Major depression, statistically more than twice as common in women as men, bears an alarming lifetime prevalence rate of seventeen percent, with the highest incidence in the 25-44 age group. Not only is the risk for suicide a major concern for these patients, but the risks of alcoholism and comorbid psychiatric disorders are also very high for this population. Criteria for diagnosis of major depression or major depressive disorder, which can be observed either as a single event or multiple events, are detailed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The Manual discusses four criteria that apply to a set of nine symptoms, five or more of which must be observable for the same two-week period.
The Criteria: The five or more qualifying symptoms observed must: Comprise a change from previous function; and at least one symptom must be depressed mood or loss of interest or pleasure; Cause clinically significant distress or impairment in social, occupational, or other important functional aspects; Not be due to the direct physiological effects of a medication, a drug of abuse, or a general medical condition; and Not meet criteria for a Mixed Episode and not be better accounted for by bereavement.
The Symptoms Depressed mood lasting most of the day, almost every day Diminished interest or pleasure in all or almost all activities lasting most of the day, almost every day Significant weight loss without dieting, weight gain, or change in appetite almost every day Insomnia or hypersomnia almost every day Psychomotor agitation or retardation (not merely subjective feelings of restlessness or being slowed down) almost every day Fatigue or loss of energy almost every day Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional and not merely self-reproach or guilt about being ill) almost every day Diminished ability to think, concentrate, or make decisions almost every day Recurrent thoughts of death (not merely fear of dying), recurrent suicidal ideation, or a suicide attempt.
Accordingly, as mentioned in Criterion 3, it is imperative in diagnosis to rule out both organic and pharmacological causes or contributing factors as well as other psychiatric factors that might drastically affect any treatment plan.
Possible Contributing Organic or Psychiatric Factors Cardiovascular conditions Cerebral arteriosclerosis Congestive heart failure Myocardial infarction Paroxysmal dysrrhythmias Collagen diseases Rheumatoid arthritis Systemic lupus erythematosus Deficiency states Anemia Pernicious anemia Wernicke’s encephalopathy Endocrine disorders Acromegaly Addison’s disease Cushing’s disease Diabetes mellitus Hyperparathyroidism Hyperthyroidism Hypoparathyroidism Hypothyroidism Insulinoma Pheochromocytoma Pituitary dysfunction Infections AIDS Encephalitis Epstein-Barr (chronic fatigue syndrome) Mycotic infections Influenza Meningitis Mononucleosis Neurosyphilis Tuberculosis Malignancies Breast Gastrointestinal Pulmonary Pancreatic Prostatic Metabolic disorders Electrolyte imbalance Hepatic encephalopathy Hypokalemia Hyponatremia Pick’s disease Uremia Wilson’s disease Neurological disorders Alzheimer’s disease Amyotrophic lateral sclerosis Chronic pain syndrome CNS tumors Cruetzfeld-Jakob disease Huntington’s disease Multiple sclerosis Myasthenia gravis Parkinson’s disease Stroke Trauma Psychiatric disorders Alcoholism/Drug abuse Anxiety disorders Eating disorders Schizophrenia Pulmonary conditions Emphysema Pneumonia Chronic bronchitis
Possible Pharmacological Contributing Factors Antihistamines Cetrizine Anti-inflammatory and analgesic Indomethacin Pentazocine Phenacetin Phenylbutazone Antimicrobial Cycloserine Ethambutol Gram-negative antibiotics (some) Sulfonamides Cardiovascular Atenolol Clonidine Digitalis Diuretics Felodipine Guanethidine Hydralazine Indapamide Losartan Methyldopa Prazocin Procainamide Propranolol Reserpine CNS Alcohol Amantadine Amphetamines Barbiturates Benzodiazepines Carbamazepine Carbidopa/Levodopa Chloral hydrate Cocaine Haloperidol Phenothiazines Succinimides Hormonal ACTH Corticosteroids Estrogen Melatonin Progesterone Miscellaneous Antineoplastic agents Cimetidine Disulfuram Famatodine Gemfibrozil Lansoprazole Pesticides Physistigmine Simvastatin
Diagnosis is further complicated by the recognition and clinical differentiation of a variety of depressive disorders, also defined in DSM-IV. Depressive disorders are divided into the two major categories, unipolar disorders and bipolar disorders, which are then further divided. Unipolar disorders, characterized in general by the absence of any manic or hypomanic episodes, include dysthymia (with a longstanding history of at least two years), adjustment disorder with depressed mood (traceable to an identifiable stressor occurring within the last three months), and major depressive disorder (discussed above). Bipolar disorders, characterized in general by depression in the presence of manic or hypomanic episodes of less than psychotic magnitude, are further divided into cyclothymia (again with a long-standing history of two years), bipolar I disorder (with manic episodes), and bipolar II disorder (with hypomanic episodes). Optimal treatment for any depressive disorder would include professional counseling or psychotherapy and may include therapy with one or more of the antidepressants, the choice of which would be dictated by the symptoms presented as well as other patient-specific factors. With the evolution of more reliably effective medications and the growing tendency of insurers to limit psychiatric benefits, therapy with antidepressants has become increasingly popular. Obviously, concurrent medical conditions and medical therapeutic regimens will have substantial influence on the psychopharmacological choice. General consensus attributes the pathophysiology of depressive disorders to various imbalances in the levels of and/or responses to various CNS synaptic neurotransmitters , most notably norepinephrine (NE), serotonin (5-HT), and dopamine (DA). The medications used to treat the depressive disorders act in different and similar ways to make adjustments in the amounts, activities, and effects of these neurotransmitters. Therapy should be continued for four to six weeks before assuming therapeutic failure and changing agents or even before upward titration of dosage. If one agent fails to produce desired results, another class of medication should be tried. Duration of therapy for less than four months is not recommended, as the rate of relapse is much higher with shorter durations. Therapeutic doses should be continued prophylactially for four to nine months after desired therapeutic effect is attained, and patients suffering more than one depressive episode within five years should remain on long-term therapy. Tricyclic antidepressants (TCA’s) inhibit the reuptake of norepinephrine and serotonin in the central nervous system and were accepted initially for the treatment of depressive conditions. They have proven beneficial in a variety of medical conditions over the past forty years, though, for not only are they effective in many cases of major depressive episodes, but atypical depression, panic disorder, social phobia, bulimia, narcolepsy, attention deficit disorder (ADD) with or without hyperactivity, migraine and other chronic pain syndromes, enuresis, and obsessive-compulsive disorder. Depressive symptoms with other major conditions like bipolar disorder, schizophrenia, and schizoaffective disorder, are treated with tricyclics with some success, as well as depressive conditions not meeting strict criteria for major depressive episodes (dysthymia, depressive neurosis, and prolonged or pathological mourning), for agoraphobia without panic attacks, and for symptoms of post-traumatic stress disorder. Chemically, the TCA’s are either secondary amines (nortriptyline, desipramine, and protriptline) or tertiary amines (amitriptyline, imipramine, and doxepin); and they may be preferred over the SSRI’s for patients who would benefit from the sedation produced by the TCA’s over the activation generally seen with the SSRI’s. Aside from sedation, the TCA’s bear the additional liability of a variety of other side-effects that can limit their usefulness in particular patient populations: Cardiac disorders, orthostatic hypotension, increased suicidal tendencies, lowered seizure thresholds, anticholingeria, cognitive and memory difficulties, and ECG changes. Particularly lethal in overdose situations, but often required in high doses for therapeutic effect, the prudent quantity to dispense at any one time to potentially suicidal patients is always a valid concern. Side effects of TCA’s frequently prompt cessation of therapy or precluded attainment of full therapeutic dosages. Urinary retention, dry mouth, constipation, blurred vision, sedation, weight gain, and sexual dysfunction tend to reduce a patient’s quality of life and even contribute to depression, though tolerance develops over time with some. The secondary amines (nortriptyline, desipramine), with lower binding affinity for muscarinic, histaminergic, and adrenergic receptors, generally produce less unpleasant side effects than the tertiary amines (amitriptyline, imipramine). Desipramine has been associated with sudden death in pediatric patients. Mirtazapine (Remeron ), a long-acting tetracyclic, is a selective presynaptic alpha-2-adrenergic receptor antagonist that enhances transmission of norepinephrine (via alpha-2-autoreceptor blockade) and serotonin (via alpha-2-heteroreceptor blockade – affecting both 5HT2 and 5HT3 receptors) and histamine. Sedation due to histamine antagonizing activity and orthostatic hypotension due to antagonizing peripheral adrenergic activity are prominent side effects. Mirtazapine also tends to cause increased appetite and weight gain, dry mouth, constipation, increase in cholesterol and triglyceride levels, increase in liver enzyme levels, neutropenia, and agranulocytosis. Venlafaxine (Effexor ), a phenylethylamine chemically unrelated to either tricyclic or tetracyclics, acts similarly on both serotonin and norepinephrine reuptake, both the medication (half-life of four hours) and its major metabolite, O-desmethylvenlafaxine (ODV – half-life eleven hours), being potent inhibitors of neuronal serotonin and norepinephrine reuptake and only weak inhibitors of dopamine reuptake. Since neither entity has significant affinity for muscarinic, histaminergic, or alpha1-adrenergic receptors, venlafaxine is relatively free from side effects compared to the tricyclics. It’s side-effect profile greatly resembles that of the SSRI’s, highlighting dose-related nausea, constipation, somnolence, dry mouth, dizziness, nervousness, sweating, asthenia, sexual dysfunction, hypertension, and anorexia. Most such side effects are mild to moderate, occur early in the course of treatment, tend to resolve with continued therapy, and can be minimized by beginning therapy with doses below 25mg with gradual upward titration. Blood pressure should be monitored while the patient is on venlafaxine, as dosages greater than 75 mg/day are frequently associated with hypertension. Other therapeutic choices might be more appropriate for patients with borderline or existing hypertension. The triazolopyradines, trazodone (Desyrel ) and nefazodone (Serzone ), are both 5HT2 receptor antagonists and inhibit the reuptake of serotonin. The active metabolite of trazodone (m-CPP) also shows postsynaptic serotonin agonist activity, while nefazodone also inhibits the reuptake of norepinephrine and is an alpha-adrenergic antagonist. Though not observed with nefazodone, priapism has been associated with trazodone therapy, and common side effects seen with both agents include lightheadedness, dizziness, orthostatic hypertension, somnolence, dry mouth, nausea, and asthenia, all of which tend to abate with continued therapy. Trazodone is particularly noted for causing sedation. The aminoketone, bupropion (Wellbutrin ), chemically resembling the phenylehylamines, is thought to inhibit neuronal uptake of serotonin, norepinephrine, and dopamine, with no effect on monoamine oxidase. Its dose-related liability of precipitating seizures precludes its use in patients prone to seizure, those with a history of head trauma or CNS tumor, and those with a history of anorexia nervosa or bulimia; as those patients tend to develop seizures with bupropion therapy with greater frequency than that seen in the general population. Fortunately, the risk of seizures is generally minimal when the total daily dose remains below 450 mg or when single doses remain below 150 mg. Other common side effects include tremors, agitation, headache, dizziness, vision disturbances, palpitations, insomnia, dry mouth, constipation, and nausea. Monoamine oxidase inhibitors, or MAOI’s – phenelzine (Nardil and tranylcypromine (Parnate) inhibit monoamine oxidases (both type A and type B), a mitochondrial intracellular enzyme, to block the deamination of biogenic amines (norepinephrine, serotonin, and dopamine). Adverse reactions associated with MAOI’s are generally more frequent and severe than with other antidepressants, so other products are generally preferable if effective. Monoamine oxidase inhibition results in an increase in the concentration of synaptic monoamines, presumably responsible for the therapeutic benefit of the medication class; but it also impairs the metabolism of other compounds, such as tyramine, present in certain aged cheeses, wines, and other foods, causing them to accumulate, precipitating acute hypertensive crisis. A number of other medications, both prescription and non-prescription, similarly metabolized, can produce the same effect.
Foods and medications that interact with MAOI’s Foods Aged and cured meats Aged cheeses Anchovies Avocado (ripe) Banana peel Broad bean pods Canned figs Cheese (American, cottage, and Swiss) Chocolate Coffee Fish Licorice Liver Marmite (meat extract) Meats (aged, canned, or processed) Monosodium glutamate Pepperoni Pickled herring Poultry (more than 2 days old) Raisins Sauerkraut Sausage Sour Cream Soy sauce Soybean condiments Tap beer Wines (especially Chianti & sherry)
Medications Amphetamines Antidepressants, other Appetite suppressants Asthma inhalants Buspirone Carbamazepine Cocaine Cyclobenzaprine Decongestants Dextromethorphan Dopamine Ephedrine Epinephrine Guanethidine Levodopa Meperidine Methyldopa Methylphenidate Reserpine Sympathomimetics Tryptophan

Concurrent therapy with serotonergic agents (TCA’s, SSRI’s, trazodone, nefazodone, venlafaxine, narcotics) should be undertaken with great caution, since serotonin levels may become dangerously elevated to precipitate serotonin syndrome—tachycardia, hyperactivity, hypertension, hyperpyretic crisis, and severe seizures. MAOI’s are contraindicated with bupropion or buspirone; and patients on MAOI’s should not be given general anesthesia, local anesthesia with sympathomimetic vasoconstrictors, cocaine, or guanethidine, as potential adverse effects of such combinations can be fatal. Selective serotonin reuptake inhibitors, or SSRI’s – fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), clomipramine (Anafranil), and sertraline (Zoloft), bind to the serotonin transporter and inhibit reuptake to enhance synaptic serotonin activity. At clinical doses, the SSRI’s have little effect on the norepinephrine or dopamine transporters and a low affinity for the histaminic, muscarinic/cholinergic, and alpha receptors, producing a group of medications that are effective at relatively low doses with relatively few side effects. Side effects are generally mild and short-lived with nausea, vomiting, and diarrhea topping the list, which also includes headache, insomnia, and fatigue. Those tend to abate with continued therapy, usually within two weeks of therapy initiation or dosage reduction. Though most SSRI’s reduce anxiety associated with depressive states, fluoxetine may actually exacerbate this symptom, particularly early in therapy. Treatment-resistant depression Underdosing is a frequent cause of treatment failure, so ensuring that adequate doses get an adequate trial is imperative. Increasing dosages of TCA’s even beyond recommended ranges may be considered when response to a 6-week trial at the high end of the recommended range is less than optimal; though there is little data supporting this tactic with SSRI’s. Half of treatment-resistant patients will respond favorably to an MAOI, and venlafaxine proven its worth in such cases. Combinations of a TCA with an SSRI or a TCA with an MAOI have also proven safety and efficacy records. Carbamazepine (Tegretol) and valproate (Depakene, Depakote) have been used with some success in treatment-resistant depression, but newer agents have supplanted them in this application. Gabapentin (Neurontin) and Lamotrigine (Lamictal), two of the newer anticonvulsant medications, have been used with some success in treatment-resistant depressive disorders, and their side effects are substantially less significant than those of carbamazepine and valproate. Though more useful in hard-to-treat bipolar syndromes, treatment-resistant unipolar disorders have been treated with good results, especially as prophylaxis against recurrent episodes. The favorable side-effect profiles of these latter agents make them viable alternatives over dangerously high doses and combinations of more traditional antidepressants in treatment-resistant cases, and they seem particularly helpful in reducing associated anxiety. Toxicology and Suicide Risk Depression obviously carries a serious risk of suicide, and some of the commonly used antidepressant classes (TCA’s and MAOI’s) have a very low therapeutic index. A week’s-worth of medication can easily be a lethal dose of a TCA when taken all at once. 1500mg of a amitriptyline or imipramine can be a lethal cardiotoxic dose, as can as little as 8mg/kg in a child, with hypotension, seizures, cardiac arrhythmias, and coma complicating treatment By contrast, the SSRI’s have a relatively wide therapeutic index and are significantly safer in overdose situations; while experience with bupropion and venlafaxine have yet to adequately prove their lethality in overdose.
Websites to visit. . . Depression FAQ is a comprehensive discussion of just about every aspect of depression from symptoms and variations to treatments of all kinds. It’s very informative and worth your browsing time. http://avocado.pc.helsinki.fi/~janne/asdfaq/
Health Guide Online provides a similar broad overview of all kinds of psychiatric conditions (ADHD, Anxiety & PTSD, Bipolar Disorder, Depression, OCD, Panic and Agoraphobia, Personality Disorders, and Schizophrenia) all accessible by a convenient menu. http://www.healthguide.com/
The Behavioral Health Virtual Clinic is a “jumping-off place” for your patients in need of researching the world of psychiatry. http://www.virtualclinic.com/
Imagine being clinically depressed and being unable to afford the optimal medication(s) to bring you out of it. What could be more depressing? This website has answers for your patients that fall between the financial cracks radiating outward from the impact points of health insurance and Medicaid. Several manufacturers have established procedures for providing medications for such patients. http://www.fairlite.com/ocd/medres/pma.shtml
How do SSRI’s work? This website discusses the scientific principles in a way that almost anyone can understand, using everyday analogies. It’s a great way to explain the complicated world of neurotransmitters and SSRI’s in intricate detail to non-medically oriented patients. http://www.fairlite.com/ocd/articles/serindex.shtml
For a quick reference of every psychoactive drug you can think of – generic name, brand name, and most frequent psychoactive use – check out this site and print out the chart for future reference. It’s a handy summary when counseling patients on their antidepressant therapies. http://uhs.bsd.uchicago.edu/~bhsiung/tips/names.html
This site presents an alternative view of the SSRI’s and their benefit to society. It’s good to know what your patients are reading. http://www.geocities.com/HotSprings/3568/
Most antidepressants have some effect on a patient’s sexual function, and depending on the age and normal lifestyle of the patient, regaining previous levels of sexual activity can be a large part of the recovery process. This article is a frank discussion of the sexual effects of the various agents that affect neurotransmitter activities, how they can affect sexual function, and what can be done about drug-induced sexual dysfunction in both sexes. And if you can type this website address without making a mistake, you probably need to turn off your computer and get out more. http://www.goto.com//p/resultframes.mp?rawq=antidepressants&index=1&urllist=eD%2f%2bdQ02dZJLctwwDERPFHGycFxeZpO1kwukIBIiYZMAzY8044XPHkr0JxrZO1Wp2XiNxn%2bfeEYd9SZ%2b0ZJGhKogmwmehnIuu1c6IHGXrgNivhQKmFW8uz3d2eU4BkOUBVNALs%2fCuA0xGP8%2bsiwHdzAmlO4%2bUcplbwezaDAyNFSHPhM%2f0jCRenkAZnwF%2firtgt4z5gxmNSmdI5cHcZzVLuGY0FriDXSs3mMhjkmeQd%2fscdYlztXPYi5MsOltxQ69czQSiEnYSY5UwPcduLaF1Ijaj6Pv5DR8aO%2f%2fqNOP76efq27nHKQ4TAylpp7oFwTyF%2fV75VA93uFRzUZ0kfRWxQpxEDkEX5zE0vDyq%2fKMJlGr8JqiawPCZ8qro9tsv7UD3TzbXmrr4tqQKbiByQ1WZhXr6KlVpmo0O6UlPWQK0eObnUmqrWP8KnjntJXM%2bxl%2bVO8k4ECcELTb2PAspmaV60S6He9u9Fp9m5rsZYG5mzHZFgNS1%2f0DmRQ%2fcQ%3d%3d&type=search”
Depression In The News A recent study reported on in The Journal of The American Medical Association evaluated the risk of precipitating cardiovascular events in patients with heart disease by treating their depression with paroxetine and nortriptyline. Eighteen percent of the cardiac patients treated with nortriptyline and only two percent of patients treated with paroxetine experienced adverse cardiac symptoms (increased heart rate, for instance), clearly indicating the relative value of the SSRI over the TCA in this application. Patients who develop post-myocardial-infarction depression show greater risk for death than who do not develop depression, a significant predictor of cardiac mortality at 18 months in this patient population.
The University of Michigan Division of Kinesiology has studied survivors of breast cancer to evaluate their depression. Depression is seen as a major problem among such patients as some forty percent remain depressed over their condition a year after surgery. Those who regularly engage in even light exercise have significantly less depression; and the sooner after surgery they begin exercising, the sooner they derive emotional benefit.
Indicated for the acute treatment of depressive illness/major depression, Pharmacia & Upjohn’s new antidepressant, Edronax?? (reboxetine), has added Germany and Italy to its long list of countries in which its use is approved. The list includes the United Kingdom, Sweden, Denmark, Ireland, Austria and Finland. The agent is a selective noradrenaline reuptake inhibitor, whose selective activity on noradrenaline appears to help restore patients’ energy and motivation for improved social functioning.