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Chapter 2
Depression

The Web site for NAMI, the National Alliance for Mental Illness, at www.nami.org, describes Major Depression as follows:
The symptoms of depression include:
When several of these symptoms of depressive disorder occur at the same time, last longer than two weeks, and interfere with ordinary functioning, professional treatment is needed.
(It is the author's opinion that excessive anger, which does not abate, should also be added to this list, especially in the case of depression in men.)
Major Depression is severe and typically episodic. It may last weeks or months before fading away, then return months or years later.
Dysthymia is a term for mild chronic depression, which does not abate.
Double Depression refers to Major Depression experienced on top of Dysthymia.
The term depression will be used generically for both Major Depression and Dysthymia throughout.
Current medications for the treatment of depression, generally referred to as antidepressant medications, or antidepressants, work by increasing the concentration, in the brain, of one or more of these neurotransmitters: serotonin, norepinephrine, and dopamine.

2.1  Causes of Depression

Some symptoms of depression, such as melancholia (sadness), are common responses to unhappy experiences, such as the breakup of a close relationship, or death of a loved one. It is the persistence of the symptoms that characterizes the condition of Major Major Depressive Disorder as distinct from the sadder emotional fluctuations of a normal life.
Depression (meaning the disorder) may be triggered by external events (such as an emotional trauma), or simply appear for no obvious reason (in which case it is referred to as Endogenous Depression).
While the causes of depression at a neurological level remain unknown, there are reasons to believe that depression is related to abnormalities in brain chemistry, specifically the chemistry of neurotransmitter processes. One piece of evidence that supports this chemical imbalance hypothesis is the report of lower-than-normal levels of the neurotransmitter serotonin, found during autopsies in the brains of people who had been severely depressed at the time of death. Another piece of evidence is the empirical observation that medications that are known to influence neurotransmitter chemistry (especially by increasing neurotransmitter concentration) often alleviate depression.
It is not currently possible to measure neurotransmitter concentrations in the brains of living people, a limitation that makes analysis and treatment of depression more difficult than anyone likes. Nor (and largely as a result) is there any reliable way to connect specific neurotransmitter abnormalities in the brain to specific mood problems in an individual. Nevertheless, results trump theoretical discussions, and the fact is that most people who suffer from depression and seek medical treatment find that antidepressant medications alleviate their depression. In some cases, the alleviation is total and permanent, even after cessation of the medication. In some cases, the alleviation is partial, only happens while the medication is used, or both. In some individuals, unfortunately, existing medications do not alleviate depression, a painful fact that highlights the immaturity of the field, and the need for continuing research and development of better treatments for this life-destroying illness.

2.2  Treatments for Depression

Broadly speaking, the available treatments for depression fall into two general categories: Therapy and medical treatment. Some cases of depression can be resolved with therapy alone, while others can be resolved with medication alone. In general, though, success is more likely when therapy and medical treatment are combined.
The most effective technique for treating depression is that of electroconvulsive therapy, or ECT. This technique, which is described in Section 1.7.2, deserves careful consideration. Because of its drawbacks, ECT is not the method of choice for treating depression; however, it is effective, and worth considering if medication has failed.
The experimental treatments described in Section 1.8 may be of interest as well, although their effectiveness for depression has not yet been well established. However, the reader is advised to review these approaches in addition to the other techniques described below.
The following sections describe other medical treatments for depression that are in current use. The most common treatment strategy is that of antidepressant medications, which are discussed in more detail below.

2.2.1  Vagus-Nerve Stimulation (VNS)

The vagus nerve is one of 12 pairs of "cranial nerves," meaning nerves that originate in the brain. It is a very important nerve, one that is involved in motor functions (larynx, stomach, and heart) as well as sensory functions (ears, tongue), and so forth.
The technique of Vagus-Nerve Stimulation (VNS) was developed to treat epileptic seizures. An electric pulse generator (stimulator) is implanted in the chest, with a wire running up to the vagus nerve in the left side of the neck. The generator stimulates the vagus nerve with periodic pulses of programmed amplitude, duration, and frequency. This stimulation reduces the frequency of seizures.
While the effectiveness of VNS in treating seizures is well established, its usefulness in treating depression has been hotly contested. The Food and Drug Administration (FDA) approved VNS for the treatment of refractory (treatment-resistant) depression in 2005. However, the supporting evidence for this use is widely considered to be weak, and the decision produced much controversy.
Further research in the use of VNS to treat depression is necessary, but the lack of strong statistical indications of its effectiveness, combined with the expense and invasive nature of the device, makes this approach difficult to recommend at this time.

2.2.2  Transcranial Magnetic Stimulation (TMS)

Transcranial Magnetic Stimulation (TMS) is even more experimental, and less well-proven, than Vagus-Nerve Stimulation. Electromagnets placed outside the skull generate magnetic pulses of programmed amplitude, duration, and frequency. These time-varying magnetic pulses induce electric currents in targeted regions of the brain, stimulating them. There is some evidence to show that these pulses can alleviate depression in some people. The technique is an interesting one, and more appealing than ECT or VNS, as it does not cause seizures, require anesthesia, impair short-term memory, or require surgical implantation of any device.
This technique is far from proven at this time, and much progress needs to be made before it could be considered a reliable treatment for depression. However, given its lack of invasiveness, there seems to be little drawback in trying the procedure, if it is locally available.

2.2.3  Deep Brain Stimulation (DBS)

Deep Brain Stimulation (DBS) is a technique for treating neurological disorders such as the symptoms (but not cause) of Parkinson's disease, and primary dystonia (movement disorders). Surgery is used to implant electrodes in specfic areas in the brain, connected to an implanted pacemaker device. The pacemaker generates carefully-tailored electrical signals to the target areas of the brain, which serve to alleviate the undesirable symptoms.
Preliminary research has indicated that DBS also alleviates depression in some test subjects. Statistics are not available at this time to indicate how effective the device is for treating depression, but the early results are promising. More research is needed to determine how useful this approach will be to the general population.
Given the lack of information about its effectiveness, and considering its requirement for brain surgery, this technique cannot be recommended at this time.

2.2.4  Antidepressant Medication

Antidepressant medications come in a variety of categories, though all operate by similar mechanisms (i.e., they modify neurotransmitter concentrations in the brain). The reader would undoubtedly wish to know which medication, or category, is the most effective in treating depression, but there is little that can be said in this regard.4 For the most part, the different categories of medications are equally effective in treating depression, with a success rate of approximately 33% (which means that the average patient can expect to try two or three different medications before finding the most effective one for his or her case). The differences between the various medications are not in their effectiveness, but in their side-effect profiles. Some categories (generally, the more modern medications) have fewer or less unpleasant side effects than others, so that selection is often made as much on the basis of likely side effects as any other reason.
The exception to the rule of uniform effectiveness is the category of Monoamine Oxidase Inhibitors, described in Section 2.4. The MAO inhibitors are generally regarded as somewhat more effective than the other categories, but are not often prescribed, because of the drug interactions, food interactions, and dietary requirements that attend their use.
Psychiatrists tend to speak of MAO inhibitors much as they would speak of, say, SSRIs (Selective Serotonin Reuptake Inhibitors), meaning as a category of medications with a very specific mechanism. However, this comparison is misleading. It is more appropriate to speak of standard antidepressants as falling into two major categories, the reuptake inhibitors, and the MAO inhibitors. The reuptake inhibitors are distributed among many other classes, depending on which neurotransmitters they affect, their chemical structure, and so forth, but all exhibit the common mechanism of increasing the concentration of one or more neurotransmitters in the synaptic gap by blocking the re-absorption (reuptake) of neurotransmitters by the emitting neuron.
Similarly, the MAO inhibitors share the common mechanism of increasing the concentration of some neurotransmitters, by disabling the enzymes (Monoamine Oxidase) that destroy free-floating neurotransmitter molecules in the synaptic gap. However, the various MAO inhibitors fall into different sub-categories, with substantially different properties. The tendency to lump them all together into a single category is understandable but misguided. The differences are important.
It is a curious fact, doubtless driven at least in part by the phenomenal market success of Prozac, that the great majority of antidepressant medications act largely, or wholly, to boost the concentration of serotonin in the brain. Medications that increase the concentration of norepinephrine or dopamine are much less common, and medications that boost either of the latter without a concomitant increase in serotonin are few in number.
However, there is no particular reason to believe that serotonin should be singled out as the sole neurotransmitter whose tweaking is most likely to alleviate depression. The medication most likely to alleviate depression for a particular person is the one that affects the neurotransmitter(s) that are involved in that particular case of depression. (See Section 1.3 for a discussion of the connection between depressive symptoms and specific neurotransmitters.) While no widely-accepted test exists to identify the most appropriate medications for a particular person, the experimental technique of Section 1.8.1.1 may be worth investigating for this purpose.
While Section 1.3 may provide some rough indication as to which types of antidepressant medication are more likely to be effective for different depressive symptoms, the most reliable advice is to try a different category of medication if one or two in the first category don't work. There is likely to be little benefit to trying a third or fourth SSRI if the first or second don't work, and much greater likelihood that a medication that affects norepinephrine or dopamine will prove useful.


Warning! It is very important that anyone suffering from bipolar disorder (as in Chapter 3) not take any antidepressant that increases serotonin concentration (such as the SSRI, SNRI, TCA, and MAOI categories), without taking a mood-stabilizer medication at the same time. Taking one of these antidepressants without a mood stabilizer can trigger manic states. If you find that taking one of these antidepressants leads to excessive spending, grandiose behavior, hyperactivity and insomnia, consult your psychiatrist immediately. You may have bipolar disorder, and require an appropriate treatment for it.


Warning! As with all medications, an overdose of antidepressants can be dangerous. Overdose of medications that increase serotonin concentration can lead to a dangerous condition known as Serotonin Syndrome. This condition arises most frequently when people take two medications that both increase serotonin levels, not realizing that the effect on serotonin is cumulative.

2.3  Non-Prescription Antidepressants

While many non-prescription formulations might be considered candidates for the label "antidepressant" by people who have come to believe in them, only a few stand out as effective enough to be widely accepted. These medications do exist, however, and are worth considering as options for the treatment of depression. (Note that, as with all antidepressant medications, benefits may take from two to four weeks to become apparent.)
Motivations for trying non-prescription antidepressants include availability, cost, specific benefits (i.e., effectiveness and benign side-effect profile), and the belief, among some, that some of these medications are "natural" substances and therefore safer than prescription medications. While the author does not subscribe to the latter philosophy ("naturalness" does not guarantee absence of side effects), the other reasons are sufficient to justify consideration of these medications.
Most familiar non-prescription medications (such as allergy medicines) are widely accepted to produce the benefits for which they are sold. Such is not the case with the medications discussed in this section, none of which have FDA approval for any use. For this reason, these medications cannot legally be labeled as treating depression or other medical conditions, at least in the United States. However, while the reader should be aware of this fact, it is also true that a substance can be useful even though it lacks an FDA seal of approval.
The immediate practical benefit of most non-prescription antidepressants is their low cost. However, they also come with significant drawbacks, even if one assumes that they are generally effective. The most immediate drawback is the lack of reliable information about dosage. No firm guidelines are available as to amount per dose, and number of doses per day. Manufacturers typically supply suggestions, but these suggestions lack the weight of experience (and evidence) that inform the instructions for prescription medications. Thus the average consumer can easily take too little or too much of the medication, or take it at the wrong intervals. As a result, he may not experience the benefits the medication could provide if properly administered, or (even worse) experience only unpleasant effects.
The first rule for non-prescription antidepressants is caveat emptor: Let the buyer beware! Read as much as possible about the medication before taking it, to understand the pros, the cons, and the proper dosing.

2.3.1  Serotonin Precursors

A precursor is a chemical that is converted into another chemical of interest. More specifically, a serotonin precursor is any chemical that is converted, by one or more steps, into serotonin. Since prescriptions medications that increase serotonin concentration are often effective at treating depression, it makes sense that any mechanism that increases serotonin concentration is also a candidate for this purpose. Thus serotonin precursors, which are easily obtained without need for prescription, are often used to treat depression.

2.3.1.1  Mechanism

The immediate precursor to serotonin, which is converted directly into it, is 5-Hydroxytryptophan (5-HTP). Another chemical of interest, L-Tryptophan, is a precursor to 5-HTP, and thus also a serotonin precursor. Consumption of either 5-HTP or L-Tryptophan, therefore, can increase serotonin concentration in the body and brain.
The practical differences between 5-HTP and L-Tryptophan arise from the fact that the former passes more easily into the central nervous system, and its absorption is not affected by dietary factors. Thus the amount of serotonin produced is linked more closely to the amount of 5-HTP consumed, than to the amount of L-Tryptophan consumed, and the effects of 5-HTP manifest more rapidly.

2.3.1.2  Benefits

The serotonin precursors have relatively little in the way of side effects, as they are chemicals that naturally occur in both foods and the human body.

2.3.1.3  Principal Drawbacks

The serotonin precursors have short half-lives, which means their effects wear off quickly. Thus the effects of a single dose of L-Tryptophan, taken at bed time as a sleep aid, may wear off earlier than desired, and result in premature awakening.
The short half-lives have a more serious consequence for the treatment of depression. A dose of, say, 5-HTP, taken in the morning, will have completely disappeared from the body before bedtime, and its benefits may quickly follow. The result can be a roller-coaster ride of calmness alternating with depression and anxiety. In addition, the unpleasant symptoms can be even worse than normal, aggravated by the sudden decline in serotonin concentration.
Ideally, the serotonin precursors would be provided in a time-release formulation for steady release throughout a 24-hour cycle. In the absence of time-release formulations, one will typically need to take three doses per day, spaced uniformly.
Finally, people who have bipolar disorder should not take a serotonin precursor without also taking a mood stabilizer, since these medications can trigger manic episodes in people who have bipolar disorder (as can any medication that increases serotonin concentration).

2.3.1.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
5-HTP 5-Hydroxytryptophan  90 minutes 8 hours None (non-prescription medication) Depression; Insomnia; overeating (as appetite suppressant)
Optimax L-Tryptophan  2 hours 10 hours None (non-prescription medication) Depression; Insomnia


2.3.1.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
5-Hydroxytryptophan 5-HTP
L-Tryptophan Optimax

2.3.2  St. John's Wort

St. John's Wort is both a non-prescription medication, and the name of the plant from which it is derived. (The medication is often called Hypericum, from the Latin name for the plant. The term Hypericum will be used here as a shorthand for the active ingredients of St. John's Wort.) The preparation supplied to consumers (hereafter called SJW) consists of capsules or teas made from the flowering tops of the plant. Because of its preparation, SJW contains a complex mix of chemicals (including hyperforin, hypericin and biapigenin), and thus generates an equally complex set of chemical reactions in the body. Although commercial preparations often state the amount of hypericin per dose, hypericin is only one component of the mixture. The assumption is that other active ingredients will comprise fixed fractions of the dose, relative to hypericin, so that capsules with twice the amount of hypericin will also contain twice the amount of other active ingredients. This assumption is true only in the most approximate sense, and wide variations in proportions should be expected across manufacturers (indeed, some manufacturers deliberately change the proportions in an effort to improve effectiveness).
Clinical studies have shown that the effectiveness of SJW in treating depression is comparable to, or better than, Paroxetine, Fluoxetine, Sertraline, and Imipramine. At the same time, side effects from SJW are typically less troublesome than those of most prescription antidepressants.

2.3.2.1  Mechanism

The mechanism of SJW is not known (certainly less well known than for prescription medications), in part because standard preparations contain multiple active ingredients that work in different ways. Evidence exists that SJW inhibits reuptake of multiple neurotransmitters, including serotonin, norepinephrine, dopamine, GABA, and glutamate. It also appears to stimulate the release of adenosine and acetylcholine, and block NMDA receptors.
These observations must be considered preliminary, incomplete, and subject to revision by future research. What is clear is that SJW has many more effects on brain chemistry than does any of the prescription antidepressants. It is likely that the wide variety of effects contributes to the medication's effectiveness. In this regard, SJW somewhat resembles the early MAO inhibitors, which also have the reputation of being more effective than most other antidepressants. (Unlike SJW, MAO inhibitors are also more dangerous than other antidepressants.)
The half-life of SJW is difficult to estimate, as the different active ingredients have different half lives. The value usually quoted is the half-life of hypericin, which ranges from 26 to 42 hours (most sources use the figure of 26 hours).

2.3.2.2  Benefits

SJW is an effective antidepressant, with remarkably little in the way of unpleasant side effects. The combination of effectiveness and benign side-effect profile is unique among antidepressants. SJW has also been used to treat anxiety and somatoform disorder.

2.3.2.3  Principal Drawbacks

One problem that is unique to SJW, compared to prescription medications, is that its preparation is not rigidly controlled. The result is that capsules from one manufacturer may contain significantly different concentrations of effective elements than anothers. The buyer is advised to seek advice on reputable brands, and stay with a brand that has been found to be effective (and for which the individual's appropriate dose has been determined).
While side effects are usually absent or mild, they do exist, and can include anxiety, dry mouth, dizziness, gastrointestinal symptoms, fatigue, drowsiness, headache, and sexual dysfunction.
The major drawbacks to SJW are its potentially serious interactions with other medications. The National Center for Complementary and Alternative Medicine provides the following list of affected drugs (see nccam.nih.gov/health/stjohnswort):
Caution should be exercised when taking SJW with a prescription antidepressant. The cumulative effect may be beneficial for depression, or may produce too much serotonin and cause serotonin syndrome. If symptoms of serotonin syndrome start to appear, reduce one or more of the antidepressant medications.
People who have bipolar disorder should not take SJW without also taking a mood stabilizer, since SJW can trigger manic episodes in people who have bipolar disorder (as can any medication that increases serotonin concentration).

2.3.2.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
St. John's Wort Hypericum  26 hours 6 days None (non-prescription medication) Depression; anxiety; Somatoform Disorder


2.3.2.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Hypericum St. John's Wort, Saint John's Wort


2.3.3  SAM-e

SAM-e is an abbreviation for S-Adenosylmethionine, a chemical that is derived from the amino acid L-Methionine, and which occurs naturally in the body. SAM-e is involved in a variety of metabolic processes, including the production of norepinephrine and serotonin.
Clinical studies have shown that non-prescription SAM-e supplements can treat depression successfully, with an effectiveness comparable to prescription antidepressants, and relatively little in the way of side effects.

2.3.3.1  Mechanism

It is known that SAM-e is required for the production of norepinephrine and serotonin, so it is logical to conclude that SAM-e supplementation leads to an increase in the concentration of these two neurotransmitters. If so, then it may produce antidepressant effects for roughly the same reason as prescription medications such as Venlafaxine, which cause a similar increase, although by a different mechanism. However, this is only speculation, and the mechanism by which SAM-e alleviates depression is not known.

2.3.3.2  Benefits

SAM-e has been shown to be effective in the treatment of depression, and to relieve the pain of osteoarthritis as effectively as non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen. (The latter benefit is particularly significant, as prolonged use of NSAID medications often causes significant damage to the stomach lining, occasionally to a fatal degree.) Since the chemical occurs naturally in the body, it has little in the way of side effects, so long as it is not taken to excess.

2.3.3.3  Principal Drawbacks

Theoretically, taking substantial amounts of SAM-e could cause an undesirable buildup of homocysteine (a natural metabolic product), though no such cases have been reported. If this is a concern, folate and vitamin B supplements can be taken to help metabolize homocysteine.
People who have bipolar disorder should not take SAM-e without also taking a mood stabilizer, since SAM-e can trigger manic episodes in people who have bipolar disorder (as can any medication that increases serotonin concentration).

2.3.3.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
SAM-e S-adenosylmethionine  100 minutes 8 hours None (non-prescription medication) Depression; Osteoarthritis (for pain)


2.3.3.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
S-adenosylmethionine SAM-e

2.4  Monoamine Oxidase Inhibitors (MAOI)

The Monoamine Oxidase Inhibitors were the first antidepressant family discovered (in the 1950s). These medications were discovered in a quest for improved tuberculosis treatments. They failed in that role, but were found to alleviate depression markedly in many patients. Though quite effective, as antidepressants go, MAO inhibitors are seldom used at the present time. The main reason for their infrequent use is that they can react with some medications and foods to cause a hypertensive crisis, a dramatic rise in blood pressure that can cause severe headaches, permanent injury, or death.
Physicians are understandably reluctant to prescribe medications that can harm their patients, especially if alternatives exist. However, it is perhaps unfortunate that the MAO inhibitors are so seldom offered to patients, given that they are quite effective as antidepressants. While no other antidepressants outperform MAO inhibitors, there is anecdotal evidence to suggest that MAO inhibitors outperform all other antidepressants for difficult cases.
The greater safety of reuptake inhibitors makes them the obvious choice for initial treatment, but MAO inhibitors are worth considering if the first few reuptake inhibitors fail to help.
This category of medication is receiving renewed interest as a result of the recent introduction of the Emsam transdermal (skin) patch, which supplies the MAO inhibitor Selegiline through the skin. Selegiline is a very effective antidepressant, and the patch's delivery mechanism bypasses the digestive tract, thus avoiding the food-interaction problems that have plagued this category of medication. The Emsam patch has revitalized MAO inhibitor therapy, which is excellent news for those who suffer from depression. (The off-label use of Selegiline for the treatment of sexual dysfunction, as described in Chapter 5, may further boost the popularity of this medication.)

2.4.1  Mechanism

MAOIs inhibit (deactivate) one or both types of monoamine oxidase (MAO), the enzymes that metabolize (destroy) neurotransmitters in the synaptic gap after signal transmission. Inhibition of neurotransmitter metabolization increases the concentration of neurotransmitters serotonin, norepinephrine, and dopamine (see Section 1.3 for details).
There are two types of MAO: MAO-A and MAO-B. MAO-A preferentially metabolizes serotonin and norepinephrine, and dopamine to a lesser extent. It is found primarily in the placenta, gut, and liver. MAO-B is found primarily in the brain, liver, and platelets. It breaks down only dopamine and phenylethylamine. Both MAO-A and MAO-B metabolize the amino acid tyramine, but MAO-A does so more strongly.
MAO Inhibitors work by bonding to monoamine oxidase molecules and therefore inactivating them, since the molecular bonds previously available to the enzyme for use in metabolizing neurotransmitters are no longer available for that purpose.
MAO Inhibitors may be selective (specific) or nonselective (nonspecific), and reversible or irreversible ("Reversible MAO Inhibitor" is sometimes abbreviated as RIMA).
Selective means that the MAOI inhibits only (or mostly) one of the two MAO types (A or B). Selectivity strongly influences the metabolization of tyramine, in that MAOI s that are selective for MAO-B are less likely to present dietary difficulties than the unselective type.
Reversible means that the bond between the MAOI molecule and the MAO enzyme can be broken, thus re-activating the MAO molecule, while "irreversible" means that the bond is permanent and cannot be broken. In the case of irreversible MAOIs, the return of MAO concentration to normal is limited by the body's ability to produce MAO to replace the missing quantities, a process that can take 10-14 days. In the case of reversible MAOIs, the MAO concentration should return to normal over approximately the same time scale as the drug's elimination from the body (i.e., a few half lives). However, the recommended washout time is typically nearly as long for the reversible as the irreversible MAOIs. The practical effect of reversibility appears to be that reversible MAOIs affect brain chemistry less strongly (i.e., are milder) than the irreversible versions, and do not require dietary restrictions (possibly because MAO binds more strongly to tyramine than the MAOI molecules).
A particular medication may have any combination of selectivity and reversibility. Since a particular MAOI drug might in principle affect either MAO-A or MAO-B or both, and, for each version it does affect, inhibit it either reversibly or irreversibly, there are eight possible categories of MAO inhibitors, as illustrated in the table below.


Effect on MAO-A Effect on MAO-B Abbreviation
Reversible No effect MAO-RA
No effect Reversible MAO-RB
Reversible Reversible MAO-RA,RB
Irreversible No effect MAO-IA
No effect Irreversible MAO-IB
Irreversible Irreversible MAO-IA,IB
Reversible Irreversible MAO-RA,IB
Irreversible Reversible MAO-IA,RB
































The variety of possible actions should dispel the notion that MAO inhibitors represent one monolithic category. The effects of the different categories are quite distinct.
As of this writing, three of the eight possible categories correspond to available medications. These will be discussed in more detail below.

2.4.2  Reversible MAO-A Inhibitor (MAO-RA)

The selective inhibition of MAO-A produces an increase in the concentration of serotonin and norepinephrine in the brain.
Moclobemide is a reversible MAO inhibitor (RIMA), which is selective for MAO-A. At a 300 mg dose, the inhibition of MAO-A is approximately 80%, while the inhibition of MAO-B is approximately 20-30%. The MAO-A inhibition is both reversible and short-lasting (no more than 24 hours). Because the reaction with MAO-A is reversible, while the reaction between tyramine and MAO-A is not, the competition between Moclobemide and tyramine for MAO-A favors tyramine sufficiently that tyramine is metabolized by MAO-A even in the presence of Moclobemide. Thus even though Moclobemide is selective for MAO-A, it does not typically present any difficulties with food interactions.

2.4.2.1  Benefits

Moclobemide has no dietary restrictions, and relatively modest drug interactions. It may work better when combined with a tricyclic antidepressant or lithium.

2.4.2.2  Principal Drawbacks

Moclobemide's drawbacks stem from the same selectivity and reversibility that provide its benign lack of food and drug interactions. Because it affects only one of the two MAO enzymes, and because its chemistry is reversible, its effects are relatively weak. It is the least effective of all the MAO inhibitors in the treatment of depression.

2.4.2.3  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Manerix Moclobemide  90 minutes 1 day Depression  

2.4.2.4  Brand Names



Chemical Name Brand Names (Principal in Bold)
Moclobemide Manerix, Aurorix, Moclaime, Moclamide, Moclamine, Moclobemid, Moclobemida, Moclobemidum, Modobemde

2.4.3  Irreversible MAO-B Inhibitor (MAO-IB)

The selective inhibition of MAO-B produces an increase in the concentration of dopamine in the brain. Since dopamine is a precursor to norepinephrine, the increase in dopamine concentration leads directly to an increase in norepinephrine concentration as well.
The first (and for a long time, only) medication in this category was Selegiline. Selegiline was discovered in the 1960s, and initially approved by the Food and Drug Administration (FDA) for the treatment of Parkinson's disease. In 2006, Selegiline was finally approved for the treatment of depression, at which it is quite effective.
Selegiline is also used on an off-label basis for the treatment of sexual dysfunction resulting from lack of libido. Other off-label uses for Selegiline include the treatment of Alzheimer's disease, and the negative symptoms of schizophrenia.
Selegiline's unusual effectiveness for a wide variety of disorders, combined with its relative obscurity, make it perhaps the most under-prescribed psychotropic medication known. The good news is that the introduction of the Emsam skin-patch formulation of Selegiline is beginning to address this unfortunate obscurity.
Rasagaline, the newest medication in this category, was approved in 2006 for the treatment of Parkinson's disease. Because it shares the same primary mechanism as Selegiline, Rasagiline is likely to be useful for many of the same disorders, especially for depression and sexual dysfunction. However, this medication has not been in use long enough to provide a good understanding of off-label uses for which it may be appropriate.
Rasagiline is known to inhibit MAO-B. It is believed to inhibit only MAO-B, not MAO-A; however, conclusive proof has not yet been obtained to demonstrate that no MAO-A inhibition occurs. Until such proof becomes available, foods that contain tyramine should be avoided.
The chemistry of Selegiline is complex. At the lower doses typical of treatment for Parkinson's disease (10 mg orally), it irreversibly metabolizes MAO-B, and is a weak reversible inhibitor of MAO-A. Thus at these doses, tyramine ingestion is not a problem, and dietary restrictions are not required. At higher doses (20 mg or more, orally) typical for antidepressant use, Selegiline becomes an irreversible inhibitor of both MAO-A and -B, and has the same problems with tyramine as most of the MAOIs. (Selegiline is also unusual in that it has developed something of a cult following, with claims made that it improves thinking, increases intelligence, extends lifespan, and protects the brain against damage from oxidative damage, free radicals, ionizing radiation, and the illegal drug MDMA, known as "Ecstasy".)

2.4.3.1  Benefits

These are among the very few prescription medications that have a pronounced dopaminergic action, i.e., which give a powerful boost to the brain's dopamine chemistry (much more so than, say, Bupropion). Thus they are particularly effective at treating anhedonia and lack of libido, as libido, and the ability to feel pleasure, are both driven largely by dopamine chemistry. Also, because they does not increase serotonin concentration significantly in most cases, they do not actively suppress sexual performance or libido.
Eating foods that contain tyramine can cause a dangerous hypertensive crisis (episode of high blood pressure) for someone taking a medication that inhibits MAO-A. The medications of this section have as their primary mechanism the selective inhibition of MAO-B, which in principle eliminates this danger. Unfortunately, the reality is not quite this clear-cut (see Section 2.4.3.2 below), but it is true that these medications greatly reduce problems with tyramine compared to the non-selective MAO inhibitors.
While Selegiline does cause some MAO-A inhibition at higher doses, the degree to which effect this translates into danger of high blood pressure varies with the individual, and may not be significant for many people at doses of therapeutic use in the treatment of depression (for example, up to 40 mg orally).
The transdermal (skin patch) version of Selegiline supplies the medication gradually, through the skin. The gradual dispensation provides for a more constant level of medication in the body than does the oral form. Also, because it bypasses the gut, this delivery mechanism reduces or eliminates food interactions and dietary restrictions associated with the oral form.

2.4.3.2  Principal Drawbacks

The principal drawback of these medications are dangerous interactions with some other medications (something that is true for all irreversible MAO inhibitors). The most common of the dangerous medications are over-the-counter cold medications (decongestants, and cough medicine containing Dextromethorphan, but not antihistamines), and the pain medicine Meperidine (Demerol). The combination of an MAO-B inhibitor with any of these medications can produce dangerous reactions such as increases in blood pressure, convulsions, and psychotic episodes.
Given the uncertainty around the possibility of tyramine interactions, the patient is strongly advised to purchase an inexpensive blood-pressure gauge and measure blood pressure before and after eating foods that contain tyramine (starting with small quantities), in order to understand his or her individual sensitivity. It is much better to know, than to guess and risk a hypertensive crisis.
Since Selegiline can cause MAO-A inhibition, some people who take Selegiline orally may experience an increase in blood pressure after eating foods that contain tyramine, especially at the higher doses. Monitoring of blood pressure in conjunction with eating these foods is recommended. The likelihood and severity of food interactions can be reduced further by taking an orally-dissolving formulation (Zelapar), or by using the transdermal (skin-patch) formulation (Emsam), both of which bypass the digestive tract.

2.4.3.3  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Azilect Rasagiline  3 hours 14 days Parkinson's Disease Depression; Sexual Dysfunction
Eldepryl Selegiline (oral)  10 hours 14 days Depression; Parkinson's Disease (Adjunctive) Sexual Dysfunction; Alzheimer's Disease; Schizophrenia (negative symptoms)
Emsam Selegiline (patch)  1 day 14 days Depression Sexual Dysfunction


2.4.3.4  Brand Names



Chemical Name Brand Names (Principal in Bold)
Rasagiline Azilect
Selegiline (oral) Eldepryl, Apo-Selegiline, Atapryl, Carbex, Cyprenil, Deprenyl, Eldeprine, Gen-Selegiline, Jumex, Jumexal, Lesotal, L-Deprenalin, Movergan, Novo-Selegiline, Nu-Selegiline, Sd Deprenyl, Selegeline Hcl, Selegilina, Selegiline-5, Selegilinum, Selpak, Zelapar
Selegiline (patch) Emsam

2.4.4  Irreversible MAO-A and MAO-B Inhibitor (MAO-IA,IB)

The non-selective inhibition of both MAO-A and MAO-B produces an increase in the concentration of serotonin, norepinephrine, and dopamine in the brain. The broad-spectrum boost in neurotransmitter chemistry provides a powerful antidepressant effect. It also provides for some of the negative side effects-this category of medications, like others that boost serotonin levels, tend to impair or suppress libido and sexual function.
Tranylcypromine is most often described as an irreversible inhibitor of both MAO-A and MAO-B, although there are a few references which contradict this assertion and claim that it is reversible. In any event, the washout times cited are more like those of irreversible MAO inhibitors, so it will be considered irreversible here.

2.4.4.1  Benefits

This category of MAO inhibitors represents the very first antidepressants discovered. They are often described as the most effective antidepressants known, and, for some, are the only ones that work.

2.4.4.2  Principal Drawbacks

These medicines are the antidepressants of last resort, rather than first, because they interact dangerously, even fatally, with foods that contain the amino acid tyramine (most cheeses, preserved meats, red wine, etc.) and numerous medications. Ingesting any of these foods or medications while taking this category of MAO inhibitor can cause a dramatic, painful, and even fatal skyrocketing of blood pressure (a hypertensive crisis). They also, as noted above, tend to reduce libido and sexual function.
While it makes a great deal of sense to first try antidepressants that are inherently safer than these, one should nevertheless not be frightened of this category if the safer medications prove inadequate. It is not difficult to avoid the troublesome foods and other medications, and their avoidance is a small price to pay for feeling good again. (However, one might want to start with the safer varieties of MAO inhibitors before trying this particular category.)
The burden of judging whether a particular food is safe can be reduced by purchasing a blood-pressure gauge, and checking blood pressure after meals that may contain some amount of tyramine. A blood-pressure gauge is also a good way to determine if a headache or other symptom indicates a hypertensive crisis, or is benign. Everyone who takes one of the medications in this category should own, and frequently use, one of these devices.

2.4.4.3  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Marplan Isocarboxazid    Depression  
Nardil Phenelzine  12 hours 10 days Depression (especially Atypical, Non-endogenous, Neurotic), with anxiety, phobia, or hypochondria; Depression (Endogenous, less evidence of usefulness)  
Parnate Tranylcypromine  2 hours 7 days Depression (Major Depressive Episode without Melancholia)  

2.4.4.4  Brand Names



Chemical Name Brand Names (Principal in Bold)
Isocarboxazid Marplan, BMIH, Benazide, Enerzer, Isocarbonazid, Isocarbossazide, Isocarboxazida, Isocarboxazide, Isocarboxazidum, Isocarboxyzid, Maraplan, Marplon
Phenelzine Nardil, Beta-phenylethylhydrazine, Fenelzin, Fenelzina, Fenelzyna, Fenelzyne, Kalgan, Monofen, Nardelzin, Phenalzine, Phenelezine, Phenelzinum, Phenethylhydrazine, Phenylethyl hydrazine-HCl, Phenylethylhydrazine, Stinerval
Tranylcypromine Parnate, Dl-Tranylcypromine, Parmodalin, Sicoton, Transamin, Transamine, Transapin, Tylciprine

2.5  Reuptake Inhibitors

The second major category of antidepressant medications is the category of reuptake inhibitors. These medications were developed largely in reaction to the hypertensive dangers inherent in the MAO inhibitors. Reuptake inhibitors (of which the brand-name Prozac is undoubtedly the most famous) have been a tremendous success, bringing relief from depression to millions of people. The "Prozac revolution" put antidepressants on the map in the public mind, and forever changed the practice of psychiatry. That the revolution has had drawbacks (and that the medications have drawbacks) is indisputable, but also indisputable is the fact that those who suffer from depression have vastly more help available than was previously the case.

2.5.1  Mechanism

Reuptake inhibitors increase neurotransmitter concentrations by inhibiting the reuptake of neurotransmitters emitted into the synaptic gap. Since less of the emitted neurotransmitter is absorbed by the emitting neurons, the concentration of the neurotransmitter in the synaptic gap increases (see Section 1.3 for details).
There is a wide variety of reuptake inhibitors to choose from. Some are categorized by molecular structure, and some by function. All of them inhibit reuptake for some combination of serotonin, norepinephrine, and dopamine. The medications vary widely in terms of their selectivity. Some inhibit reuptake of a single neurotransmitter, while others inhibit the reuptake of two. As of this writing, none of the reuptake inhibitors strongly inhibit reuptake of all three of these neurotransmitters.

2.5.2  Tricyclic/Tetracyclic Antidepressants (TCA)

This category is named after the chemical structure of the medications, not for their mechanism. The medications are sometimes referred to as "second generation" antidepressants, although their discovery was contemporaneous with MAOIs. They are also known as non-selective cyclic antidepressants.

2.5.2.1  Mechanism

Most tricyclics suppress reuptake of serotonin and norepinephrine from the synaptic gap by the neuron that emitted them, thus increasing their concentration. They are not called SNRIs because the latter name is applied to newer medications, whose chemical structures are unrelated to the tricyclics.
Amoxapine not only suppresses reuptake of serotonin and norepinephrine, but blocks the response of dopamine receptors to dopamine (i.e., is a dopamine antagonist). (Note that dopamine antagonists are typically used for the treatment of psychosis.)
Amineptine, another tricyclic, is discussed in Section 2.5.10.
The site home.avvanta.com/~charlatn/depression/tricyclic.faq.html has this to say about the major classes of tricyclics:
There are two broad chemical classes of tricyclics. The tertiary amines (amitriptyline, imipramine, trimipramine and doxepin), which have proportionally more effect in boosting serotonin than norepinephrine, produce more sedation, anticholinergic effects and orthostatic hypotension. Amitriptyline and doxepin are especially sedating. Secondary amines (nortriptyline, desipramine, and protriptyline) tend more toward enhancement of norepinephrine levels and hence toward irritability, overstimulation and disturbance of sleep. The tertiary amines, thus, are more useful where depression is accompanied by sleep disturbance, agitation and restlessness; whereas the secondary amines may be preferable where the depressed patient is fatigued, withdrawn, apathetic and inert. The psychiatrist's initial evaluation, therefore, must go into extensive detail about the pattern of depressive symptoms you have experienced, to tailor the agent to the condition. An impression about which side effects you would best tolerate (or even benefit from) will enter into the physician's choice of tricyclic as well. Overall, desipramine and nortriptyline are perhaps the most benign in terms of patient tolerance, and are often the initial tricyclic of choice.

2.5.2.2  Benefits

The tricyclics are effective antidepressants. The sedating tendency that many of them have can be useful when depression is accompanied by insomnia. Also, some of the tricyclics do not have the dramatic negative impact on sexual function for which the SSRIs (and other medications that increase serotonin concentration) are notorious, and can even be used to help resolve the problem. (See Section 5.3.4 for details.)
Protriptyline has an energizing effect, and may be particularly useful for those who suffer from fatigue and lack of energy.

2.5.2.3  Principal Drawbacks

The side effects of the tricyclics are substantially more unpleasant than those of the later-generation antidepressants, such as the SSRI drugs. As a result, they are now seldom prescribed for depression.
Typical problems are anticholinergic effects (dry mouth, urinary hesitation or retention, blurry vision, memory problems, or confusion), sedation (due to antihistamine properties), and weight gain. Other side effects that can occur include CNS toxicity, orthostatic hypotension, cardiovascular toxicity, and delirium. Like all medications that increase serotonin concentration, they may suppress libido and sexual performance, sometimes dramatically. (See Section 5.2 for ways to resolve these problems.)
Amoxapine exhibits some neuroleptic (antipsychotic) activity. As is often the case for neuroleptic medications, Amoxapine may, rarely, lead to Tardive Dyskinesia or Neuroleptic Malignant Syndrome. For these reasons, Amoxapine would not be a drug of first choice, and the physician and patient should be careful to note early symptoms of these two medical conditions and be prepared to stop administration of the medication immediately, should symptoms appear.


Warning! Maprotiline has the second-highest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level have been associated with QT Prolongation, but not proven to cause it. The risk for QT Prolongation is not considered high, but medications with lower risk are preferred, especially for anyone who has Long QT Syndrome. If you cannot substitute a medication with lower risk, be alert for heart palpitations. If you experience palpitations, report them to your doctor immediately.


Note. Amitriptyline, Amoxapine, Clomipramine, Desipramine, Doxepin, Imipramine, Nortriptyline, Protriptyline, and Trimipramine have the lowest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level are unlikely to cause problems when used at recommended dosage, but should be avoided by anyone who has Long QT Syndrome. However, be alert and report any heart palpitations to your doctor immediately.

2.5.2.4  Medications

All of these medications, except for Maprotiline are tricyclics, although Maprotiline is usually grouped with the tricyclics because of its similarity to them. Technically, Maprotiline is a tetracyclic (which still allows the use of the abbreviation TCA). Collectively, these medications may all be referred to as hetero-cyclics, but the term tricyclic is almost always used.


Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Anafranil Clomipramine Tricyclic 3 days 14 days Obsessive-Compulsive Disorder Depression
Asendin Amoxapine Tricyclic 24 hours 5 days Depression; Psychotic Depression; anxiety  
Elavil Amitriptyline Tricyclic 20 hours 4 days Depression  
Ludiomil Maprotiline Tetracyclic 2 days 10 days Depression; Bipolar Disorder (Depressive phase); Psychotic Depression  
Norpramin Desipramine Tricyclic 1 day 5 days Depression  
Pamelor Nortriptyline Tricyclic 20 hours 4 days Depression  
Prothiaden Dothiepin Tricyclic 1 day 5 days Depression; anxiety Pain (from cancer); Fibromyalgia
Sinequan Doxepin Tricyclic 1 day 5 days Depression; Psychotic Depression; anxiety  
Surmontil Trimipramine Tricyclic 1 day 5 days Depression  
Tofranil Imipramine Tricyclic 19 hours 4 days Depression  
Vivactil Protriptyline Tricyclic 16 days 80 days Depression  

2.5.2.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Amitriptyline Elavil, Adepress, Adepril, Amitid, Amitril, Amitrip, Amitriprolidine, Amitriptylin, Amitryptiline, Amitryptyline, Amytriptiline, Apo-Amitriptyline, Damilan, Damilen, Damitriptyline, Domical, Elanil, Emitrip, Endep, Enovil, Etravil, Flavyl, Hexathane, Horizon, Lantron, Laroxil, Laroxyl, Lentizol, Levate, Miketorin, Novotriptyn, Pinsanu, Proheptadiene, Quietal, Redomex, Saroten, Sarotex, Seroten, Sylvemid, Tridep, Tryptal, Triptanol, Triptilin, Triptisol, Triptizol, Tryptanol, Tryptizol, Uxen, Vanatrip
Amoxapine Asendin, Amoxepine, Ascendin, Asendis, Defanyl, Demolox, Moxadil
Clomipramine Anafranil, Chlorimipramine, Clofranil, Clomifril, Clomipramina, Clomipraminum, Clopress, Gromin, Hydiphen, Monochlorimipramine, Placil, 3-Chloroimipramine
Desipramine Norpramin, DMI, Demethylimipramine, Desimipramine, Desimpramine, Desipramin, Desmethylimipramine, Dezipramine, Dimethylimipramine, Methylaminopropyliminodibenzyl, Metylyl, Monodemethylimipramine, Norimipramine, Norpramine, Nortimil, Pertrofane, Pentofran, Pertofran, Pertofrane, Pertofrin, Sertofran, Sertofren
Dothiepin Prothiaden, Dosulepin, Dosulepine, Dothapax, Dothep, Prepadine, Thaden
Doxepin Sinequan, Adapin, Aponal, Curatin, Desidox, Doneurin, Doxal, Doxedyn, Doxepina, Doxepine, Doxepinum, Novo-Doxepin, Poldoxin, Quitaxon, Triadapin, Zonalon
Imipramine Tofranil, Antideprin, Apo-Imipramine, Berkomine, Censtim, Censtin, DPID, Declomipramine, Dimipressin, Dyna-Zina, Dynaprin, Estraldine, Ethipramine, Eupramin, IM, Imavate, Imidobenzyle, Imipramina, Imiprin, Imizin, Imizine, Imizinum, Impramine, Impril, Intalpram, Iramil, Irmin, Janimine, Melipramin, Melipramine, Mipralin, Nelipramin, Norfranil, Novopramine, Pramine, Prazepine, Presamine, Promiben, Pryleugan, Psychoforin, Sedacoroxen, Sk-Pramine, Surmontil, Surplix, Timolet, Tipramine, Tofranil-PM, Tofraniln A, Trimipramine Maleate, Venefon
Maprotiline Ludiomil, Aneural, Deprilept, Maprotilina, Maludil, Maprotilinum, Maprotylina, Maprotylina, Melodil, Psymion, Retinyl
Nortriptyline Pamelor, Acetexa, Allegron, Altilev, Ateben, Avantyl, Aventyl, Demethyl-Amitryptyline, Demethylamitriptylene, Demethylamitriptyline, Demethylamitryptyline, Desitriptilina, Desmethylamitriptyline, Lumbeck, Noramitriptyline, Noritren, Nortrilen, Nortryptiline, Norzepine, Psychostyl, Sensaval, Sensival Ventyl, Sesaval, Vividyl
Protriptyline Vivactil, Amimetilina, Anafranil, Apo-Amitriptyline, Apo-Imipramine, Apo-Trimip, Asendin, Aventyl, Impril, Levate, Norpramin, Novo-Doxepin, Novo-Tripramine, Novopramine, Novotriptyn, Pertofrane, Protryptyline, Rhotrimine, Surmontil, Tofranil, Triadapin 5, Triptil
Trimipramine Surmontil, Apo-Trimip, Beta-Methylimipramine, Concordin, Concordine, Maximed, Novo-Tripramine, Rhotrimine, Sapilent, Trimeprimina, Trimeprimine, Trimipramina, Trimipraminum, Triptil

2.5.3  Selective Serotonin Reuptake Inhibitors (SSRI)

These SSRIs were developed in the hope that inhibiting reuptake of just a single neurotransmitter (serotonin) would avoid the unpleasant side effects of the MAOI and TCA medications. These medications are sometimes called the "third generation" family of antidepressants, although the first NDRI (Bupropion) was developed at about the same time.

2.5.3.1  Mechanism

SSRIs suppress reuptake of serotonin from the synaptic gap by the neuron that emitted them, thus increasing serotonin concentration.
Symbyax is a combination of the antidepressant Fluoxetine, and the atypical antipsychotic Olanzapine. This combination is sometimes more effective at treating symptoms of depression than Fluoxetine alone.

2.5.3.2  Benefits

The SSRIs are effective antidepressants. While they are no more effective at treating depression than the tricyclics they have largely replaced, their side effects are generally much less unpleasant. Similarly, the SSRIs do not have the problems of food and drug interactions common with the MAOIs. As a result, the SSRIs are used much more often than the tricyclics and MAOIs.

2.5.3.3  Principal Drawbacks

SSRIs may cause emotional "flatness," or flattened affect, that can be unpleasant. They usually suppress libido and sexual performance, sometimes dramatically. (See Section 5.2 for ways to resolve these problems.)
Withdrawal effects often arise when the medication is stopped. The withdrawal effects can be unpleasant, especially the peculiar "brain shock" feelings typical of SSRI withdrawal. Paroxetine is often cited as the worst offender in this regard. Withdrawal effects should be minimized by tapering slowly off the medication.
The side effects of Symbyax include those of both the antidepressant Fluoxetine (Section 2.5.3), and the atypical antipsychotic Olanzapine (Sections 4.3 and 4.5). The side effects are serious enough that use of Symbyax requires significant justification (i.e., other, safer medications have proven ineffective).


Warning! Venlafaxine has the second-highest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level have been associated with QT Prolongation, but not proven to cause it. The risk for QT Prolongation is not considered high, but medications with lower risk are preferred, especially for anyone who has Long QT Syndrome. If you cannot substitute a medication with lower risk, be alert for heart palpitations. If you experience palpitations, report them to your doctor immediately.


Note. Citalopram, Fluoxetine, Paroxetine, and Sertraline have the lowest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level are unlikely to cause problems when used at recommended dosage, but should be avoided by anyone who has Long QT Syndrome. However, be alert and report any heart palpitations to your doctor immediately.

2.5.3.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Celexa Citalopram Bicyclic Phthalane derivative 35 hours 1 week Depression  
Lexapro Escitalopram Citalopram derivative 30 hours 1 week Depression; Generalized Anxiety Disorder  
Luvox Fluvoxamine Monocyclic 16 hours 3 days Obsessive-Compulsive Disorder Depression
Paxil Paroxetine Phenylpiperidine 21 hours 5 days Depression; Obsessive-Compulsive Disorder; Panic Disorder (with or without agoraphobia); Social Anxiety Disorder; Generalized Anxiety Disorder; Post-Traumatic Stress Disorder  
Prozac Fluoxetine Bicyclic 1 week 5 weeks Depression; Obsessive-Compulsive Disorder; Bulimia  
Symbyax Fluoxetine + Olanzapine  1 week 5 weeks Bipolar Disorder (Depressive phase) Depression
Zoloft Sertraline Tetrahydronaphthylmethylamine 26 hours 1 week Depression; Obsessive-Compulsive Disorder; Panic Disorder (with or without agoraphobia); Social Anxiety Disorder; Post-Traumatic Stress Disorder  

2.5.3.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Citalopram Celexa, Celexa, Cipram, Cipramil, Citalopramum, Nitalapram, Seropram
Escitalopram Lexapro, Cipralex, Escitalopram Oxalate
Fluoxetine Prozac, Adofen, Affectine, Animex-On, Ansilan, Deprex, Deproxin, Erocap, Eufor, Fluctin, Fluctine, Fludac, Flufran, Flunil, Fluoxeren, Fluoxac, Fluoxeren, Fluoxetina, Fluoxetina, Fluoxil, Fluoxetinum, Flutin, Flutine, Fluval, Fluxil, Fontex, Foxetin, Lorien, Lovan, Margrilan, Modipran, Neupax, Nopres, Oxedep, Portal, Pragmaten, Prizma, Prodep, Prozac Weekly, Pulvules, Reneuron, Rowexetina, Sanzur, Sarafem, Zactin, Zepax.
Fluoxetine + Olanzapine Symbyax
Fluvoxamine Luvox, Avoxin, Depromel, Dumirox, Dumyrox, Faverin, Fevalat, Favoxil, Fevarin, Floxyfral, Fluvoxamina, Fluvoxamine maleate, Fluvoxaminum, Luvoxe, Maveral, Servox
Paroxetine Paxil, Aropax, Deroxat, Lumin, Paroxetina, Paroxetinum, Paxil Cr, Pexeva, Pondera, Seroxat
Sertraline Zoloft, Apo-Sertraline, Atruline, Lustral, Sertralina, Sertralinum, Sultamicillin Tosylate

2.5.4  Serotonin Antagonist/Reuptake Inhibitors (SARI)

2.5.4.1  Mechanism

SARIs suppress reuptake of serotonin from the synaptic gap by the neuron that emitted them, and also promote conversion of the serotonin precursor 5-HTP to serotonin (see Section 2.3.1). The result is to increase serotonin concentration. At the same time, they block the serotonin 5HT-2A receptor specifically, which reduces their negative impact on sexual function.

2.5.4.2  Benefits

These medications are effective antidepressants, and have the virtue of not suppressing libido and sexual function. They may even be used to alleviate sexual dysfunction caused by other antidepressants (see Section 5.3.4).

2.5.4.3  Principal Drawbacks

These medications may cause drowsiness and dizziness.
Nefazodone may cause life-threatening hepatic (liver) failure. This is a rare condition, with liver failure estimated to occur at a rate of one case per 250,000 patient-years. The prescribing physician should monitor the patient's liver function carefully and terminate the medication if signs of stress or injury appear. Nefazodone has been banned in some countries because of this problem.
Trazodone may cause priapism in men, a sustained and dangerous erection that can last for a day or more. It constitutes a medical emergency, and must be treated quickly by medication or surgery, to avoid permanent damage to the penis.

2.5.4.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Desyrel Trazodone Triazolopyridine 12 hours 3 days Depression  
Serzone Nefazodone Monocyclic 18 hours 4 days Depression  

2.5.4.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Nefazodone Serzone, Dutonin, Menfazona, Nefadar, Nefazodona, Nefazodonum, Nefirel, Reseril, Rulivan
Trazodone Desyrel, Beneficat, Bimaran, Deprax, Desirel, Desyrel, Manegan, Molipaxin, Pragmarel, Pragmazone, Sideril, Taxagon, Thombran, Tombran, Trazalon, Trazodil, Trazodon, Trazodona, Trazodona, Trazodonum, Trazodonum, Trazolan, Trazonil, Trialodine, Trittico

2.5.5  Serotonin/Norepinephrine Reuptake Inhibitors (SNRI)

These medications were developed in the hope that inhibiting reuptake of two neurotransmitters (serotonin and norepinephrine) would be more effective than the SSRI medications, which inhibit reuptake of serotonin alone. Some studies show that the probability of medications in this category relieving depression is slightly, if not dramatically, higher than for the SSRIs.

2.5.5.1  Mechanism

SNRIs suppress reuptake of serotonin and norepinephrine from the synaptic gap by the neuron that emitted them, thus increasing their concentration.
In addition to strongly inhibiting reuptake of serotonin and norepinephrine, Duloxetine also weakly inhibits reuptake of dopamine.

2.5.5.2  Benefits

These medications are very similar to the SSRIs in terms of how they work, how they feel, and their safety. They are sometimes said to be more effective, because they increase the concentration of two neurotransmitters, instead of just one.
There have been anecdotal reports that Milnacipran is less likely to suppress libido or cause sexual dysfunction, the way SSRI medications and other SNRI medications do; however, it isn't clear why this should be the case.

2.5.5.3  Principal Drawbacks

The SNRI medications frequently suppress libido, and impair the ability to have orgasm (i.e., cause anorgasmia), even if libido and erectile function are present. (See Section 5.2 for details about why this problem occurs, and strategies to alleviate it.) The other most commonly reported side effects are nausea, diarrhea, or other gastrointestinal disorders, and insomnia.
Withdrawal effects often arise when the medication is stopped. The withdrawal effects can be unpleasant, especially the peculiar "brain shock" feelings typical of SNRI withdrawal. Venlafaxine is often cited as the worst offender in this regard. Withdrawal effects should be minimized by tapering slowly off the medication.

2.5.5.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Cymbalta Duloxetine  12 hours 3 days Depression Urinary Incontinence in Women
Dalcipran Milnacipran Tricyclic 8 hours 2 days Depression  
Effexor Venlafaxine Bicyclic 16 hours 3 days Depression; Generalized Anxiety Disorder; Social Anxiety Disorder  

2.5.5.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Duloxetine Cymbalta, Domperidone, Yentreve
Milnacipran Dalcipran, Ixel
Venlafaxine Effexor, Efexor, Effexor Xr, Elafax, Trevilor, Vandral, Venlafaxina

2.5.6  Norepinephrine Reuptake Inhibitors (NRI)

2.5.6.1  Mechanism

NRIs suppress reuptake of norepinephrine from the synaptic gap by the neuron that emitted them, thus increasing norepinephrine concentration.

2.5.6.2  Benefits

NRI medications are energizing, and improve the ability to concentrate. They have relatively little in the way of unpleasant side effects.
Stimulants (see Section 2.8) also increase norepinephrine concentration, boost energy, and improve concentration, but the mechanisms by which they do so are very different from the reuptake inhibitors in this category. Stimulants cause neurons to increase the rate at which they emit norepinephrine, while reuptake inhibitors reduce the rate at which norepinephrine is re-absorbed by the emitting neuron. Thus the reuptake inhibitors do not produce the negative effects of tolerance and addiction that are characteristic of stimulants. They are intrinsically more benign, better tolerated, and, because they are not controlled substances, easier to obtain.

2.5.6.3  Principal Drawbacks

Side effects are typically minor, and include decreased appetite, irritability, cough.


Warning! Atomoxetine has the third highest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level should be avoided by anyone who has Long QT Syndrome, but should otherwise be safe. However, be alert and report any heart palpitations to your doctor immediately.

2.5.6.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Edronax Reboxetine Tricyclic 12 hours 3 days Depression  
Strattera Atomoxetine  5 hours 1 day Attention Deficit Hyperactivity Disorder Depression


2.5.6.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Atomoxetine Strattera, Tomoxetina, Tomoxetine, Tomoxetine, Tomoxetinum
Reboxetine Edronax, Norebox, Reboxetinemesylate, Vestra

2.5.7  Norepinephrine/Dopamine Reuptake Inhibitors (NDRI)

The only member in this category as of this writing, Bupropion (Wellbutrin), was developed at about the same time as the first SSRI (Fluoxetine, or Prozac). Unfortunately, early users of Bupropion were found to be more prone to seizures than the general population. Bupropion was reformulated into a sustained-release version that reduced the seizure incidence to roughly normal levels, but its history scared off physicians for many years. As a result, SSRIs, and especially Prozac, dominated the market for several years. After it became clear that Bupropion seldom decreases libido, and can even counteract the libido-suppression of SSRI medications when taken concurrently, its popularity surged. At this time, Bupropion is commonly prescribed.

2.5.7.1  Mechanism

NDRIs suppress reuptake of norepinephrine and dopamine from the synaptic gap by the neuron that emitted them, thus increasing their concentration.

2.5.7.2  Benefits

This medication is effective in treating depression. Unlike the SSRIs and most other antidepressant categories, it does not normally suppress libido. Bupropion is often prescribed along with SSRIs to alleviate the libido-suppression effects of SSRIs. This category has become increasingly popular as the libido issues have become better understood. (Bupropion is also prescribed as an aid in smoking cessation, under the name Zyban.)

2.5.7.3  Principal Drawbacks

Side effects include anxiety, jitteriness, insomnia, and increased possibility of seizures for seizure-prone populations (e.g., people with epilepsy).

2.5.7.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Wellbutrin Bupropion Bicyclic 21 hours 8 days Depression; Nicotine Addiction Sexual Dysfunction (Antidepressant-induced)


2.5.7.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Bupropion Wellbutrin, Wellbatrin, Zyban

2.5.8  Noradrenergic/Specific Serotonergic Antidepressants (NaSSA)

2.5.8.1  Mechanism

NaSSA medications increase the release of norepinephrine and serotonin, and block two specific serotonin receptors.

2.5.8.2  Benefits

These medications not only treat depression, but are particularly benign with respect to the kind of side effects that typically accompany medications that increase serotonin concentration. Blockage of the serotonin receptors reduces the negative impact on sexual function, and results in less nausea, nervousness, and diarrhea compared to SSRIs. This type of medication may even be used to alleviate sexual dysfunction caused by other antidepressants (see Section 5.3.4).

2.5.8.3  Principal Drawbacks

Side effects include drowsiness, increased appetite, weight gain, dizziness, dry mouth, and constipation.
A very small number in clinical trials for Mirtazapine (two out of 2796) developed agranulocytosis (drop in white-blood cell count, increasing vulnerability to infection), though it isn't clear that there was any connection with the medication. However, if symptoms of infection (sore throat, fever, mouth sores) develop while on this medication, they should be reported to a physician immediately.

2.5.8.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Remeron Mirtazapine Tetracyclic 30 hours 1 week Depression  

2.5.8.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Mirtazapine Remeron, Avanza, Axit, Mepirzepine, Mirtabene, Mirtaz, Mirtazapina, Mirtazapinum, Mirtazepine, Norset, Olsalazine, Remergil, Remergon, Remeron Soltab, Rexer, Zispin

2.5.9  Serotonin Reuptake Accelerators (SRA)

2.5.9.1  Mechanism

Medications in this category accelerate the reuptake of serotonin. It is counterintuitive that a reuptake accelerator would act as an antidepressant, given that serotonin reuptake inhibitors (SSRIs) are the most well-known antidepressants. One might expect an SRA to be a "depressant." Nevertheless, the sole entry in this category, Tianeptine (an atypical tricyclic antidepressant related to Amineptine) does alleviate depression.
Why Tianeptine relieves depression is not clear. Part of the reason may have to do with the fact that a decrease in serotonin concentration produces an increase in dopamine concentration, which can help some cases of depression.

2.5.9.2  Benefits

This medication is effective in treating depression. Because this type of medication reduces serotonin concentration, it should not cause sexual dysfunction, and may help to alleviate sexual problems. Other serotonergic side effects (nausea, nervousness, and diarrhea) should also be less common than with the SSRIs.

2.5.9.3  Principal Drawbacks

Side effects include nausea, constipation, abdominal pain, headache, dizziness, and changes in dreaming.

2.5.9.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Stablon Tianeptine Tricyclic 3 hours 1 day Depression  

2.5.9.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Tianeptine Stablon, Ardix

2.5.10  Dopamine Reuptake Inhibitors (DRI)

2.5.10.1  Mechanism

Amineptine is a dopamine reuptake inhibitor, and also promotes dopamine release at higher dosages. It stimulates the adrenergic system. Its antidepressant effects are similar to the other tricyclic antidepressants (TCAs), but it acts more rapidly, and is better tolerated (in terms of the usual side effects).
Amineptine can produce effects similar to psychomotor stimulants, such as amphetamines. It sometimes has the odd effect of causing spontaneous orgasms. It does not act on serotonin, and does not impair libido as SSRIs do.

2.5.10.2  Benefits

Amineptine has none of the serotonergic effects (e.g., loss of libido, sexual dysfunction) typical of SSRIs. In fact, it improves sexual dysfunction present in some patients. It is also reputed to improve quality of sleep.

2.5.10.3  Principal Drawbacks

Amineptine has a higher-than-normal risk for hepatotoxicity (liver damage), and, largely for this reason, is not available in many countries. There have also been claims that it is addictive, in the same sense that amphetamines are addictive, because of its psychomotor stimulant effects, and these claims have undoubtedly influenced the medication's availability (or lack thereof).
Other effects include gastralgia, abdominal pain, dryness of the mouth, anorexia, nausea, vomiting, flatulence; insomnia, drowsiness, nightmares, asthenia; tachycardia, extrasystole, precordialgia; dizziness, headaches, faintness, trembling, upsets; respiratory discomfort, tightness of the throat; myalgia, and lumbago.

2.5.10.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Survector Amineptine Tricyclic 8 hours 2 days Depression  

2.5.10.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Amineptine Survector, Maneon, Directim

2.6  Medications for Bipolar Disorder

Some of the medications used to treat bipolar disorder have been found useful in treating depression as well, usually as adjunctive medications (taken along with an antidepressant). Lithium and Lamotrigine are perhaps the most commonly used for this purpose. Chapter 3 describes these medications in more detail.

2.7  Dopamine Agonists (DA)

This section differs from most in this chapter in that none of the medications described have been approved by the Food and Drug Administration (FDA) as a treatment for depression. The use of dopamine agonists to treat depression is still experimental. However, sufficiently dramatic results have been achieved in some cases to warrant a discussion of these medications in the context of treating depression. Based on the evidence available to date, and given that these medications are not considered unusually dangerous, the author has concluded that they merit serious consideration as treatments for depression in situations where other approaches have been unsuccessful.

2.7.1  Mechanism

The neurotransmitter dopamine is heavily involved in the subjective experience of pleasure, and the capacity for libido (sexual desire). Some standard antidepressants achieve their results in part by increasing the concentration of dopamine, either by inhibiting its reuptake, or inhibiting its destruction by Monoamine Oxidase. Thus it is not surprising that a dopamine agonist, which can be thought of as supplying a replacement (agonist) for dopamine, would also act to increase the capacity for pleasure and sexual desire, in those whose capacity has been diminished by depression. In this context, dopamine agonists serve as a treatment for Anhedonia and sexual dysfunction (see Chapter 5).
The principle on-label uses of dopamine agonists are treatment for Parkinson's disease (usually in conjunction with l-dopa), and hyperprolactinemia. In the case of Parkinsons disease, dopamine agonists act to supplement the decreasing supply of dopamine in the brain. In the case of hyperprolactinemia, dopamine agonists act to suppress production of prolactin by the pituitary gland. This latter action can also result in shrinkage of pituitary gland tumors, when the illness is due to such a tumor.
Amantadine is known as an indirect dopamine agonist, because it does not act directly as a dopamine replacement. For this reason, it is also the weakest of the of the dopamine agonists. The mechanism by which Amantadine affects neurotransmitter chemistry is unknown; however, there is some evidence to suggest that it does one or both of the following: (1) Enhances dopamine concentration by increasing release, or decreasing reuptake, of dopamine; and (2) Stimulates the dopamine receptors directly, or makes the receptors more sensitive to dopamine. However, these suggested mechanisms are not regarded as reliably understood at this point.

2.7.2  Benefits

Anecdotal reports indicate an improved capacity for positive emotions, and improved libido, for individuals in whom these capacities are reduced by depression.
Perhaps because of its long half life (which minimizes fluctuations in blood levels), Cabergoline is least likely of all dopamine agonists to cause severe nausea, and is tolerated more easily than the others. One study showed that it had one third of the discontinuation rate (due to adverse side effects of nausea and headache) of Bromocriptine.

2.7.3  Principal Drawbacks

Dopamine agonists frequently cause nausea, headaches, and a variety of less common side effects. Nausea and headache are the two symptoms most likely to result in discontinuation of the medication.


Warning! Amantadine has the second-highest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level have been associated with QT Prolongation, but not proven to cause it. The risk for QT Prolongation is not considered high, but medications with lower risk are preferred, especially for anyone who has Long QT Syndrome. If you cannot substitute a medication with lower risk, be alert for heart palpitations. If you experience palpitations, report them to your doctor immediately.


Warning! Bromocriptine, Pergolide, Pramipexole, and Ropinirole have been identified as causing people to fall asleep suddenly, without warning signs such as drowsiness, even as late as a year after initiating treatment. Anyone taking any of these medications should exercise care in driving and other circumstances where sudden sleep would be hazardous, until it has been established that this problem is unlikely to occur.

2.7.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Dostinex Cabergoline  3 days 15 days Hyperprolactinemia Depression; Sexual Dysfunction
Mirapex Pramipexole  8 hours 2 days Parkinson's Disease Depression; Sexual Dysfunction
Parlodel Bromocriptine Ergot derivative 1 day 5 days Acromegaly; Hyperprolactinemia; Parkinson's Disease Depression; Sexual Dysfunction
Permax Pergolide Ergot derivative 24 hours 5 days Parkinson's Disease (adjunctive) Depression; Sexual Dysfunction
Requip Ropinirole  6 hours 2 days Parkinson's Disease Depression; Sexual Dysfunction
Symmetrel Amantadine  17 hours 4 days Parkinson's Disease; Viral Infection (Influenza Type A) Depression; Sexual Dysfunction
Trivastal Piribedil  21 hours 5 days Parkinson's Disease Depression; Sexual Dysfunction


2.7.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Amantadine Symmetrel, Adamantamine, Adamantanamine, Adamantylamine, Amantidine, Aminoadamantane, Endantadine, Gen-Amantadine, Mantadine, Pk-Merz, Symadine
Bromocriptine Parlodel, Alti-Bromocriptine, Apo-Bromocriptine, Bromergocryptine, Bromocriptin, Bromocriptina, Bromocriptinum, Bromocryptine, Bromoergocriptine, Bromoergocryptine
Cabergoline Dostinex, Cabaser, Cabergolina, Cabergolinum, Dostinex
Pergolide Permax, Pergolida, Pergolide Mesylate, Pergolide Methanesulfonate, Pergolidum
Piribedil Trivastal, Pronoran
Pramipexole Mirapex, Furfuryl Acetate, Pramipexol, Pramipexol, Pramipexolum, SUD919CL2Y
Ropinirole Requip, Ropinirol, Ropinirolum

2.8  Stimulants

Stimulants represent another category of medication that has not been approved by the Food and Drug Administration (FDA) as a treatment for depression; however, the use of stimulants for this purpose is becoming increasingly common. Stimulants are used as an adjunctive therapy, in combination with more traditional antidepressants.
The major FDA-approved use of stimulants is for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
Why use stimulants to treat depression? Simply because, in a small subset of patients, adding stimulants to an antidepressant regimen has been found to alleviate depression when other approaches have failed. Thus while stimulants would not be a first-line (or monotherapy) treatment for depression, there are times when their use as an adjunctive therapy does help.
Stimulants are most likely to provide benefits for cases of depression where inability to feel pleasure (anhedonia) and lack of energy (anergia) are major problems. Whether they are the best choice for treating these conditions is an evaluation the physician must make in light of the patient's condition, and of alternative treatments available.

2.8.1  Mechanism

The standard CNS stimulants increase activity in the central nervous system. They are thought to block the reuptake of norepinephrine and dopamine, and to increase the total amounts of these neurotransmitters released from storage vesicles in the neurons. The result is to increase the concentration of norepinephrine and dopamine in the synaptic gap.
Medications that increase dopamine activity typically improve anhedonia and lack of libido, while medications that increase norepinephrine typically increase energy. Thus it is not surprising that stimulants can improve both mood and energy.
The mechanism by which stimulants alleviate ADHD is not known, but it appears that increasing norepinephrine concentration not only provides additional energy, but improves the ability to concentrate. Thus it makes sense that norepinephrine-reuptake inhibitors (NRIs) are also prescribed for ADHD (see Section 2.5.6).
However, given that safer medications exist that are non-addictive and produce stimulating effects (by increasing concentration of the relevant neurotransmitters), it makes sense to investigate the alternatives first. (Modafinil, which is not addicting, and which works by different mechanism than the standard CNS stimulants, is an exception. Modafinil's more benign behavior makes it the most appealing candidate, among the stimulants, for treating depression.)
An NRI medication, possibly in conjunction with a dopamine agonist (Section 2.7), provides one alternative to CNS stimulants. Another is the irreversible MAO-B inhibitor, Selegiline (Section 2.4.3), which may be taken in conjunction with a dopamine agonist, if necessary. If neither of these alternatives proves useful, stimulants would then be more attractive.
Lisdexamfetamine has no direct effects on the nervous system. However, it is a "pro-drug" of the stimulant dextroamphetamine, which means that it is converted to the latter in the body. As this conversion takes time, the overall effect is to provide a time-release mechanism for dextroamphetamine.
The mechanism by which Modafinil promotes wakefulness is not known, but is known to be different from that of amphetamines. Although Modafinil is known to increase dopamine concentration by inhibiting dopamine reuptake, the increase in dopamine concentration is not responsible for the improvement in wakefulness. (However, it would not be surprising if the dopaminergic effects contributed to alleviating depression, among those taking the medication for anti-depressant benefits.)

2.8.2  Benefits

Stimulants increase energy, improve the ability to focus (if not taken to excess), promote wakefulness, and often decrease appetite. The first two attributes are clearly beneficial to depressed people who lack energy and find it difficult to concentrate. The decrease in appetite and increase in wakefulness may be benefits or drawbacks, depending on circumstances.
The time-release effect provided by Lisdexamfetamine increases the duration of the medication's usefulness, compared to taking Dextroamphetamine directly. This formulation may also have less potential for addiction than Dextroamphetamine.
Modafinil's benefits consist largely of the absence of drawbacks associated with standard stimulants, such as Methylphenidate and the Amphetamines. In particular, Modafinil is not addictive, and is generally more benign in terms of its side effects.
Pemoline has a relatively low potential for addiction, and is classified as a Schedule-IV controlled substance.

2.8.3  Principal Drawbacks

Most stimulants (excepting Modafinil, for which the following drawbacks do not apply) have a high potential for addiction, and are therefore categorized by the Drug Enforcement Administration (DEA) as Schedule-II controlled substances. Medications in this category require a more tightly-regulated prescription process than do most medications.
Addiction in the narrow sense of chemical dependence, and vulnerability to withdrawal symptoms are significant issues, but not by themselves dangerous, in a therapeutic context. More dangerous is the potential for abuse by those who become addicted to stimulant-induced "highs," and seek greater effects by taking higher doses. Abuse of stimulants by deliberate overdosing can cause psychotic episodes, as well as other unfortunate effects (such as coma and death). Not everyone who takes stimulants experiences "highs," but those who do are at more risk than those who do not.
The benefit of stimulants can be short-lived. They act in part by inducing neurons to release neurotransmitters from storage vesicles at a greater-than-normal rate. The stimulated rate of emission can exceed the rate at which the neurons are capable of producing the neurotransmitters. If so, then the stimulant will stop working at the current dose. Increasing the dose at this point may boost the release and production rates, or, if the neurons are overtaxed, have no useful effect. At this point the person taking the stimulant may "crash," feeling suddenly fatigued, depressed, and ill, possibly to extreme degrees.
Abuse of Pemoline (as by deliberate overdosing) can cause psychotic episodes. More significantly, patients taking Pemoline have experienced acute hepatic (liver) failure at 4-17 times the average rate. Of the 15 reported cases between 1975 and 1998, 12 resulted in death or liver transplantation. The earliest onset of liver abnormalities occurred six months after initiation of Pemoline. Because of this increased risk for liver damage, Pemoline should not normally be considered for first-line drug therapy. If Pemoline is prescribed, the patient's liver function should be monitored periodically. (The reader should be aware that Pemoline has been withdrawn from the market in the United States, because of this issue.)


Warning! Amphetamines and Methylphenidate have the third highest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level should be avoided by anyone who has Long QT Syndrome, but should otherwise be safe. However, be alert and report any heart palpitations to your doctor immediately.

2.8.4  Medications



Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Adderall Amphetamine (mixture) Amphetamine 12 hours 3 days Attention Deficit Hyperactivity Disorder; Narcolepsy Depression (Adjunctive)
Cylert Pemoline  12 hours 3 days Attention Deficit Hyperactivity Disorder Depression (Adjunctive)
Dexedrine Dextroamphetamine Amphetamine 12 hours 3 days Attention Deficit Hyperactivity Disorder; Narcolepsy Depression (Adjunctive)
Provigil Modafinil  15 hours 3 days Narcolepsy Depression (Adjunctive)
Ritalin Methylphenidate  3 hours 14 hours Attention Deficit Hyperactivity Disorder; Narcolepsy Depression (Adjunctive)
Vyvanse Lisdexamfetamine Amphetamine 15 hours 3 days Attention Deficit Hyperactivity Disorder Depression (Adjunctive)


2.8.5  Brand Names



Chemical Name Brand Names (Principal in Bold)
Amphetamine (mixture) Adderall
Dextroamphetamine Dexedrine, Actedron, Adipan, Allodene, Amphetamine, Anorexide, Anorexine, Benzebar, Benzedrine, Benzolone, Deoxy-Norephedrine, DL-alpha-Methylphenethylamine, Desoxyn, Dexampex, Dextroamphetamine Sulfate, Dextrostat, Elastonon, Fenamin, Fenylo-izopropylaminyl, Ferndex, Finam, Isoamycin, Isoamyne, Isomyn, Mecodrin, Methampex, Methamphetamine HCL, Norephedrane, Novydrine, Oktedrin, Ortedrine, Paredrine, Percomon, Phenamine, Phenedrine, Phenylisopropylamine, Profamina, Propisamine, Psychedrine, Raphetamine, Rhinalator, Simpatedrin, Simpatina, Sympamin, Sympamine, Sympatedrine, Weckamine, [1-(3-Methoxyphenyl)-2-propyl]amine, Alpha-Methylbenzeneethaneamine, Beta-Aminopropylbenzene, Dl-1-Phenyl-2-aminopropane, Dl-Amphetamine, Dl-Benzedrine, M-Methoxy-a-methylphenethylamine, M-Methoxyamphetamine, Racemic-Desoxynorephedrine,(+/-)-Benzedrine, (+/-)-Desoxynorephedrine, (+/-)-beta-Phenylisopropylamine, 1-Methyl-2-phenylethylamine, 1-Phenyl-2-aminopropane, 3-Methoxy-a-methylbenzeneethanamine, 3-Methoxyamphetamine, 3-Methoxyphenylisopropylamine
Lisdexamfetamine Vyvanse
Methylphenidate Ritalin, 4311/B Ciba, Calocain, Centedein, Centedrin, Centedrine, Centredin, Concerta, Focalin, Focalin XR, Methylphen, Meridil, Metadate, Metadate CD, Metadate ER, Methyl phenidyl acetate, Methylin, Methylin ER, Methylofenidan, Methylphenidan, Methylphenidatum, Methylphenidylacetate hydrochloride, Methypatch, Metilfenidat hydrochloride, Metilfenidato, Metilfenidato, Phenidylate, Plimasine, PMS-Methylphenidate, Riphenidate, Ritalin LA, Ritalin SR, Ritalin-SR, Ritaline, Ritcher Works
Modafinil Provigil, Dea No. 1680, Modafinilo, Modafinilum, Moderateafinil, Modiodal
Pemoline Cylert, Azoksodon, Azoxodon, Azoxodone, Betanamin, Centramin, Constimol, Cylert Chewable, Dantromin, Deltamin, Deltamine, Endolin, Fenoxazol, Fio, Hyton, Hyton asa, Juston-Wirkstoff, Kethamed, Myamin, NPL 1, Nitan, Notair, Okodon, PIO, Pemolin, Pemolina, Phenalone, Phenilone, Pheniminooxazolidinone, Phenoxazole, Phenylisohydantoin, Phenylpseudohydantoin, Pioxol, Pomoline, Pondex, Ronyl, Senior, Sigmadyn, Sistra, Sistral, Sofro, Stimul, Stimulol, Tradon, Tradone, Volital, Volitol, Yh 1
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