Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are medications that increase the amount of the neurochemical serotonin in the brain. (Remember that brain serotonin levels are low in depression.) As their name implies, the SSRIs work by selectively inhibiting (blocking) serotonin reuptake in the brain. This block occurs at the synapse, the place where brain cells (neurons) are connected to each other. Serotonin is one of the chemicals in the brain that carries messages across these connections (synapses) from one neuron to another.
The SSRIs work by keeping the serotonin present in high concentrations in the synapses. These drugs do this by preventing the reuptake of serotonin back into the sending nerve cell. The reuptake of serotonin is responsible for turning off the production of new serotonin. Therefore, the serotonin message keeps on coming through. This, in turn, helps arouse (activate) cells that have been deactivated by depression, and relieves the depressed person's symptoms.
In the United States, SSRIs have been used successfully for a decade to treat depression. They have fewer side effects than the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), which are discussed below. SSRIs do not interact with the chemical tyramine in foods, as do the MAOIs. Also, SSRIs do not cause orthostatic hypotension and heart rhythm disturbances, like the TCAs do. Therefore, SSRIs are often the first-line treatment for depression. Examples of SSRIs include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and fluvoxamine (Luvox).
SSRIs are generally well tolerated and side effects are usually mild. The most common side effects are nausea, diarrhea, agitation, insomnia, and headache. However, these side effects generally go away within the first month of SSRI use. Some patients experience sexual side effects, such as decreased sexual desire (decreased libido), delayed orgasm, or an inability to have an orgasm. Some patients experience tremors with SSRIs. The so-called serotonergic (meaning caused by serotonin) syndrome is a serious neurologic condition associated with the use of SSRIs. It is characterized by high fevers, seizures, and heart rhythm disturbances. This condition is very rare and has been reported only in very ill psychiatric patients taking multiple psychiatric medications.
All patients are unique biochemically. Therefore, the occurrence of side effects or the lack of a satisfactory result with one SSRI does not mean that another medication in this group will not be beneficial. However, if someone in the patient's family has had a positive response to a particular drug, that drug would be the preferable one to try first.
Dual Action Antidepressants: The biochemical reality is that all classes of medications that treat depression (MAOIs, SSRIs, TCAs, and atypical antidepressants) have some effect on both norepinephrine and serotonin, as well as on other neurotransmitters. However, the various medications affect the different neurotransmitters in varying degrees.
Some of the newer antidepressant drugs, however, appear to have particularly robust effects on both the norepinephrine and serotonin systems. These drugs seem to be very promising, especially for the more severe and chronic cases of depression. (Psychiatrists, rather than family practitioners, see such cases most frequently.) Venlafaxine (Effexor) is one of these dual action compounds. It is a serotonin reuptake inhibitor that, at lower doses, shares many of the safety and low side effect characteristics of the SSRIs. At higher doses, this drug appears to block the reuptake of norepinephrine. Thus, venlafaxine can be considered an SNRI, a serotonin and norepinephrine reuptake inhibitor.
Another newer antidepressant, mirtazapine (Remeron), is a tetracyclic compound (four-ring chemical structure). It works at somewhat different biochemical sites and in different ways than the other drugs. It affects serotonin, but at a post-synaptic site (after the connection between nerve cells.) It also increases histamine levels, which can cause drowsiness. For this reason, mirtazapine is given at bedtime and is often prescribed for people who have trouble falling asleep. Like venlafaxine, it also works by increasing levels in the norepinephrine system. Other than causing sedation, this medication has side effects that are similar to those of the SSRIs, but to a lesser degree in many cases.
Atypical antidepressants are so named because they work in a variety of ways. Thus, atypical antidepressants are not TCAs or SSRIs, but they act like them. More specifically, they increase the level of certain neurochemicals in the brain synapses (where nerves communicate with each other). Examples of atypical antidepressants include nefazodone (Serzone), trazodone (Desyrel), venlafaxine (Effexor), and bupropion (Wellbutrin). The United States Food and Drug Administration (FDA) has also approved bupropion for use in weaning from addiction to cigarettes. This drug is also being studied for treating attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD). These problems affect many children and adults and restrict their ability to focus or concentrate on one thing at a time.
Lithium (Eskalith, Lithobid), valproate (Depakene, Depakote) carbamazepine (Epitol, Tegretol), neurontin (Gabapentin), and lamictal (Lamotrigine) are mood stabilizers and anticonvulsants. They have been used to treat bipolar depression. Certain antipsychotic medications, such as ziprasidone (Geodon), risperidone (Risperdal), and quetiapine (Seroquel), have sometimes also been used to treat bipolar depression, usually in combination with other antidepressants and/or the mood stabilizers.
Monoamine oxidase inhibitors (MAOIs) are the earliest developed antidepressants. Examples of MAOIs include phenelzine (Nardil) and tranylcypromine (Parnate). MAOIs elevate the levels of neurochemicals in the brain synapses by inhibiting monoamine oxidase. Monoamine oxidase is the main enzyme that breaks down neurochemicals, such as norepinephrine. When monoamine oxidase is inhibited, the norepinephrine is not broken down and, therefore, the amount of norepinephrine in the brain is increased.
MAOIs also impair the ability to break down tyramine, a substance found in aged cheese, wines, most nuts, chocolate, and some other foods. Tyramine, like norepinephrine, can elevate blood pressure. Therefore, the consumption of tyramine-containing foods by a patient taking an MAOI drug can cause elevated blood levels of tyramine and dangerously high blood pressure. In addition, MAOIs can interact with over-the-counter cold and cough medications to cause dangerously high blood pressures. The reason for this is that these cold and cough medications often contain drugs that likewise can increase blood pressure. Because of these potentially serious drug and food interactions, MAOIs are usually only prescribed after other treatment options have failed.
Tricyclic antidepressants (TCAs) were developed in the 1950's and 60's to treat depression. They are called tricyclic antidepressants because their chemical structures consist of three chemical rings. TCAs work mainly by increasing the level of norepinephrine in the brain synapses, although they also may affect serotonin levels. Doctors often use TCAs to treat moderate to severe depression. Examples of tricyclic antidepressants are amitriptyline (Elavil), protriptyline (Vivactil), desipramine (Norpramin), nortriptyline (Aventyl, Pamelor), trimipramine (Surmontil), and perphenazine (Triavil).
Tetracyclic antidepressants are similar in action to tricyclics, but their structure has four chemical rings. Examples of tetracyclics include maprotiline (Ludiomil) and mirtazapine (Remeron), a drug that was discussed above under dual action antidepressants.
TCAs are safe and generally well tolerated when properly prescribed and administered. However, if taken in over-dose, TCAs can cause life-threatening heart rhythm disturbances. Some TCAs can also have anti-cholinergic side effects, which are due to the blocking of the activity of the nerves that are responsible for control of the heart rate, gut motion, and saliva production. Thus, some TCAs can produce dry mouth, constipation, and dizziness upon standing. The dizziness results from low blood pressure that occurs upon standing (orthostatic hypotension). Anti-cholinergic side effects can also aggravate narrow angle glaucoma, urinary obstruction due to benign prostate hypertrophy, and cause delirium in the elderly. TCAs should also be avoided in patients with seizure disorders and a history of strokes.
Stimulants such as methylphenidate (Ritalin) or dextroamphetamine (Dexedrine) are used primarily for the treatment of depression that is resistant to other medications. The stimulants are most commonly used along with other antidepressants or other medications, such as mood stabilizers, anti-psychotics, or even thyroid hormone. They are sometimes used alone, but rarely. The reason they are usually used with other medications for depression is that unlike the other medications, they induce a rush and a high in both depressed and non-depressed people. Therefore, the stimulants are highly addictive drugs.

The pregnancy and postpartum periods are considered to be relatively high risk times for depressive episodes in women, particularly for those with pre-existing psychiatric illnesses. Therefore, it may be necessary to start or continue the pharmacological treatment of depression during these two timeframes. Hence, the aim of this review is to examine the effects on the fetus and infant of exposure, through the placenta and maternal milk, to the following drugs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, mirtazapine, venlafaxine, reboxetine and bupropion. The teratogenic risks, perinatal toxicity and effects on the neurobehavioural development of newborns associated with exposure through the placenta or maternal milk to these medications need to be carefully assessed before starting psychopharmacological treatment in pregnant or lactating women. In spite of the limitations of some of the studies reviewed, the older selective serotonin-reuptake inhibitors (SSRIs) [as we await further data regarding escitalopram] and venlafaxine seem to be devoid of teratogenic risks. By contrast, the data concerning possible consequences related to exposure to SSRIs via the placenta and breastmilk on neonatal adaptation and long-term neurocognitive infant's development are still controversial. Nevertheless, a number of reports have shown that an association between placental exposure to SSRIs and adverse but self-limiting effects on neonatal adaptation may exist. In addition, the information on both teratogenic and functional teratogenic risks associated with exposure to bupropion, mirtazapine and reboxetine is incomplete or absent; at present, these compounds should not be used as first-line agents in the pharmacological treatment of depression in pregnancy and breastfeeding. Untreated depression is not without its own risks since mothers affected by depression have a negative impact on the emotional development of their children and major depression, especially when complicated by a delusional component, may lead to the mother attempting suicide and infanticide. Consequently, clinicians need to help mothers weigh the risks of prenatal exposure to drugs for their babies against the potential risks of untreated depression and abrupt discontinuation of pharmacological treatment. Given these situations, we suggest that choosing to administer psychopharmacological treatment in pregnant or breastfeeding women with depression will result primarily from a careful evaluation of their psychopathological condition; currently, the degree of severity of maternal disease appears to represent the most relevant parameter to take this clinical decision.

BACKGROUND: A substantial number of women of childbearing age suffer from depression. Despite this, relatively little is known about the safety of antidepressant use during pregnancy. PURPOSE: We conducted a meta-analysis of prospective comparative cohort studies to quantify the relationship between maternal exposure to the newer antidepressants and major malformations. METHODS: We searched Medline, Embase and Reprotox from 1996 to the present for studies comparing outcomes in first trimester exposures to citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, reboxetine, venlafaxine, nefazodone, trazodone, mirtazapine and bupropion to those of non-exposed mothers. Data were combined using a random effects model; heterogeneity was tested with chi(2), and publication bias with a funnel plot and the Begg-Mazumdar statistic. RESULTS: Twenty-two studies were identified, 15 were rejected (4 reviews, 4 without comparison groups, 2 third trimester exposures, 2 retrospective database studies, 2 case reports and 1 duplicate); 7 studies (n = 1774) met inclusion criteria. Effects were not heterogeneous (chi(2) = 2.04, p = 0.92); funnel plot and test (tau = -0.24, p = 0.45) indicated no publication bias. The summary relative risk was 1.01 (95%CI: 0.57-1.80). CONCLUSIONS: As a group, the newer antidepressants are not associated with an increased risk of major malformations above the baseline of 1-3% in the population.

Bipolar Disorder Research Program, Cambridge Hospital, Cambridge, MA and Harvard Medical School, Boston, MA, USA Center on Neuroscience, Medical Progress, and Society and Department of Psychiatry and Behavioral Sciences, George Washington University, Washington, DC, USA.

The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re-examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood-cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15-20% of bipolar depressed patients).

OBJECTIVE: To describe and compare psychiatrists' opinion on antidepressant drugs and their prescriptions to depressed patients. METHOD: Between January and September 1999 a representative sample of French psychiatrists was asked their opinion of the 15 most prescribed antidepressants, and then to describe the treatments of the current depressive episode of four depressive patients each, their changes and the reason thereof. RESULTS: A total of 232 psychiatrists and 935 patients participated. The best ranked antidepressants were clomipramine, paroxetine and amitriptyline for efficacy, tianeptine, paroxetine and citalopram for tolerability. In patients, the most often prescribed were paroxetine, fluoxetine and venlafaxine. Those least often stopped for intolerance were tianeptine (2.9%), citalopram (5.2%), venlafaxine (3.3%) and amitriptyline (5.7%) for lack of efficacy. There was no difference in stopping rates for inefficacy of tricyclics and serotonin-selective agents. CONCLUSION: The best predictors for the prescribed antidepressants were the psychiatrists' overall rankings and opinions of the tolerability of the drug.

BACKGROUND: Pharmacological treatments have been successfully used to treat Generalized Anxiety Disorder (GAD). The mainstay for the pharmacological treatment of GAD in past decades has been the use of benzodiazepine and non benzodiazepine anxiolytics. Data emerging over the last two decades have shown that antidepressants may be equally effective to anxiolytics for treating GAD. The use of antidepressants for treating GAD may be advantageous, due to the fact that GAD presents a high co morbidity ratio with major depressive disorder (62%) and dysthymia (37%). OBJECTIVES: To assess the efficacy and acceptability of antidepressants for treating generalized anxiety disorder. SEARCH STRATEGY: Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register - CCDANCTR (up to May 2002), Anxiety Neurosis (up to May 2002) and Cochrane Controlled Trials Register (CENTRAL/CCTR) (up to May 2002), MEDLINE (1966 to May 2002), LILACS (1982 to May 2002); reference searching; personal communication; conference abstracts and book chapters on the treatment of generalized anxiety disorder. SELECTION CRITERIA: Randomised controlled trials were included. Exclusion criteria were: non randomised studies; studies which included patients with generalized anxiety disorder and another Axis I co-morbidity. DATA COLLECTION AND ANALYSIS: The data from studies were extracted independently by two reviewers and relative risks, weighted mean difference and number needed to treat were estimated. People who died or dropped out were regarded as having had no improvement. MAIN RESULTS: Antidepressants (imipramine, venlafaxine and paroxetine) were found to be superior to placebo in treating GAD. The calculated NNT for antidepressants in GAD is 5.15. Dropout rates did not differ between antidepressants. Only one study presented data on imipramine and trazodone. Imipramine was chosen as the reference drug and, therefore, data on trazodone could not be included in the meta analysis. Only one study was conducted among children and adolescents (~~Rynn 2001~~). The latter study showed very promising results of sertraline in children and adolescents with GAD, which warrants its replication in larger samples. REVIEWER'S CONCLUSIONS: The available evidence suggests that antidepressants are superior to placebo in treating GAD. There is evidence from one trial suggesting that paroxetine and imipramine have a similar efficacy and tolerability. There is also evidence from placebo-controlled trials suggesting that these drugs are well tolerated by GAD patients. Further trials of antidepressants for GAD will help to demonstrate which antidepressants should be used for which patients.