Antidepressant Drugs

Definition

Antidepressant drugs are medicines that relieve symptoms of depressive disorders.

Purpose

Depressive disorders may either be unipolar (depression alone) or bipolar (depression alternating with periods of extreme excitation). The formal diagnosis requires a cluster of symptoms, lasting at least two weeks. These symptoms include, but are not limited to, mood changes, insomnia or hypersomnia, and diminished interest in daily activities. The symptoms are not caused by any medical condition, drug side effect, or adverse life event. The condition is severe enough to cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.Secondary depression, or depression caused by unfavorable life events, is normally self limiting, and may best be treated with cognitive/behavioral therapy rather than drugs.

Description

Antidepressant agents act by increasing the levels of excitatory neurostransmitters, or nerve cell chemicals that act as messengers in the brain's nervous system. In 2003, a report showed that in addition to treating depression, use of antidepressant drugs may protect the brain from damage depressive episodes cause to the hippocampus, the area of the brain involved in learning and memory. Antidepressant drugs may be prescribed as a first-line treatment for depression, or in conjunction with other methods of controlling depression, such as behavioral therapy and exercise.The main types of antidepressant drugs in use today are listed below, though the drugs available change frequently. For example, in mid-2003, the manufacturer of Wellbutrin released Wellbutrin XL, the only once-daily norepinephrine and dopamine reuptake inhibitor for treating depression in adults.

Key terms

Cognitive behavioral therapy — A type of psychotherapy in which people learn to recognize and change negative and self-defeating patterns of thinking and behavior.Depression — A mental condition in which people feel extremely sad and lose interest in life. People with depression also may have sleep problems and loss of appetite and may have trouble concentrating and carrying out everyday activities.Pregnancy category — A system of classifying drugs according to their established risks for use during pregnancy. Category A: Controlled human studies have demonstrated no fetal risk. Category B: Animal studies indicate no fetal risk, but no human studies; or adverse effects in animals, but not in well-controlled human studies. Category C: No adequate human or animal studies; or adverse fetal effects in animal studies, but no available human data. Category D: Evidence of fetal risk, but benefits outweigh risks. Category X: Evidence of fetal risk. Risks outweigh any benefits.

tricyclic antidepressants, such as amitriptyline (Elavil), imipramine (Tofranil), nortriptyline (Pamelor)
selective serotonin reuptake inhibitors (SSRIs or serotonin boosters), such as fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft)
monoamine oxidase inhibitors (MAO inhibitors), such as phenelzine (Nardil), and tranylcypromine (Parnate)

tetracyclic compounds and atypical antidepressants which do not fall into any of the above categories

Selective serotonin reuptake inhibitors maintain levels of the excitatory neurohormone serotonin in the brain. They do not alter levels of norepinephrine. These have become the drugs of choice for a variety of psychiatric disorders, primarily because of their low incidence of severe side effects as compared with otherdrugs in this therapeutic class. SSRIs show similar actions and side effect profiles, but may vary in duration of action.Tricyclic compounds, identified by their chemical structure containing three carbon rings, are an older class of antidepressants. Although generally effective, they have a high incidence of anticholinergic effects, notably dry mouth and dry eyes, which can cause discomfort. They also cause cardiac arrythmias. Because tricyclics act on both serotonin and norepinephrine, they may have some value in treatment of patients who fail to respond to SSRIs. Drugs in this class often are available at low prices, which may be significant when cost is a major factor in treatment. They also have been found useful in control of some neurologic pain syndromes.Tricyclic antidepressants are similar, but may vary in severity of side effects, most notably the degree of sedation and the extent of the anticholinergic effects.Tetracyclic compounds and atypical antidepressants are chemically distinct from both the major groups and each other. Although maprotilene (no brand name, marketed in generic form only) and mirtazepine (Remeron) are similar in chemical structures, they differ in their balance of activity on serotonine and norepinephrine levels.Monoamine oxidase inhibitors (phenelzine [Nardil], tranylcypromine [Parnate]) have largely been supplanted in therapy because of their high risk of severe adverse effects, most notably severe hypertension. They act by inhibiting the enzyme monoamine oxidase, which is responsible for the metabolism of the stimulatory neurohormones norepinephrine, epinephrine, dopamine, and serotonin. The MAOIs are normally reserved for patients who are resistant to safer drugs. Two drugs, eldepryl (Carbex, used in treatment of Parkinson's disease) and the herb, St. John's wort, have some action against monoamine oxidase B, and have shown some value as antidepressants. They do not share the same risks as the non-selective MAO inhibitors.All antidepressant agents, regardless of their structure, have a slow onset of action, typically three to five weeks. Although adverse effects may be seen as early as the first dose, significant therapeutic improvement is always delayed. Similarly, the effects of antidepressants will continue for a similar length of time after the drugs have been discontinued.

Recommended dosage

Dose varies with the specific drug and patient. Specialized references or a physician should be consulted.

Precautions

Antidepressants have many significant cautions and adverse effects. Although a few are listed here, specific references should be consulted for more complete information.SSRIs. The most common side effect of SSRIs is excitation and insomnia. Excitation has been reported in over 20% of patients, and insomnia in 33%. Significant weight loss has been frequently reported, but most commonly in patients who are already underweight. A 2003 report showed that SSRIs also increase the risk of upper gastrointestinal tract bleeding. SSRIs may cause some sedation, and patients should be cautioned not to perform tasks requiring alertness until they have evaluated the effects of these drugs. SSRIs are pregnancy category C drugs. In 2003, a new report demonstrated that late-term (third trimester) use of these drugs could cause neurological symptoms in newborns, including tremor, restlessness and rigidity. Most SSRIs are excreted in breast milk, and there have been anecdotal reports of drowsiness in infants whose mothers were taking SSRIs while breastfeeding.Most notably, a joint panel of the U.S. Food and Drug Administration (FDA) issued strong warnings to parents and physicians in 2004 about the risk of suicidal behavior in children and adolescents taking SSRIs.Tricyclic antidepressants. Amoxepine (not marketed by brand, generic available), although a tricyclic antidepressant rather than a neuroleptic (major tranquilizer), displays some of the more serious effects of the neuroleptics, including tardive dyskinesias (drug induced involuntary movements) and neuroleptic malignant syndrome, a potentially fatal syndrome with symptoms including high fever, altered mental status, irregular pulse or blood pressure, and changes in heart rate. These adverse effects have not been reported with other tricyclic antidepressants.The most common adverse effects of tricyclic antidepressants are sedation and the anticholinergic effects, such as dry mouth, dry eyes, and difficult urination. Alterations in heartbeat also are common, and may progress to congestive heart failure, stroke, and sudden death.Tricyclic antidepressants are in pregnancy categories C or D, although there have been no formal studies of the drugs on fetal development. There are no studies of effects on newborns, but some anecdotal reports of malformations have resulted from animal studies. The drugs are excreted in breast milk.Monoamine oxidase inhibitors. The greatest risk associated with these drugs is a hypertensive crisis which may be fatal and most often occurs when the drugs are taken with interacting foods or drugs. More common adverse reactions may include low blood pressure and slowing of heartbeat. Sedation and gastrointestinal disturbances also are common. MAOIs are in pregnancy category C. Safety in breast feeding has not been established.Tetracyclics and atypicals. Because these drugs are individual, there are no group patterns of adverse reactions. Specific references should be consulted.

Interactions

The antidepressants have many drug interactions, some severe. Although a few are listed here, specific references should be consulted for more complete information.SSRIs should not be administered with MAOIs. A wash-out period of about four weeks should be allowed before switching from one class of drugs to the other, five weeks if switching from fluoxetine (Prozac) to an MAOI.MAOIs have many interactions, however the best known are those with foods containing the amino acid tyramine. These include aged cheese, chianti wine, and many others. Patients and providers should review the MAOI diet restrictions before using or prescribing these drugs. Because of the severity of MAOI interactions, all additions to the patient's drug regimen should be reviewed with care.Tricyclic compounds have many interactions, and specialized references should be consulted. Specifically, it is best to avoid other drugs with anticholinergic effects. Tricyclics should not be taken with the antibiotics grepafloxacin and sprafloxacin, since the combination may cause serious heart arrythmias.Tricyclic compounds should not be taken with the gastric acid inhibitor cimetidine (Tagamet), since this increases the blood levels of the tricyclic compound. Other acid inhibiting drugs do not share this interaction.SSRIs interact with a number of other drugs that act on the central nervous system. Care should be used in combining these drugs with major or minor tranquilizers, or with anti-epileptic agents such as phenytoin (Dilantin) or carbamazepine (Tegretol). In 2003, one of the biggest concerns regarding new prescriptions for tricyclic antidepressants was data concerning overdoses from these drugs. Information in Great Britain showed that this class of antidepressants was responsible for more than 90% of all deaths from antidepressant overdose. Physicians were being advised to prescribe SSRIs in new patients, but not to change the course of those who had taken tricyclics for years with success.

Resources

Periodicals

"Antidepressant Drugs May Protect Brain from Damage." Mental Health Weekly Digest (August 18, 2003): 2."FDA Approves Once-daily Supplement." Biotech Week (September 24, 2003): 6."FDA Panel Urges Stronger Warnings of Child Suicide." SCRIP World Pharmaceutical News (February 6, 2004): 24."GPs Told Not to Prescribe Tricyclics." Pulse (October 13, 2003): 1."Late-term Exposure to SSRIs May Cause Neurological Symptoms in Babies." Drug Week (August 8, 2003): 255."SSRIs Increase the Risk of Upper GI Bleeding." Psychiatric Times (July 1, 2003): 75.

Antidepressant Drugs (Cyclic): Amitriptyline, Nortriptyline, Protriptyline, Doxepin, Imipramine

Synonym/acronym: Cyclic antidepressants: amitriptyline (Elavil, Endep, Etrafon, Limbitrol, Triavil); nortriptyline (Allegron, Aventyl HCL, Nortrilen, Norval, Pamelor); protriptyline (Aventyl, Sinequan, Surmontil, Tofranil, Vivactil); doxepin (Adapin, Co-Dax, Novoxapin, Sinequan, Triadapin); imipramine (Berkomine, Dimipressin, Iprogen, Janimine, Pentofrane, Presamine, SK-Pramine, Tofranil PM).

Common use

To monitor subtherapeutic, therapeutic, or toxic drug levels in evaluation of effective treatment modalities.

Specimen

Serum (1 mL) collected in a red-top tube.

Drug	Route of Administration	Recommended Collection Time
Amitriptyline	Oral	Trough: immediately before next dose (at steady state)
Nortriptyline	Oral	Trough: immediately before next dose (at steady state)
Protriptyline	Oral	Trough: immediately before next dose (at steady state)
Doxepin	Oral	Trough: immediately before next dose (at steady state)
Imipramine	Oral	Trough: immediately before next dose (at steady state)

Normal findings

(Method: Chromatography for amitriptyline, nortriptyline, protriptyline, and doxepin; immunoassay for imipramine)

Drug	Therapeutic Range Conventional Units	Conversion to SI units	Therapeutic Range SI Units	Half-Life (h)	Volume of Distribution (L/kg)	Protein Binding (%)	Excretion
Amitriptyline	125–250 ng/mL	SI units = Conventional Units × 3.6	450–900 nmol/L	20–40	10–36	85–95	Hepatic
Nortriptyline	50–150 ng/mL	SI units = Conventional Units × 3.8	190–570 nmol/L	20–60	15–23	90–95	Hepatic
Protriptyline	70–250 ng/mL	SI units = Conventional Units × 3.8	266–950 nmol/L	60–90	15–31	91–93	Hepatic
Doxepin	110–250 ng/mL	SI units = Conventional Units × 3.58	394–895 nmol/L	10–25	10–30	75–85	Hepatic
Imipramine	180–240 ng/mL	SI units = Conventional Units × 3.57	643–857 nmol/L	6–18	9–23	60–95	Hepatic

Description

Cyclic antidepressants are used in the treatment of major depression. They have also been used effectively to treat bipolar disorder, panic disorder, attention deficit-hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), enuresis, eating disorders (bulimia nervosa in particular), nicotine dependence (tobacco), and cocaine dependence. Numerous drug interactions occur with the cyclic antidepressants.

Many factors must be considered in effective dosing and monitoring of therapeutic drugs, including patient age, patient ethnicity, patient weight, interacting medications, electrolyte balance, protein levels, water balance, conditions that affect absorption and excretion, and the ingestion of substances (e.g., foods, herbals, vitamins, and minerals) that can either potentiate or inhibit the intended target concentration. Trough collection times should be documented carefully in relation to the time of medication administration.

The metabolism of many commonly prescribed medications is driven by the cytochrome P450 (CYP450) family of enzymes. Genetic variants can alter enzymatic activity that results in a spectrum of effects ranging from the total absence of drug metabolism to ultrafast metabolism. Impaired drug metabolism can prevent the intended therapeutic effect or even lead to serious adverse drug reactions. Poor metabolizers (PM) are at increased risk for drug-induced side effects due to accumulation of drug in the blood, while ultra-rapid metabolizers (UM) require a higher than normal dosage because the drug is metabolized over a shorter duration than intended. Other genetic phenotypes used to report CYP450 results are intermediate metabolizer (IM) and extensive metabolizer (EM). Genetic testing can be performed on blood samples submitted to a laboratory. The test method commonly used is polymerase chain reaction. Counseling and informed written consent are generally required for genetic testing. CYP2D6 is a gene in the CYP450 family that metabolizes drugs such as tricyclic antidepressants like nortriptyline, antipsychotics like haloperidol, and beta blockers. Testing for the most common genetic variants of CYP2D6 is used to predict altered enzyme activity and anticipate the most effective therapeutic plan. Incidence of the PM phenotype is estimated to be 10% of Caucasians and Hispanics, 2% of African Americans, and 1% of Asians.

Important note: These medications are metabolized and excreted by the liver and are therefore contraindicated in patients with hepatic disease. Information regarding medications must be clearly and accurately communicated to avoid misunderstanding of the dose time in relation to the collection time. Miscommunication between the individual administering the medication and the individual collecting the specimen is the most frequent cause of subtherapeutic levels, toxic levels, and misleading information used in calculation of future doses. If administration of the drug is delayed, notify the appropriate department(s) to reschedule the blood draw and notify the requesting health-care provider (HCP) if the delay has caused any real or perceived therapeutic harm.

This procedure is contraindicated for

N/A

Indications

Assist in the diagnosis and prevention of toxicity
Evaluate overdose, especially in combination with ethanol (Note: Doxepin abuse is unusual.)
Monitor compliance with therapeutic regimen

Potential diagnosis

Level	Response
Normal levels	Therapeutic effect
Subtherapeutic levels	Adjust dose as indicated
Toxic levels	Adjust dose as indicated
Amitriptyline	Hepatic impairment
Nortriptyline	Hepatic impairment
Protriptyline	Hepatic impairment
Doxepin	Hepatic impairment
Imipramine	Hepatic impairment

Critical findings

It is important to note the adverse effects of toxic and subtherapeutic levels of antidepressants. Care must be taken to investigate signs and symptoms of too little and too much medication. Note and immediately report to the HCP any critically increased or subtherapeutic values and related symptoms.
It is essential that a critical finding be communicated immediately to the requesting HCP. A listing of these findings varies among facilities.
Timely notification of a critical finding for lab or diagnostic studies is a role expectation of the professional nurse. The notification processes will vary among facilities. Upon receipt of the critical finding the information should be read back to the caller to verify accuracy. Most policies require immediate notification of the primary HCP, hospitalist, or on-call HCP. Reported information includes the patient’s name, unique identifiers, critical finding, name of the person giving the report, and name of the person receiving the report. Documentation of notification should be made in the medical record with the name of the HCP notified, time and date of notification, and any orders received. Any delay in a timely report of a critical finding may require completion of a notification form with review by Risk Management.

Cyclic Antidepressants

Amitriptyline: Greater Than 500 ng/mL (SI: Greater Than 1800 nmol/L)
Nortriptyline: Greater Than 500 ng/mL (SI: Greater Than 1900 nmol/L)
Protriptyline: Greater Than 500 ng/mL (SI: Greater Than 1900 nmol/L)
Doxepin: Greater Than 500 ng/mL (SI: Greater Than 1790 nmol/L)
Imipramine: Greater Than 500 ng/mL (SI: Greater Than 1785 nmol/L)
Signs and symptoms of cyclic antidepressant toxicity include agitation, drowsiness, hallucinations, confusion, seizures, arrhythmias, hyperthermia, flushing, dilation of the pupils, and possible coma. Possible interventions include administration of activated charcoal; emesis; gastric lavage with saline; administration of physostigmine to counteract seizures, hypertension, or respiratory depression; administration of bicarbonate, propranolol, lidocaine, or phenytoin to counteract arrhythmias; and electrocardiographic monitoring.

Interfering factors

Blood drawn in serum separator tubes (gel tubes).
Cyclic antidepressants may potentiate the effects of oral anticoagulants.

Nursing Implications and Procedure

Pretest

Positively identify the patient using at least two unique identifiers before providing care, treatment, or services.
Patient Teaching: Inform the patient this test can assist in monitoring subtherapeutic, therapeutic, or toxic drug levels.
Obtain a history of the patient’s complaints, including a list of known allergens, especially allergies or sensitivities to latex.
These medications are metabolized and excreted by the kidneys and liver. Obtain a history of the patient’s genitourinary and hepatobiliary systems, symptoms, and results of previously performed laboratory tests and diagnostic and surgical procedures.
Obtain a list of the patient’s current medications, including herbs, nutritional supplements, and nutraceuticals (see Effects of Natural Products on Laboratory Values online at DavisPlus). Note the last time and dose of medication taken.
Review the procedure with the patient. Inform the patient that specimen collection takes approximately 5 to 10 min. Address concerns about pain and explain that there may be some discomfort during the venipuncture.
Sensitivity to social and cultural issues, as well as concern for modesty, is important in providing psychological support before, during, and after the procedure.
Note that there are no food, fluid, or medication restrictions unless by medical direction.

Intratest

Potential complications:
Lack of consideration for the proper collection time relative to the dosing schedule can provide misleading information that may result in erroneous interpretation of levels, creating the potential for a medication-error-related injury to the patient.
Avoid the use of equipment containing latex if the patient has a history of allergic reaction to latex.
Instruct the patient to cooperate fully and to follow directions. Direct the patient to breathe normally and to avoid unnecessary movement.
Observe standard precautions, and follow the general guidelines in Patient Preparation and Specimen Collection. Consider recommended collection time in relation to the dosing schedule. Positively identify the patient, and label the appropriate specimen container with the corresponding patient demographics, initials of the person collecting the specimen, date, and time of collection, noting the last dose of medication taken. Perform a venipuncture.
Remove the needle and apply direct pressure with dry gauze to stop bleeding. Observe/assess venipuncture site for bleeding or hematoma formation and secure gauze with adhesive bandage.
Promptly transport the specimen to the laboratory for processing and analysis.

Post-Test

Inform the patient that a report of the results will be made available to the requesting HCP, who will discuss the results with the patient.
Nutritional Considerations: Include avoidance of alcohol consumption.
Recognize anxiety related to test results and reinforce information given by the patient’s HCP regarding further testing, treatment, or referral to another HCP. Explain to the patient the importance of following the medication regimen and instructions regarding drug interactions. Instruct the patient to immediately report any unusual sensations (e.g., severe headache, vomiting, sweating, visual disturbances) to his or her HCP. Blood pressure should be monitored regularly. Answer any questions or address any concerns voiced by the patient or family.
Instruct the patient to be prepared to provide the pharmacist with a list of other medications he or she is already taking in the event that the requesting HCP prescribes a medication.
Depending on the results of this procedure, additional testing may be performed to evaluate or monitor progression of the disease process and determine the need for a change in therapy. Evaluate test results in relation to the patient’s symptoms and other tests performed.

Related Monographs

Related tests include ALT, albumin, AST, bilirubin, BUN, creatinine, CBC, electrolytes, GGT, and protein blood total and fractions.
See the Genitourinary and Hepatobiliary systems tables at the end of the book for related tests by body system.

Patient discussion about Antidepressant Drugs

Q. My sister is taking antidepressants for her depression. My sister is taking antidepressants for her depression. Antidepressant causes her severe headache. Her medicines were changed but there is no impact in her headache. This headache is continuous and reduces only after a good sleep. I think she can try with Chinese medicines for her headache? Will it be of any help?A. Yes. You can try Chinese Medicines not only for headache but also for depression. Chinese medicine can help cure depression and they will not show any side effects. But headaches can be treated by Chinese medicines. Just meet the doctor and tell him the problem. She will be fine.
http://www.youtube.com/watch?v=GYsN-FiceXA&eurl=http://www.imedix.com/health_community/vGYsN-FiceXA_acupuncture_chinese_medicine?q=depression%20chinese%20medicine&feature=player_embedded

Q. Please suggest me the natural or alternative ways to beat depression without taking any antidepressants? I suffer from clinical depression yet never tried antidepressants due to the fear of getting addicted to them. Please suggest me the natural or alternative ways to beat depression without taking any antidepressants?A. Hi, I felt so when depressed. Later I tried psychotherapists and psychologists and that has really helped me to come out from depression. You need to exercise regularly to keep you fit and healthy. All the best!

Q. I was diagnosed with depression and have taken a whole host of antidepressants. I’m Mark, 29 years old male. I was diagnosed with depression and have taken a whole host of antidepressants. My eyes are extremely blurry, I’m worrying about that. Does this side effect go away with time, or is it permanent while on medications?A. Mark, you really need to consult your doctor. I hope you're not relying totally on the Internet for medical advice. Side effects are common with most drugs, and some are more tolerable than others. "Extremely blurry" eyes seems like it could affect your driving, as cbellh47 wrote, but many other things as well.
Sometimes it does take many, many attempts to discover an anti-depressant or a combination of more than one to achieve a better mood balance. We're all chemically different and react to drugs differently. There's many options and I had to endure years of experimentation before I was satisfied, but I now have the rest of my life to appreciate what I went through.
I also used the help of different doctors and psychiatrists, as well as self-learning. If your doctor doesn't seem to be beneficial, consider asking him/her to recommend a specialist. New treatments come to light regularly and not all docotrs are wise to them.
Just yesterday (01.20.09) a new, control

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