challenge, which may increase their risk of relapse even with treatment. This abnormality usually doesn’t improve with antidepressants. ​ Growth Factor:​ ○​ GH is released when stimulated by norepinephrine, dopamine. Individuals with depression tend to have lower levels of somatostatin (a hormone that regulates GH), while higher levels are seen in mania. ​ Prolactin ○​ Prolactin, a hormone influenced by serotonin and dopamine, doesn’t show major abnormalities in most depressed patients. ​ Brain-Derived Neurotrophic Factor (BDNF) ○​ BDNF is a protein that aids in neuronal maintenance. Low levels of BDNF can lead to decreased neuronal size and number and this has been linked to depression. ○​ Depressed patients who respond to antidepressants often show higher BDNF levels in their blood. ○​ Chronic stress reduces BDNF activity and brain cell growth. ○​ Treatments like antidepressants, estrogen, lithium, and neurostimulation may increase BDNF, potentially explaining their effectiveness in depression. Circadian Rhythm Disruption in Depression ​ Common issues in sleep: ○​ Premature loss of deep (slow-wave) sleep. ○​ Increased nocturnal awakenings and reduced total sleep time. ○​ Increased rapid eye movement (REM) sleep and core body temperature. ​ Specific Sleep Pattern in Depression: ○​ Reduced first period of non-REM sleep (called reduced REM latency). ○​ Often linked to blunted growth hormone (GH) secretion. ○​ This sleep pattern can persist even after recovery from depression. Neurotransmitter Deficits ​ Norepinephrine (NE) in Depression: ○​ Antidepressant response is linked to downregulation or decreased sensitivity of β-adrenergic receptors. ○​ Presynaptic β2-receptors decrease norepinephrine release and regulate serotonin release. ​ Serotonin in Depression: ○​ Most antidepressants target serotonin, making it the neurotransmitter most associated with depression. ○​ Serotonin depletion may trigger depression, and low serotonin metabolites are found in patients with suicidal tendencies. ○​ Low serotonin uptake sites are observed in platelets of some patients. ​ Dopamine in Depression: ○​ Dopamine activity may be reduced in depression and increased in mania. ○​ Drugs or conditions that reduce dopamine (e.g., reserpine, Parkinson’s disease) can cause depression. ○​ Drugs that increase dopamine (e.g., amphetamine, bupropion) may alleviate depression symptoms. ​ Acetylcholine (ACh) in Depression: ○​ ACh is found in neurons throughout the brain and interacts with monoamine systems. ○​ Abnormal choline levels have been found in the brains of some depressed patients. ○​ Cholinergic agonists can cause lethargy and psychomotor retardation, mimicking depression symptoms. ○​ Some people with mood disorders show increased sensitivity to cholinergic agonists. ​ Gamma-Aminobutyric Acid (GABA) in Depression: ○​ GABA inhibits monoamine systems, and reduced GABA levels are found in depression. ○​ Chronic stress depletes GABA levels, while antidepressants upregulate GABA receptors, potentially aiding treatment. ​ Glutamate and Glycine in Depression: ○​ Glutamate is an excitatory neurotransmitter, and glycine is an inhibitory one, both linked to NMDA receptors. ○​ Excessive glutamate stimulation can be neurotoxic, especially in the hippocampus, and may contribute to the neurocognitive effects of depression. ○​ NMDA receptor antagonists may have antidepressant effects. Chapter 21.2: Antidepressants → Currently Approved indications of SSRIs in the US for Adult and Pediatric Populations Pharmacokinetics ​ Half-lives: ○​ Fluoxetine (Prozac): the most prolonged half-life of 4-6 days and its active metabolite has a half-life of 7-9 days ○​ Sertraline (Zoloft): 26 hrs and its less active metabolite has half-life of 3-5 days ​ Absorption may be slightly enhanced by food ○​ Citalopram (Celexa): 35 hrs ○​ Escitalopram (Lexapro): 27-32 hrs ○​ Paroxetine (Paxil): 21 hrs ○​ Fluvoxamine (Paxil): 15 hrs ​ SSRIs in general are well absorbed after oral admin a Selective serotonin reuptake inhibitors ​ All SSRIs are equally effective ​ Differences lie in pharmacokinetics, pharmacodynamics, and side effects Pharmacologic actions  ​ Pharmacokinetics ○​ SSRIs are well absorbed after oral administration ○​ Peak effects range from 3-8 hours ○​ There are differences in plasma protein-binding percentages among the SSRIs ○​ Most highly bound: sertraline, fluoxetine, and paroxetine ○​ Least bound: escitalopram ○​ Generally have a broad therapeutic index ○​ Each SSRI possess a potential for slowing or blocking the metabolism of many drugs ​ Fluvoxamine most problematic for this ​ Pharmacodynamics ​ Therapeutic effect exerted through serotonin reuptake inhibition ​ Higher dosages do not increase antidepressant efficacy but may increase risk of adverse effects ​ Concurrent use of SSRIs and triptans may result in serotonin syndrome (similar reaction can result when taken with tramadol) Therapeutic indications ​ Depression ​ All SSRIs other than fluvoxamine have been approved by the FDA for treatment of depression ​ Comparisons if individual SSRIs have not revealed any to be consistently superior to another ​ Before shifting to non-SSRI antidepressants, it is most reasonable to try other agents in the SSRI class for persons who did not respond to the first SSRI ○​ Suicide ​ FDA issued a black box warning for antidepressants and suicidal thoguhts and behavior in children and young adults ​ Suicidal thoguhts and behavior decreased over time for adult and geriatric patients treated with antidepressants ​ SSRI and SNRIs have a protective effect against suicide that is mediated by decreases in depressive symptoms with treatment ​ For youths, no significant effects of treatment on suicidal thoughts and behavior were found ​ No evidence of increased risk was observed in youths receiving active medication ​ SSRIs prevent potential sucides as a result of their primary action ○​ Depression during pregnancy and postpartum ​ Rates of relapse during pregnancy among ​ women who discontinue, attempt to discontinue, or modify their antidepressants is very high ​ Many women need to continue taking their medication during pregnancy and postpartum ​ No significantly increased risk for major congenital malformations after exposure to SSRIs during pregnancy ○​ Exception to this is paroxetine ​ In paroxetine, their is a potential for infant to get discontinuation syndrome ​ Paroxetine increases the risk of congenital disabilities, particularly heart defects ○​ Occurs when women take it during first 3 months of pregnancy  ​ Babies whose mothers are taking an SSRI in the latter part of pregnancy may have a slight risk of developing pulmonary hypertension ​ Minimal amounts of SSRIs are found in breast milk and no harmful effects have been found in breastfed babies ○​ Depression in elderly and medically ill persons ​ Safe and well tolerated ​ Paroxetine has some anticholinergic activity which may lead to constipation and worsening of cognition ​ Can produce subtle cognitive deficits, prolonged bleeding time, and hyponatremia ​ Effective in poststroke depression and dramatically reduce the symptom of crying ○​ Depression in children ​ Fluoxetine has most consistently demonstrated effectiveness ​ Sertraline is effective in treating social anxiety disorder in this population ​ Anxiety disorders ​ Generalized anxiety disorder ○​ Obsessive-compulsive disorder ​ Indicated for treatment of OCD: fluvoxamine, paroxetine, sertraline and fluoxetine ​ Approved for children aged 6-17 years: fluvoxamine, fluoxetine, and sertraline ​ SSRI doses may need to be higher than those needed to treat depression ​ May take several months for maximum effects to become evident  ​ Those who fail to get adequate symptom relief will benefit from addition of small dose of risperidone ​ Monitor for extrapyramidal side effects and increases in prolactin levels when this combination is used ​ Hyperprolactinemia can manifest as gynecomastia, galactorrhea, and loss of menses ○​ Panic disorder ​ Indicated for panic disorder with or without agoraphobia: paroxetine, fluoxetine, and sertraline ​ Fluoxetine can initially heighten anxiety symptoms ○​ Begin with small doses (5 mg) and increase the dosage slowly ○​ Low doses of benzodiazepine may be given to manage this side effect ○​ Social anxiety disorder ​ SSRIs are safer to use than MAOIs and benzodiazepine ○​ Posttraumatic stress disorder ​ Target specific symptoms in four clusters: reexperiencing, avoidance, negative changes in mood and thinking, and arousal ​ SSRIs have broader spectrum of therapeutic effects on PTSD symptom clusters ○​ Associated with marked improvement of both intrusive and avoidant symptoms ​ Bulimia nervosa and other eating disorders ​ Fluoxetine is indicated for the treatment of bulimia (60mg/day)  ○​ Anorexia nervosa ​ Effective treatments for anorexia include various therapies in addition to a trial with SSRIs ○​ Obesity ​ All SSRIs may cause initial weight gain ○​ Premenstrual dysphoric disorder ​ Reduces symptoms: sertraline, paroxetine, fluoxetine, and fluvoxamine ​ Off label uses ○​ Premature ejaculation ​ Fluoxetine and sertraline ○​ Paraphilias ​ SSRIs diminish the average time spent per day in unconventional sexual fantasies, urges, and activities ○​ Autism ​ May respond to SSRIs and clomipramine ​ Sertraline and fluvoxamine ​ Fluoxetine Precautions and adverse reactions Sexual dysfunction ​ All SSRIs cause sexual dysfunction ​ Patients may need to be switched to antidepressants that do not interfere with sexual functioning GI adverse effects ​ Most frequent complaints are nausea, diarrhea, anorexia, vomiting, flatulence, and dyspepsia ​ Sertraline and fluvoxamine produce the most intense GI symptoms ​ Delayed release paroxetine has less intense GI side effects ​ ⅓ of persons taking SSRIs will gain weight  ○​ Due to a metabolic mechanism, an increase in appetite, or both ○​ Happens gradually ○​ Resistant to diet and exercise regimens ​ Paroxetine associated with most frequent, pronounced, and rapid weight gain Cardiovascular effects ​ All SSRIs can lengthen the QT interval ​ Risk of QT prolongation increases when an antidepressant and an antipsychotic are used in combination ​ FDA recommendations regarding citalopram use ○​ Max dose is 20 mg/day for those with hepatic impairment, older than 60 years of age, CYP2C19 poor metabolizers, or are also taking cimetidine ○​ Dont prescribe doses greater than 40 mg/day ○​ Dont use in patients with congenital QT syndrome ○​ Correct hypokalemia and hypomagnesemia before administering ○​ Monitor electrolytes as clinically indiicatedb Headaches ​ Fluoxetine is most likely to cause headaches ​ All SSRIs are effective prophylaxis against migraines and tension type headache Central nervous system effects ​ Anxiety ​ Fluoxetine may cause anxiety particularly in first few weeks of treatment ​ Insomnia and sedation ​ Primary effect SSRIs exert in area of insomnia and sedation is improved sleep resulting from treatment of depression and anxiety ​ Other sleep effects  ​ Can have extremely vivid dreams or nightmares ​ Emotional blunting ​ This side effect often leads to treatment discontinuation, even when drugs provide relief from depression and anxiety ​ Yawning- increased ​ Seizures ​ More frequent at highest doses of SSRIs than at standard doses ​ Extrapyramidal symptoms ​ SSRIs rarely cause these symptoms ​ Anticholinergic effects ​ Paroxetine has mild anticholinergic activity that causes dry mouth, constipation, and sedation (dose dependent) ​ Hematologic adverse effects ​ Can cause functional impairment of platelet aggregation but not a reduction in platelet number ​ Can manifest through easy bruising or excessive or prolonged bleeding ​ Use of SSRIs with NSAIDs has an increased risk of gastric bleeding ​ When use together, consider use of proton pump inhibitors ​ Electrolyte and glucose disturbances ​ SSRIs may acutely decrease glucose concentrations ​ Long term use may be associated with increased glucose levels ​ Endocrine and allergic reactions ​ SSRIs can increase prolactin levels and cause mammoplasia and galactorrhea ​ Reversible upon discontinuation of the drug ​ Serotonin syndrome ​ Use of an SSRI with and MAOI, l-tryptophan, or lithium can raise blood serotonin levels to toxic ​ Severe and possibly fatal syndrome goes in order of appearance as condition worsens ​ 1. Diarrhea ​ 2. Restlessness ​ 3. Extreme agitation, hyperreflexia, and autonomic instability with possible rapid fluctuations in vital signs ​ 4. Myoclonus, seizures, hyperthermia, uncontrollable shivering, and rigidity ​ 5. Delirium, coma, status epilepticus, cardiovascular collapse, and death ​ Treatment: remove offending agents and prompt supportive care ​ ​ Sweating ​ Terazosin 1-2mg/day helps to counteract random sweating ​ Overdose ​ Selective serotonin reuptake inhibitor withdrawal ​ Usually does not appear until after at least 6 weeks of treatment and usually resolves spontaneously in 3 weeks ​ Fluoxetine- least likely to be associated with this syndrome ​ Half life of its metabolite is more than a week  Drug interactions ​ SSRIs (espeically fluvoxamine) should not be used with clozapine (raises clozapine concentrations which increases risk of seizure) ​ SSRIs may increase duration and severity if zolpidem-induced side effects including hallucinations ​ Fluoxetine ​ Can be administered with low doses of tricyclic drugs ​ Metabolized by CYP2D6 ​ May interact with warfarin which increases the risk of bleeding and bruising ​ Sertraline ​ May displace warfarin from plasma proteins and may increase prothrombin time ​ Paroxetine ​ More potent inhibitor of the CYP2D6 enzyme ​ May increase anticoagulant effect of warfarin ​ Taking paroxetine and tramadol may precipitate serotonin syndrome in the elderly ​ Fluvoxamine ​ Has most risk for drug-drug interactions ​ Metabolized by enzyme CYP3A4, which can be inhibited by ketoconazole ​ Should not be administered with alprazolam, triazolam, and diazepam ​ Citalopram ​ Not a potent inhibitor of CYP enzymes ​ Escitalopram ​ Moderate inhibitor of CYP2D6 ​ Vilazodone ​ Dose should be reduced to 20 mg when given with CYP3A4 potent inhibitors Interferences with laboratory tests ​ Do not interfere with any laboratory tests Dosage and clinical guidelines ​ Fluoxetine ​ Depression: initial dose is 10-20mg/day given in morning to mitigate insomnia risk ​ 4 weeks to reach steady state concentration ​ Max dose recommended by manufacturer is 80 mg/day ​ Sertraline ​ Initial treatment of depression- 50mg/day ​ Can increase dose 50mg weekly up to max of 200mg daily ​ For treatment of panic disorder, starting dose should be 25 mg to reduce risk of provoking a panic attack ​ To limit GI side effects, some clinicians start at 25 mg/day and increase to 50mg/day after 3 weeks ​ Paroxetine ​ For depression, starting dose is 10-20mg/day ​ Can increase dose by 10 mg weekly up to 50 mg/day ​ The SSRI most likely to produce a discontinuation syndrome ​ Fluvoxamine ​ The only SSRI not approved by the FDA as an antidepressant ​ Indicated for OCD ​ Usual starting dose is 50 mg at bedtime for the first week ​ Citalopram ​ Usual starting dose is 20mg/day for the first week then it is increased to 40 mg/day  ​ Escitalopram ​ Recommended dose is 10 mg/day ​ Vilazodone ​ Recommended therapeutic dose is 40mg/day ​ Should be taken with food, if not inadequate drug concentrations may result ​ Pregnancy and breastfeeding ​ Safe to take during pregnancy except for paroxetine ​ Loss of efficacy ​ Some report a diminished response or total loss of response to SSRIs with recurrence of depressive symptoms while remaining on a full dose of medication ​ Potential remedies ​ Increasing or decreasing dosage ​ Tapering drug use and then rechallenging with the same medication switching to another SSRI or nonSSRI antidepressant ​ Augmenting with bupropion or another augmenting agent ​ Vortioxetine ​ Recommended starting dose is 10mg/daily without regard to eals and then increase to 20mg/day ​ Max dose is 10mg/day in known CYP2D6 poor metabolizers ​ Dose be decreased to 10mg/day for 1 week before full discontinuation of 15-20 mg/day Selective serotonin-norepinephrine reuptake inhibitors ​ Vanlafaxine, desvenlafaxine, duloxetine, levomilnacipran ​ Milnacipran only available for fibromyalgia in the US ​ Venlafaxine and desvenlafaxine ○​ Therapeutic indications  ​ Venlafaxine: MDD, GAD, social anxiety disorder, and anxiety disorder ​ DVS: MDD ​ Depression ​ GAD: extended release formulation of venlafaxine is approved ​ Dosages of 75-225 mg/day ​ Social anxiety disorder: extended release formulation of venlafaxine is approved ○​ Precautions and adverse reactions ​ Nausea is the most frequently reported ​ Treatment induced nausea can be controlled by prescribing selective serotonin antagonist or mirtazapine ​ Associated with sexual side effects: decreased libido and delay to orgasm ​ As far as anticholingeric side effects go, drugs have no affinity for muscarinic or nicotinic receptors ​ Commonly associated with discontinuation syndrome- slow taper schedule should be used ○​ Drug interactions ​ Metabolized in the liver by CYP2D6 isoenzyme ​ Venlafaxine is contraindicated in patients taking an MAOI ​ MAOI should not be started for at least 7 days after stopping venlafaxine ○​ Interference with laboratory values- none ○​ Dosage and administration ​ Depression: initial therapeutic dose is 75mg/day ​ Most started ar 37.5mg/day for 4-7 days to minimize adverse effects (nausea)  ​ Dosage can be raised in increments of 75mg/day every 4 days ​ Upper dosage of ER is 225mg/day ​ DVS: therapeutic dose is 50mg/day ​ Duloxetine ○​ Pharmacologic actions ​ Peak: 6 hours after ingestion ​ Steady state plasma concentrations occur after 3 days ​ Elimination is primarily through enzymes CYP2D6 and CYP1A2 ○​ Therapeutic indications ​ Depression ​ Neuropathic pain associated with diabetes and stress urinary incontinence ○​ Precautions and adverse reactions ​ Nausea ​ Increased sweating ​ Increased blood sugar and A1C during long term treatment ​ Should not be prescribed for patients with hepatic insufficiency and end stage renal disease or uncontrolled narrow angle glaucoma ​ Abrupt disocntinuation should be avoided ○​ Drug interactions ​ Moderate inhibitor of CYP450 enzymes ○​ Interference with laboratory values- none ○​ Dosage and administration ​ Recommended therapeutic and maximum dosage is 60 mg/day ​ Milnacipran and levomilnacipran ○​ Up to 50mg/BID  ○​ Milnacipran only FDA approved for treatment of fibromyalgia ○​ Levomilnacipran approved by FDA as treatment for MDD in adults ○​ Most common adverse reactions ​ Nausea ​ Constipation ​ Hyperhidrosis ​ Tachycardia ​ Erectile dysfunction ​ Vomiting ​ palpitations ​ Bupropion ○​ Pharmacologic actions ​ Antidepressant drug that inhibits reuptake of norepinephrine and possibly dopamine ​ Low risk of sexual dysfunction and sedation ​ Modest weight loss ​ No withdrawal syndrome linked to discontinuation ​ Three ways to administer ​ Immediate release: peak concentration 2 hours ​ Sustained release: peak is seen after 3 hours ​ Extended release: peak is after 5 hours ○​ Therapeutic indications ​ Depression ​ Smoking cessation ​ Most effective when combined with nicotine substitutes ​ Bipolar disorders ​ Less likely than TCAs to precipitate mania in persons with bipolar 1 disorder  ​ Less likely than other antidepressants to exacerbate or induce rapid cycling bipolar 2 disorder ​ ADHD ​ Used as a second line agent after sympathomimetics ​ Approcproatie choice for persons with comorbid ADHD and depression or persons with comorbid ADHD, conduct disorder, or SUD ​ Considered for patients who develop tics when treated with psychostimulants ​ Cocaine detoxification- results inconclusive ​ Hypoactive sexual desire disorder ​ May improve sexual arousal, orgasm completion, and sexual satisfaction ○​ Precautions and adverse reactions ​ Most common side effects: headache, insomnia, dry mouth, tremor, nausea ​ Those with severe anxiety or panic disorder should not be prescribed burproprion ​ Can cause psychotic symptoms ​ Risk of seizure is dose dependent ​ Use by pregnant women not associated with an increased risk if congenital disabilities ​ Is secreted in breast milk ○​ Drug interactions ​ Should not be used with MAOIs due to risk of inducing a hypertensive crisis ​ 14 days should pass between administration of bupropion and discontinuation of an MAOI ○​ Interference with laboratory values  ​ May give a false-positive result on urinary amphetamine screens ○​ Dosage and clinical guidelines ​ 300 mg is the recommended dose a person should be maintained on for several weeks before increasing it further ​ Max dose is 450mg/day ​ Mirtazapine ○​ Pharmacologic actions ​ Increases both norepinephrine and serotonin through a mechanism other than reuptake blockade or monoamine oxidase inhibition ​ MOA: antagonism of central presynaptic alpha-2 adrenergic receptors and blockade of postsynaptic serotonin receptors ​ More likely to reduce nausea and diarrhea ​ Side effects: increased appetite and sedation ○​ Therapeutic indications ​ Depression ​ Well suited for melancholic features such as insomnia, weight loss, and agitation ​ Insomnia (highly sedating) ​ Used to combat severe GI side effects of cancer and chemotherapy agents ​ Often combined with SSRIs or venlafaxine to augment antidepressant response or counteract serotonergic side effects of those drugs ○​ Precautions and adverse reactions ​ Somnolence is most common adverse effect ​ May be excreted in breast milk- should not be taken by nursing mothers ​ Risk of agranulocytosis  ○​ Drug interactions ​ Can potentiate the sedation of alcohol and benzodiazepines ​ Should not be used within 14 days of an MAOI ○​ Interference with laboratory values- none ○​ Dosage and administration ​ Initial dose 15 mg if person does not respond dose can be increased in 15 mg increments every 5 days to a max of 45 mg before sleep ​ Nefazodone ○​ Pharmacologic action: ​ Half-Life: 2–4 hours; steady state reached in 4–5 days. ​ Active Metabolites: Includes hydroxynefazodone and mCPP, the latter having serotonergic effects that may cause migraine, anxiety, and weight loss. ​ Mechanism of Action: Inhibits serotonin and norepinephrine uptake; antagonizes 5-HT2A receptors (likely responsible for its antidepressant/anxiolytic effects). Mild α1-adrenergic antagonism may cause orthostatic hypotension. ○​ Therapeutic Indications ​ Uses: Effective for major depression (usual dose: 300–600 mg/day), panic disorder, generalized anxiety disorder (GAD), premenstrual dysphoric disorder (PMDD), PTSD, chronic pain, and chronic fatigue syndrome. ​ Advantages: Less sexual dysfunction compared to SSRIs. ​ Special Benefits: Improves REM sleep and sleep continuity. May help treatment-resistant depression. ​ Limitations: Ineffective for OCD. ○​ Precautions and Adverse Reactions: ​ Common Adverse Effects: Sedation, nausea, dizziness, insomnia, weakness, agitation, visual trails (seeing afterimages). ​ Hepatic Risks: Potential for severe hepatic enzyme elevation and liver failure. Serial liver function tests are essential. ​ Cardiovascular Caution: Risk of postural hypotension; use cautiously in cardiac conditions, dehydration, or with antihypertensive drugs.  ​ Switching from SSRIs: May exacerbate withdrawal symptoms due to lack of SSRI discontinuation protection. ​ Overdose: Survivable above 10 g but fatal if combined with alcohol. Toxicity symptoms include nausea, vomiting, and somnolence. ​ Elderly Considerations: Metabolism is slower in elderly, particularly women; lower doses are recommended. ○​ Dosage and Clinical Guidelines ​ Initial Dosage: ​ General Population: 100 mg twice daily ​ Elderly or Sensitive Individuals: Start at 50 mg twice daily ​ Maintenance Dosage: ​ Optimal: 300–600 mg/day in two divided doses. ​ Once-daily dosing (e.g., bedtime) may be effective for some. ​ Trazodone ○​ Pharmacological actions ​ Mechanism: Weak serotonin reuptake inhibitor; potent antagonist of 5-HT2A/5-HT2C receptors. Metabolized through liver. ○​ Therapeutic Indications ​ Depressive Disorders: Effective for MDD at doses of 250–600 mg/day. Improves sleep without reducing stage 4 sleep. ​ Insomnia: First-line treatment due to sedative effects; initial dose: 25–100 mg at bedtime. ​ Erectile Disorder: Can enhance erections but may cause priapism (rare but serious). ​ Other Uses: Low doses (50 mg/day) for agitation in dementia; >250 mg/day for GAD; PTSD-related insomnia and nightmares. ○​ Precautions and Adverse Reactions ​ Common Side Effects: Sedation, dizziness, orthostatic hypotension, headache, nausea. ​ Serious Concerns: Priapism (rare), arrhythmias in predisposed individuals, and orthostatic hypotension (worse with food or large doses). ​ Overdose: Symptoms include lethargy, dizziness, tachycardia, and coma; treatment is supportive with possible gastric lavage. ​ Contraindications: Pregnancy, nursing, hepatic/renal disease caution. ○​ Drug Interactions ​ CNS Depression: Potentiates effects of alcohol and other CNS depressants.  ​ Hypotension: Risk increases with antihypertensives. ​ No Hypertensive Crisis: Safe for MAOI-associated insomnia. ​ Increased Drug Levels: May elevate levels of digoxin, phenytoin, and warfarin (caution advised). ​ CYP3A4 Inhibitors: Raise mCPP levels, increasing side effects. ○​ Laboratory Interference: No known lab test interferences. ​ Tricyclics and Tetracyclines (TCAs) ○​ Pharmacologic Actions ​ MOA: (TCAs) work by increasing, serotonin and norepinephrine, which help regulate mood and emotions. They do this by blocking the reabsorption (or "reuptake") of these chemicals back into nerve cells, making more of them available to improve communication between brain cells. ​ TCAs also affect other receptors in the body, such as those for histamine and acetylcholine. This can help with certain symptoms but also causes side effects like drowsiness, dry mouth, and dizziness. ​ Side Effects ○​ Anticholinergic effects (constipation, sedation, dry mouth) vary by drug. ○​ Less sexual dysfunction and weight gain compared to SSRIs. ○​ Orthostatic hypotension, sedation, and lightheadedness are common. ​ Therapeutic Indications 1.​ Major Depressive Disorder (MDD) ○​ Effective for melancholic features and recurrent depression. ○​ Not recommended for bipolar depression due to risk of inducing mania. 2.​ Panic Disorder with Agoraphobia ○​ Imipramine and other TCAs useful; start with low doses. 3.​ Generalized Anxiety Disorder (GAD) ○​ FDA-approved: Doxepin; imipramine may be helpful. 4.​ Obsessive-Compulsive Disorder (OCD) ○​ Clomipramine is the most effective TCA. 5.​ Chronic Pain and Migraines ○​ Amitriptyline commonly used; lower doses are effective. 6.​ Other Disorders ○​ Childhood enuresis, PTSD, ADHD, narcolepsy, and sleep disorders (e.g., night terrors). ​ Clinical Considerations ○​ TCAs are an alternative for patients intolerant to SSRIs. ○​ Dosage adjustments required for genetic variability and drug interactions. ○​ Monitor for adverse effects like orthostatic hypotension and sedation. ​ Precautions and Adverse Reactions ○​ Psychiatric Effects ​ May induce mania or hypomania in susceptible individuals. ​ Can worsen psychotic symptoms. ​ High plasma levels can lead to confusion or delirium, especially in elderly or dementia patients. ○​ Anticholinergic Effects ​ Common side effects: dry mouth, constipation, blurred vision, delirium, and urinary retention. ​ Severe effects may lead to CNS anticholinergic syndrome (confusion, delirium), especially when combined with other anticholinergic drugs. ​ Management: ​ Sugarless gum or fluoride lozenges for dry mouth. ​ Bethanechol for urinary hesitancy. ​ Avoid TCAs in narrow-angle glaucoma; consider SSRIs instead. ​ Severe cases may require treatment with physostigmine. ○​ Cardiac Effects ​ Typical ECG changes include tachycardia, flattened T waves, prolonged QT interval, and depressed ST segments. ​ Contraindicated in patients with conduction defects or preexisting heart conditions unless absolutely necessary. ​ Persistent tachycardia can lead to drug discontinuation. ​ Overdoses can cause life-threatening arrhythmias. ○​ Other Autonomic Effects ​ Orthostatic Hypotension: The most common autonomic adverse effect, leading to falls or injuries. ​ Management: ​ Encourage adequate hydration (2+ liters daily). ​ Add salt to the diet unless contraindicated (e.g., hypertension). ​ Reduce antihypertensive medication dosage if possible. ​ Nortriptyline has the lowest risk of causing orthostatic hypotension.  ​ TCAs should be stopped days before elective surgery to prevent hypertensive episodes. ○​ Sedation ​ A frequent effect due to anticholinergic and antihistaminergic properties. ​ Most sedating agents: amitriptyline, trimipramine, and doxepin. ​ Less sedating agents: imipramine, nortriptyline, and desipramine. ○​ Clinical Implications ​ Close Monitoring: Patients with cardiac or autonomic side effects, or those on high doses, need careful monitoring. ​ Patient Education: Advise patients on managing orthostatic hypotension and recognizing signs of severe adverse effects. ​ Alternative Treatments: Consider newer antidepressants like SSRIs when TCAs pose significant risks. ○​ Neurologic Effects ​ Common: Fine, rapid tremors, myoclonic twitches, tremors of the tongue/upper extremities. ​ Rare: Speech blockage, paresthesia, peroneal palsies, ataxia. ​ Drug-Specific Effects: ​ Amoxapine: Can cause parkinsonian symptoms, akathisia, dyskinesia (due to dopaminergic blocking activity). Rarely causes neuroleptic malignant syndrome. ​ Maprotiline: Increases seizure risk, especially with rapid dose escalation or high doses. ​ Clomipramine & Amoxapine: Lower seizure threshold more than other TCAs. ○​ Allergic and Hematologic Effects ​ Common: Exanthematous rashes (4–5% with maprotiline). ​ Rare: ​ Agranulocytosis, leukocytosis, leukopenia, eosinophilia. ​ Sore throat/fever within the first months of treatment warrants immediate CBC testing. ○​ Hepatic Effects ​ Common: Mild, self-limiting increases in serum transaminase concentrations. ​ Rare but Severe: Fulminant acute hepatitis (0.1–1%), which can be life-threatening. ​ Discontinue the TCA immediately if acute hepatitis is suspected.  ○​ Teratogenicity and Pregnancy-related risks ​ TCAs cross the placenta, leading to neonatal withdrawal syndrome: ​ Symptoms: Tachypnea, cyanosis, irritability, poor sucking reflex. ​ Discontinue TCAs 1 week before delivery if possible. ​ Breastfeeding: TCAs are excreted in breast milk at low levels, usually undetectable in the infant’s plasma. ○​ Dosage Initiation and Titration ​ Starting Dose: ​ Most TCAs begin at 25 mg/day and are increased gradually. ​ Dividing doses initially can reduce adverse effects, but the entire dose can be given at bedtime once tolerance develops (especially sedating TCAs like amitriptyline). Monoamine oxidase inhibitors (MAOIs) ​ Pharmacologic actions ○​ Mechanism of action ​ MAO enzymes degrade monoamine neurotransmitters like norepinephrine, serotonin, dopamine, and tyramine. ​ MAOA: Metabolizes norepinephrine, serotonin, and epinephrine. ​ MAOB: Metabolizes dopamine and tyramine.​​ ​ Therapeutic indications ○​ Primary Use: ​ Depression, especially atypical depression (mood reactivity, hypersomnia, hyperphagia, sensitivity to rejection). ​ Adverse Effects and Precautions ○​ Common Side Effects: ​ Orthostatic Hypotension: Manage with fluid intake, dietary salt, support stockings, or fludrocortisone in severe cases. ​ Insomnia: Divide doses, avoid dosing after dinner, or use a benzodiazepine if necessary. ​ Weight Gain, Edema, Sexual Dysfunction: Often unresponsive to treatment, may necessitate switching drugs. ○​ Neurological Effects: ​ Paresthesias: Linked to pyridoxine deficiency; supplement with 50–150 mg/day. ​ Myoclonus, muscle pain, or confusion may require dosage adjustments.  ○​ Tyramine-Induced Hypertensive Crisis: ​ Mechanism: MAOIs prevent tyramine breakdown in the GI tract, allowing it to trigger severe hypertension. ​ Symptoms: Headache, stiff neck, diaphoresis, nausea, vomiting, and severe hypertension. ​ Management: Immediate medical attention; dietary restrictions for 2 weeks after discontinuation of irreversible MAOIs. ​ Avoid: Tyramine-rich foods (aged cheese, fermented products), sympathomimetics (ephedrine, pseudoephedrine). ​ Overdose ○​ It often takes 1 to 6 hours after an overdose for the toxic symptoms to occur. MAOI overdose is characterized by agitation that can progress to coma with hyperthermia, hypertension, tachypnea, tachycardia, dilated pupils, and hyperactive deep tendon reflexes” ​ Drug interactions ○​ CNS Depressants: Potentiation with alcohol, barbiturates. ○​ Serotonergic Drugs: Co-administration with SSRIs, clomipramine, lithium, or tryptophan can induce serotonin syndrome. ​ Symptoms: Tremor, hypertonicity, myoclonus, autonomic signs, progressing to hallucinosis, hyperthermia, and potential death. ○​ Opioids: Fatal reactions reported with meperidine (Demerol) or fentanyl (Sublimaze). ​ Dosage and Clinical Guidelines ○​ Phenelzine ​ Start: 15 mg/day. ​ Gradual weekly increase by 15 mg/day to reach 90 mg/day in divided doses by the fourth week. ○​ Tranylcypromine & Isocarboxazid: ​ Start: 10 mg/day. ​ Increase to 10 mg TID by the first week. ​ Divided doses may mitigate hypotensive effects. ​ Clinical Considerations ○​ Refractory depression ​ Though generally contraindicated, combinations of MAOIs with TCAs, SSRIs, or lithium can be used cautiously under expert supervision for treatment-resistant depression. ○​ Transdermal Selegiline ​ Low doses selectively inhibit MAOB, providing antidepressant effects.  ​ At higher doses, selectivity decreases, requiring monitoring for broader MAO inhibition effects. Thyroid Hormones ​ Pharmacologic action ○​ Mechanism of Action: ​ T3 binds to intracellular receptors, influencing gene transcription, including genes for neurotransmitter receptors. ​ Exact antidepressant augmentation mechanism is unknown. ​ T4 to T3 Conversion: T4 crosses the blood–brain barrier, converts into T3 within neurons, and exerts physiologic effects. ​ Therapeutic indications ○​ Adjuvant Therapy in Psychiatry: ​ Primarily used to augment antidepressants, especially in nonresponders after 6 weeks of therapy. ​ Liothyronine (T3) can convert ~50% of antidepressant nonresponders to responders. ​ Dosage: ​ Liothyronine: 25–50 µg/day added to antidepressants. ​ Effective with tricyclics, SSRIs, and other antidepressants. ​ Trial duration: 2–3 weeks; if effective, continue for 2 months before tapering ​ Precautions and Adverse Effects ○​ Adverse Effects (at 25–50 µg/day are rare): ​ Common: Headache, weight loss, palpitations, nervousness, diarrhea, tremors, insomnia. ​ Serious: Osteoporosis (long-term use), cardiac failure, and death in overdose. ○​ Contraindications: ​ Cardiac disease, angina, hypertension. ​ Thyrotoxicosis, uncorrected adrenal insufficiency, acute MI. ○​ Drug Interactions ○​ Potentiating Effects: ​ Warfarin: Enhances anticoagulant effects by increasing clotting factor catabolism. ​ Insulin & Digitalis: May increase dosage requirements. ○​ Contraindicated Combinations:  ​ Sympathomimetics, ketamine, and maprotiline (risk of cardiac decompensation). ○​ Antidepressant Interactions: ​ SSRIs, tricyclics, lithium, and carbamazepine can mildly alter thyroid function (e.g., lower serum T4, raise TSH). ​ Regular thyroid function monitoring is necessary during concurrent use. ​ Thyroid Function and Diagnostic Tests ​ Key Thyroid Tests: ○​ T4 Measurements: Competitive protein binding or radioimmunoassay. ○​ TSH and Free T4 Index (FT4I): Help identify hypothyroidism (common in depression patients). ​ Depression and Thyroid Illness: ○​ ~10% of depressed patients have underlying hypothyroidism. ○​ Lithium use may induce hypothyroidism or rarely, hyperthyroidism. ​ TRH Stimulation Test: ○​ Diagnoses subclinical hypothyroidism or lithium-induced hypothyroidism. ○​ Normal Response: TSH increase of 5–25 mIU/mL. ○​ Blunted Response (