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Table 13: Maximum initial and maintenance doses of antipsychotics

Antidepressants

The dose and dosage form of fluoxetine (Prozac) depends upon the disorder it is prescribed to treat. In bulimia nervosa, a starting dose of 60 mg may be given; however, further dose titration may be necessary. In adult depression, a dose of 20 mg/day may be given initially for the first few weeks of therapy. If no clinical improvement is observed, the dose may be increased. The maximum total daily dose should not exceed 80 mg/day. Children less than 7 years of age should be started at 10 mg/day and succeeding dose increments made at least 2 weeks after initiation of therapy. For children above 8 years of age, a similar dose should be given with succeeding dose increments made after 1 week of treatment. When fluoxetine (Prozac) is to be administered with olanzapine (Zyprexa), it is generally recommended that it be done in the evening as a once daily dose.

In children and adolescents weighing less than 70 kg, atomoxetine (Strattera) should be initiated at 0.5 mg/kg with increments made only after a minimum of three days therapy. The increments should not exceed the total dose of 1.2 mg/kg per day as a single dose or total divided doses. Generally, the dose should not exceed 1.4 mg/kg or a 100 mg in total when given to children (regardless of weight) and young adults. Patients who are co-administered with paroxetine (Paxil) and fluoxetine (Prozac) should not be given more than 80 mg/day since these two drugs are inhibitors of CYP2D6, the same enzyme that metabolizes atomoxetine. For children and adolescents above 70 kg or adults the starting dose is 40 mg, which may be increased after a minimum of 3 days therapy. It can be discontinued without tapering.

Dose adjustments need to be made with patients who have hepatic insufficiency (196). Patients with moderate and severe hepatic dysfunctions may need to reduce their dose to as much as 50% and 75%, respectively (196).

Mirtazapine (Remeron) is administered orally in 15, 30 and 45 mg tablets. The initial dose in patients with major depressive disorder is 15 mg/day given at night. It may later be increased up to 45 mg/day if adequate clinical response failed to show with the starting dose. Dose changes should only be made after a 1-2 week interval. Geriatric patients should start at half the usual adult dose, at 7.5 mg, and not exceed more than 45 mg/day. Its safety and efficacy have not been established in pediatric patients. Drug clearance may be affected in patients with renal or hepatic impairments and dose adjustments may be necessary to prevent toxic effects (197).

Venlafaxine (Effexor) is available in doses of 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg tablets. Extended release capsules are also available. The recommended dose at initiation of therapy is 75 mg given in 2-3 divided doses and preferably taken with food. If needed, dose increments of 75 mg may be made at 4-day intervals to reach a target of 225 mg/day. Some clinical trials showed that severely depressed patients responded to a dose of 375 mg. Dose adjustments are required in patients with moderate to severe renal and hepatic dysfunctions by as much as 25-50%, respectively (198).

Trazodone (Desyrel) is available in 50, 100, 150, 300 mg tablets. Extended release tablet formulations are also available. The usual adult starting dose is 150 mg/day in divided doses. A 50 mg dose increment may be made at 3 to 4 day intervals. The maximum allowable dose for outpatients is 400 mg/day and inpatients may be given up to 600 mg/day in divided doses. The latter is the maximum allowable total daily dose and should not be exceeded (200).

Trazodone (Oleptro) is available as a once daily-extended release dosage form for MDD in adults. Approved by the FDA in 2010, it provides sustained pharmacological effects minus the adverse effects associated with frequent dosing (199).

Bupropion (Wellbutrin) is supplied in tablet form in 174 mg, 348 mg, and 522 mg doses. It is recommended in major depressive disorder and in patients undergoing depressive episodes in seasonal affective disorder. It is administered in the morning as a whole pill. It should not be chewed nor crushed and its absorption is not affected by meals. The usual recommended dose for major depressive disorder is 174 mg once daily that may be increased gradually to 348 mg/day. Slow titration is important in order to prevent the risk of developing seizures. Patients with hepatic insufficiency are recommended a maximum dose of 174 mg/day. Like other antidepressants, it needs to be tapered before discontinuation (108).

Amitriptyline (Elavil) is available in oral and parenteral forms. In outpatient adults, an initial dose of 75 mg in daily divided doses is generally recommended. Usually, three doses of 25 mg are given throughout the day or at bedtime. It may be increased up to 300 mg if required. In inpatient adults, 100 mg-300 mg/ day is usually given. In adolescents and elderly patients, a dose of 10 mg three to four times a day with 20 mg at bedtime may be given. The intramuscular injections may be given as 20 to 30 mg up to four times a day. It is not recommended for use in pediatric patients, specifically below 12 years of age (201).

Selegiline (Emsam) transdermal patch has been recently approved for the treatment of major depressive disorder. Its efficacy has been tested in 6 week and 8 week- placebo-controlled trials. Selegiline (Emsam) is applied to dry, intact skin, usually applied on the upper torso, upper arm or upper thigh. The patch should not be put on any skin that is calloused, hairy, oily, scarred or broken. The patch is applied every 24 hours with the initial recommended dose of 6 mg every 24 hours. In case increased dosage requirements, increments of 3 mg/day in two weekly intervals is advised. A maximum dose of 12 mg/ day is allowed in special circumstances.

When selegiline (Emsam) is started, patients should be advised to avoid tyramine-containing foods and beverages and the same precautionary measure must be maintained until 2 weeks after dose reduction or discontinuation of the drug. Under no circumstances should selegiline (Emsam) transdermal patch be used in pediatric patients, even with strict dietary modifications (avoiding tyramine rich foods) in place.

Anxiolytics

Diazepam (Valium) is particularly indicated for the short-term management of anxiety. It is usually recommended that patients starting treatment with diazepam be periodically checked to assess the efficacy and safety of the drug. Its long-term use (more than four months) including its efficacy and safety has not been clinically established.

Depending on the severity of the anxiety symptoms, diazepam (Valium) tablets are usually started at 2-10 mg in repeated doses twice to four times daily. In the symptomatic relief of acute alcohol withdrawal, diazepam tablets may be given daily as 10 mg three to four times daily that may then be reduced to 5 mg three to four times until symptoms subside. 2-10 mg doses can be given for the relief of acute muscle spasms. In geriatric patients, the dose should generally be within the range of 2-2.5 mg once or twice daily and if the need requires, gradual dose increments may be made. It should not be administered to patients younger than 6 months of age. In older children, the lowest possible dose should be given with gradual dose increments made as required. Usually a 1-2.5 mg is given three to four times a day (202).

Mood stabilizers

Lithium is formulated in its salt form as lithium carbonate capsules. A controlled release dosage form, Eskalith CR, is also available that contains a higher dose. Immediate release tablets are usually administered thrice daily or four times and the controlled released tablets are given in no more than twice daily doses.

Lithium toxicity is a very serious side effect that can occur if excessive doses of lithium are administered, underscoring the need for dose individualization. In patients with acute mania, lithium is administered as a total of 1800 mg daily, divided in four doses. The desired lithium serum levels are between 1.0-1.5 mEq/L. Even slightly higher doses than 1.5 mEq/L can cause toxic (and even allergic) reactions such as tremor, renal impairment and ataxia, even death. For long term control and maintenance therapy, the desired lithium serum levels range between 0.6-1.2 mEq/L. The usual dose of lithium required to maintain these levels is between 900 mg to 1200 mg daily, depending on patient needs and responses. Serum levels should be monitored closely to prevent toxicity (109).

Stimulants

Amphetamine (Adderall) has a very high potential for abuse and prolonged usage may lead to altered behavior and drug dependence underlining the need for cautious prescribing habits and patient monitoring. Patients should be given the lowest possible dose and then maintained according to their clinical response. In children aged between 3-5 years with ADHD, it is usually given at a dose of 2.5 mg once a day. It should not be administered at night as it may very well cause insomnia and disturb normal sleep patterns. In children above 6 years of age with ADHD, a 5 mg dose of the drug may be given once or twice daily. The respective doses for both age groups can be increased to double at weekly intervals if required. For adult patients with narcolepsy, it may be given as 5 to 60 daily in divided doses.

Methylphenidate is available in extended-release (Ritalin LA) and immediate release (Ritalin) dosage forms. For ADHD in adults, an initial dose of the 20 mg extended release in the morning is recommended with weekly increments of 10 mg, up to the maximum total daily dose of 60 mg/day. The immediate release form is usually administered as 20-30 mg in daily divided doses. The tablets are usually given every 6-8 hours before meals. The same dose is recommended for narcolepsy (194).

The recommended doses for methylphenidate in pediatric and adolescent patients are given in the table below.


Doses

Methylphenidate-naïve patients

Patients already on methylphenidate

18 mg

Initial dose

If switching from 5 mg every 8-12 hrs

36 mg

Allowed increment after 1 week therapy

If switching from 10 mg every 8-12 hrs

54 mg

Maximum dose (6-12 years old)

If switching from 15 mg every 8-12 hrs

72 mg

Maximum dose (13-17 years old)

If switching from 20 mg every 8-12 hrs

Table 14: Recommended doses of Methylphenidate

A transdermal patch is also available for adolescents (13-17 years of age), with a starting dose at 10 mg applied to the hip for 9 hours.

Sedative-hypnotics

At sub-hypnotic doses, phenobarbital may be used as an anticonvulsant in 50 to 100 mg daily divided doses. As a pre-anesthetic in pediatric patients, a dose of 1 to 3 mg/kg is generally given preoperatively. For daytime sedation in adults, the recommended dose is between 30 to 120 mg in two to three divided doses. For bedtime hypnosis the drug can be given as either 100 mg or 320 mg dose depending upon the patient need. Geriatric patients and those with hepatic and renal impairments will need dose adjustments. Caution should be used when prescribing and administering it to geriatric patients since they are particularly more sensitive to the drug (203).

Understanding the dose–response curve

Dose response curve or the dose effect curve is defined as the graphic representation of the drug effect plotted against the dose. Essentially, it shows the relationship between the effect and changes in the dose. It is particularly useful in representing toxicity and therapeutic benefit relationship of a certain amount of drug (110).

These drug response curves are used to graphically represent the results of many experiments pertaining to different drugs, their concentrations and the effects these variations produce.


The figure above is an example of how the dose–response curve is plotted. The X-axis is the dose of the drug being studied that is plotted against the Y-axis which is the response produced.

When a full agonist is administered, it provokes a visible response on the graph. The dose response curve will shift from left to right, depending on the concentration of the agonist. A partial agonist is a drug that also provokes a response; however, the response will not be as substantial as the response produced by a full agonist. On the other hand, if an antagonist drug is administered, no response will be seen. In fact, antagonists are those drugs that do not produce a response, and instead they inhibit agonist-mediated responses. The introduction of varying concentrations of antagonist drugs will produce a dose-response curve that either moves downhill or from right to left.

Therapeutic vs Toxic

The therapeutic index is a measure of a drug’s safety. It demonstrates the relationship between its toxic dose and effective dose. Previously, it was calculated as the ratio of maximum tolerated dose to the minimum therapeutic dose. Its identification is an integral part of achieving the balance between a drug candidate’s safety and its efficacy for its proposed indication during drug development (111).

Currently, therapeutic index is calculated differently; it is the ratio of the median lethal dose to the median effective dose. Its current formula is shown below:

Where, TD50 corresponds to the dose that produces toxic effects in 50% of the population.

ED50 corresponds to the dose that produces a therapeutically beneficial effect in 50 % of the population.

Both those values are derived from quantal dose-response curves. Quantal dose-response curves are the graphic representation of the frequency with which each therapeutic and lethal doses of drug provoke the needed response or toxic effect in the population being studied.


*Pharmacology Corner.com

Therapeutic indices of drugs readily inform clinicians and pharmacists of the relative safety profile of the drug. Drugs with a large therapeutic index are often very safe even when given in large amounts, having little risk of producing toxicity. Drugs with a narrow therapeutic index are drugs to watch out for and need close therapeutic monitoring because of the small difference between the therapeutic and lethal doses.

The therapeutic index of drugs like warfarin (Coumadin), lithium (Eskalith), digoxin (Lanoxin), phenytoin (Dilantin), gentamycin (Garamycin), Amphotericin B (Amphocin), 5-fluorouracil (Efudex), AZT (zidovudine) is narrow and the potential for toxicity at therapeutic doses is a big worry to prescribers and patients.

Examples of therapeutic indices for some of the psychotropic drugs are listed below.



Drug

Therapeutic Index

Diazepam

100:1

Morphine

70:1

Cocaine

15:1

Table 15: Therapeutic indices of psychotropic drugs

SPECIAL POPULATIONS

Geriatric

An estimated 5.6 million to 8 million Americans over the age of 65 years have mental health or substance-use disorders. According to the Institute of Medicine (IOM), these numbers will continue to climb up to 14.4 million by 2030. To add to this dilemma is the decreasing number of geriatric psychiatrists working in this field. The American Geriatrics Society estimates that there are fewer than 1800 geriatric psychiatrists in the U.S. today and that by 2030 there will only be about 1650 left. These numbers mean that there will be less than 1 per 6000 older adults with mental health and substance-use disorders. The IOM's 2012 workforce report on this topic, called In Whose Hands?, confirms this shortage and states that the country simply cannot train sufficient number of train doctors specializing in geriatric medicine to meet the vacant positions. This report is backed by the fact that more than half the vacant fellowship positions in geriatric medicine or psychiatry remain unoccupied each year. Moreover, a separate survey by the American Psychological Association (APA) found that only 4.2% of practicing psychologists have specialized training in treating older adults (112).

The shortcomings of the U.S. health care system put the mentally ill geriatric population at greater risk of disabilities, poorer treatment outcomes and higher rates of hospitalization and emergency visits than those with physical illnesses alone (113).

The following are the four main challenges in the provision of appropriate mental health care to geriatric patients:


  1. Physiological changes to the body systems

  2. Presentation of psychiatric symptoms mimic many conditions that are part of the normal aging process (anxiety and, poor sleep, memory and concentration)

  3. As mentioned above, there’s limited number of specialized psychiatrists trained to handle geriatric patients

  4. Increased likelihood of existing comorbidities

There are physiologic changes to consider in the psychopharmacologic treatment of older adults (see tables 13 and 14). The pharmacokinetics of drugs including its renal and hepatic clearance, and protein binding are markedly different and at times unpredictable, adversely affecting its pharmacodynamics and therapeutic outcomes (114).

The kidneys are major routes of excretion for many non-lipid soluble drugs. One notable example is lithium (Eskalith), a popular mood stabilizer. It is almost completely renally excreted, a process strongly influenced by sodium and water excretion. One important clinical implication of this type of elimination is its low therapeutic index, a marker for increased likelihood of toxicity. Renal dysfunction, use of NSAIDs, antidepressants and diuretics, are conditions that impair lithium excretion and increase the risk of toxicity. Older adults especially are at risk because many of them take maintenance medications concomitantly for their arthritis (NSAIDs), hypertension and heart conditions (diuretics).



Renal changes

Pharmacokinetic implications

Decrease in kidney size


Reduced elimination

Decrease in renal blood flow

Increased accumulation and toxicity

Decrease in functioning neurons

Increased / decreased absorption of other drugs *

Decreased renal tubular secretion

Decreased glomerular filtration rate

Table 16: Physiologic changes to the kidneys in older adults

* Polypharmacy considerations: 25% of patients over the age of 70 take more than 5 drugs everyday

Additionally, older patients with preexisting neurologic impairments such as dementia and Parkinson’s disease, and endocrine disorders such as hypothyroidism and testicular failure, are at a greater risk for acute lithium neurotoxicity. There have been several reports that indicate persistent cerebellar and basal ganglia dysfunction after treatment with these special population groups (117). These dysfunctions can manifest as neuromuscular excitability, irregular coarse tremors, fascicular twitching, rigid motor agitation, muscle weakness, ataxia, sluggishness, delirium, nausea, vomiting, and diarrhea (118). It is worth noting that some of these signs and symptoms occur in patients with Parkinson’s disease, which makes them easy to miss to the untrained eye. Therefore, careful plasma lithium level monitoring is necessary (117).

The liver is the most common site of drug metabolism (biotransformation). Thus, drugs that undergo extensive hepatic first pass effect are adversely affected by the aging liver. Many psychoactive drugs used in the treatment of various mental disorders are lipid soluble and thus, not freely excreted in urine. Instead, they are eliminated through the liver where they are excreted in the bile and transported to the intestine (116). The SSRI, fluoxetine (Prozac), is one such example. In the liver, it undergoes demethylation to form norfluoxetine, an active metabolite (115) (116). A cirrhotic liver will delay its hepatic clearance, increasing the likelihood of toxicity.


Hepatic changes

Pharmacokinetic implications

Decrease in liver bloodflow

Reduced metabolic clearance

Decrease in liver size

Increased accumulation and toxicity

Decrease in liver mass





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