Abstract
Antidepressants have become the most widely prescribed psychotropic medication in North America and are used to treat a wide range of mental disorders, including depression, anxiety, ADHD, OCD, and alcoholism. This paper explores several topics related to antidepressants and their use in the treatment of psychiatric conditions, specifically Major Depressive Disorder. The three main classes of antidepressants-Selective Serotonin Reuptake Inhibitors (SSRIs), Monamineoxidase Inhibitors (MAOIs), and Tricyclics (TCAs)-are discussed in detail, with an emphasis on their history, pharmacokinetics, mechanisms of action, and side effects. The paper ends by evaluating the overall effectiveness of antidepressants in treating depression.
Antidepressants are the most commonly prescribed psychotropic medication. To say that the list of mental disorders for which antidepressants are prescribed is long would be an understatement. Some of these disorders include Major Depressive, Bipolar, Social Phobia, Obsessive-Compulsive, Attention-Deficit-Hyperactivity, Substance Use, and Generalized Anxiety Disorder, among others. As a result, few psychopharmacological drugs have received as much research attention as antidepressants and the present paper reviews but a fraction of this literature. But before discussing such issues as mechanisms of action and treatment efficacy, a brief review of the history of antidepressants is called for.
History of Antidepressants
The first antidepressant to be discovered was the MAOI, Iproniazid, in the 1950's. The antidepressant effects of the drug were actually discovered fortuitously. Researchers originally developed the drug to treat tuberculosis, but soon discovered that the drug alleviated depression and improved patient's moods. After the drug's antidepressant effects were publicized, several new MAOIs were developed and released on the market to treat depression. The success of the first-generation MAOIs was short lived, however, as media reports that the drug was ineffective and caused liver damage surfaced soon after its release. Although these reports were mostly unfounded and eventually refuted by subsequent research, the removal of Iproniazid from the market did inspire researchers to develop newer MAOIs that were more specific in their action and that had reversible effects.
In the late 1950's, the first TCA antidepressant, Imipramine, was also discovered by an accident. Scientists were trying to develop a drug to treat the psychotic symptoms of schizophrenia. Although it wasn't successful in treating schizophrenia, Imipramine did appear to relieve the symptoms of depression and, as a result, it was subsequently used to treat major depression. However, similar to first generation MAOIs, earlier TCAs had severe side effects. Today, many second generation TCAs have been developed which are just as effective as earlier TCAs in treating depression but which have fewer negative side effects.
Fluoxetine, or as it commonly referred to as, Prozac, was introduced to the public in 1987 as the first SSRI. Unlike its predecessors, the MAOIs and TCAs, SSRIs targeted only a specific neurotransmitter, called serotonin. Many have likened the analogy of SSRIs as North America's "happy" pills which are believed to cure all of lives problems. Today, SSRIs are the most widely prescribed antidepressant for treating depression as well as many other mental disorders, such as OCD and anxiety. In 2007 alone, there were more than 30 million prescriptions filled for Zoloft in the United States (Advanstar Communications, 2008).
Pharmacokinetics
The pharmacokinetics of a drug can be defined as the movement of the drug throughout the body, which includes the drug's method of administration; the absorption of the drug into the blood stream; the distribution of the drug to the site of action; and the removal of the drug from the body.
Antidepressants are absorbed in similar ways. They are taken orally as a pill and pass through the digestive tract, where they are absorbed into the blood through the blood vessels lining the stomach. However, before the drug enters the blood stream and reaches the brain, most of it is actually destroyed by the digestive tract and the liver, a process known as "First-pass metabolism"(McKim, 2007). Alcohol inhibits this process in all antidepressants with the exception of SSRIs, which are often prescribed to alcoholics. As a result, if someone consumes alcohol while taking certain antidepressants, toxic levels of the drug can accumulate in the blood. TCAs are absorbed quickly whereas for absorption for MAOIs and SSRIs is much slower. Antidepressants are able to cross the blood-brain and placental barrier with relative ease. The drug tends to concentrate in the liver, lungs, kidneys, and the brain (McKim, 2007), and high levels of the drug have been found in breast milk (Kim et al., 2005).
The Excretion of a drug is measured by the half life of the drug, which is the time period required for the body to eliminate half of the blood level of the drug (McKim, 2007). MAOIs have a half life of about 2-3 hours and, as a result, are taken 2-3 times a day. TCAs and SSRIs have half lives of about 15-24 hours. Most antidepressants do not have active metabolites (McKim, 2007). The exception is Prozac, whose metabolite blocks the enzyme responsible for the drugs destruction. The active metabolite of Prozac has a half-life of 16 days. Switching medications before the active metabolite of Prozac has been excreted can lead to a condition called Serotonin syndrome, which is discussed below.
Neurophysiology: How Do Antidepressants Work?
Antidepressants are believed to treat depression by increasing the activity of one or more of the monamine systems-serotonin (5-HT), dopamine (DA), and norepinephrine (NA)-in the brain (Duman, Heninger, & Nestler, 2000). Specific regions of the limbic system-such as the amygdala and hippocampus-and the medial forebrain bundle-including the NE fibres of locus coeruleus, serotonergic fibres in the raphe system, and dopaminergic fibres of the mesolimbic system-have been implicated in depression (Hercher, Turecki, & Mechawar, 2009). The three main classes of antidepressants differ depending on which monamine system(s) they target.
MAOIs work by blocking the activity of the monamine oxidase enzyme, which metabolizes the monamine neurotransmitters (MAs) 5-HT, DA, and NA. When this enzyme is blocked or inhibited, there is a build-up of neurotransmitters in the synaptic cleft, which leads to increased binding of MAs to the postsynaptic neuron. First generation MAOIs, such as Iproniazid, had an irreversible effect on the monamineoxidase enzyme, that is, they permanently destroyed it. This posed a serious problem as this enzyme metabolizes several other important chemical substances in the body aside from neurotransmitters, such as tyramine. Newer MAOIs are less "messy" or indiscriminate, that is, they generally alter the levels of only certain neurotransmitters, such as 5-HT and NE, and have irreversible effects.
SSRIs and TCAs work in similar ways. After neurotransmitters are released into the synaptic cleft, most are reabsorbed by the presynaptic neuron and recycled for subsequent use. SSRIs and TCAs increase MA neurotransmission, and supposedly alleviate depressive symptoms, by preventing the re-uptake receptors on the presynaptic neuron from reabsorbing MAs, causing an increased level of MAs in the synaptic cleft. SSRIs, as their name implies, specifically alter serotonin levels, whereas TCAs are less discriminate in their physiological effects. Newer drugs, such as Reboxetine, block the re-uptake of NE.
Harmful Effects
TCAs are the third most common cause of drug related deaths, next to only alcohol and heroine. SSRIs, although often advertised as the safest antidepressant, can also have potentially lethal effects on the body through a condition called serotonin syndrome, which occurs when 5-HT1A receptors are over stimulated (Birmes, Coppin, Schmitt, & Lauque, 2003). Serotonin syndrome can lead to unpleasant physical symptoms such as fever, shivering, and diarrhoea and cognitive symptoms such as disorientation and agitation. Serotonin syndrome often develops when antidepressants are co-prescribed with other medications or taken with psychostimulants such as amphetamines (Frank, 2008).
Soon after Fluoxetine was released in the late 1980's there were several claims that it induced intense, violent suicidal ideation in depressed patients (Teicher, Glod, & Cole, 1998). This possible link between antidepressants and suicide sparked much research and heated debate among experts in the field, and was the topic of many news reports and television talk shows. Although the preponderance of research supporting this link came in the form of case studies, the U.S. Food and Drug Administration (FDA) demanded that all drug manufacturers include warning labels about the potential dangerous effects of antidepressants. This official recognition by the FDA of the suicidal effects of antidepressants coupled with increased research attention led to many high-profile court cases in which antidepressants, Fluoxetine in particular, were blamed for violent crimes. Eric Harris, who is infamously known as one of the school shooters in the tragic Columbine massacre, had been taking antidepressants for about a year before the incident, and several news reports attempted to draw a link between Eric's violent behaviour and the suicidal effects of antidepressants (Cullen, 2009). Despite over two decades of research on the possible link between suicide and antidepressants, the issue is far from being settled. This is in part due to the fact that it is extremely difficult for researchers to investigate the topic. Suicidal ideation and attempts are, unfortunately, relatively common among people who are depressed anyway, so it is not clear whether the reported increase in suicidal ideation after taking antidepressants reflects a drug-induced effect or just a lack of response to the drug.
Nevertheless, attempts have been made to explicate the reported relationship between antidepressants and suicide. One such theory attributes the link not to a direct drug-induced effect or to even a lack of response to the drug but rather to a mismatch in symptom improvement (Machado-Vieira et al., 2008). One of the symptoms of depression (see appendix A for the full diagnostic criteria for Major Depressive Disorder) is lethargy, or lack of energy. People who are clinically depressed often report feeling extremely tired and lethargic, insofar as it is exhausting for them just to get out of bed in the morning and get dressed. According to this theory, such people are not at risk for completing suicide. Although they may be preoccupied with the idea of committing suicide, they lack the energy necessary to actually complete the suicide attempt. However, if they start taking an antidepressant, which generally improves physical energy before mood, they may have enough energy to finally carry out a suicide attempt. Although this theory makes intuitive sense, it is entirely speculative and currently lacking empirical support.
Some researchers have gone to the root of the issue and questioned the very assumption that antidepressants increase suicide. Contrary to this assumption, they argue, antidepressants prevent, rather than cause, suicide (Simon, Savarino, Operskalski, Wang, 2006). Large scale ecological studies have shown that the recent increase in the prescription of antidepressants, particularly SSRIs, has been associated with an overall decrease in the number of suicide rates (Gibbons et al., 2008; Milane, Suchard, Wong, & Licinio, 2006; Morgan, Griffiths, & Majeed, 2004). Such studies, however, due to the ecological nature of their design, do not permit cause and effect inferences. Individual level data gathered from drug trials do confirm a decrease in the incidence of suicides among patients taking antidepressants (Castelpietra et al., 2008; Isacsson, Osby, & Ahlner, 2009), suggesting that antidepressants may play a preventative role in suicide. These findings are relatively robust and have been well documented (Bramness & Walby, 2009). It's also possible, however, that other factors, such as general improvement in mental health care, are responsible for the overall decline in suicide rates (Kapusta et al., 2009).
Like with any other drug, there are certain risks associated with taking antidepressants. It's no secret that antidepressants have many unwanted side effects; in fact, there are about as many side effects for each drug as there is total number of drugs. Depending on the type of antidepressant, common side effects can include sexual dysfunction, dry mouth, constipation, irregular heartbeat, ringing in the ears, weight gain, and headaches, among others. Despite steadfast claims by the media that antidepressants induce suicidal ideation and aggression, however, extant research has failed to support this causal relationship. In fact, most of the literature suggests that antidepressants decrease, rather than increase, suicide.
The Monamine Hypothesis
The discovery of the therapeutic benefits of the first generation antidepressants Iproniazid and Imipramine, and the physiological mechanisms by which these drugs operated, gave rise to the formulation of the monamine theory of depression, which held that the disorder was caused by decreased activity of the monaminergic systems in the brain. Although this theory has received wide spread acceptance for many years, as evidenced by the steadily increasing rates of antidepressant prescriptions, there is a plethora of research calling for a complete revamp of the theory on the basis that it is oversimplified (Hindmarch, 2001; Pacher & Kecskemeti, 2004; Tang, 1999). Inspiring this recent surge in criticisms has been empirical findings that have questioned the overall efficacy of antidepressants in treating Major Depressive Disorder (see below for a review). Belmaker (2008) identified four main limitations of the monamine hypothesis: 1) The mechanism of action of several antidepressants are non-specific; 2) Monamine neurotransmitters are involved in multiple behaviours, not just ones governed by mood and emotion; 3) The placebo-drug difference in controlled studies indicates that monamine levels are causally involved in only 50% of depressed patients; and 4) Since neurotransmitter levels in the brain cannot be directly measured, the monamine theory is not falsifiable.
The effectiveness of antidepressants: Fact or fiction?
Recent research has called into question the effectiveness of antidepressants in treating people with depressive disorders (Ioannidis, 2008; Lacasse & Leo, 2005). Much of this criticism has been inspired by recent claims in the literature that antidepressants are often no more effective than placebos. For example, in a meta-analysis of 96 trials drug trials, involving 9566 people, Rief et al. (2009) concluded that as much as 68% of the improvement in people taking antidepressants can be attributed to the placebo effect. Kirsh et al. (2008) found that antidepressant efficacy increased as the level of baseline severity increased, but that this was not due to an increased responsiveness to the antidepressant, but rather to a decreased responsiveness to the placebo. Other researchers have pointed out that, due to the selective publication of antidepressant trials, the current literature overestimates the efficacy of antidepressants. For example, Turner et al. (2008) reviewed 74 drug trials submitted to the FDA and found that of the 37 studies with positive results all but one were published, whereas only 3 of the 36 studies with negative results were published.
No one is denying the potential therapeutic effects of antidepressants. About 50% of people taking antidepressants do experience some type of improvement in their depressive symptoms (Nierenberg et al., 2008), but an equal amount of patients don't respond at all to antidepressants, which suggests that the monamine theory alone cannot explain the pathophysiology of depression. It could be that those who do respond well to antidepressants represent a distinct sub-group of depressed patients, perhaps those who are more biologically predisposed to depression. Further research is needed to identify the genetic markers of depression, but available research has implicated several other neurobiological factors in the development of depression. Among these are an over-activity of hypothalamic-pituitary-adrenal axis (Dinan, 2001; Hindmarch, 2001; Leonard, 2001; Rot, Mathew, & Charney, 2009); hippocampal neural plasticity in response to stress (Hindmarch, 2001; McEwen & Magarinos, 2001; Roee et al., 2009); inflammatory response to stress (Maes, 2001; Miller, Rohleder, Stetler, & Kirschbaum, 2005); and levels of the brain-derived neurotrophic factor (BDNF) (Rot, Mathew, & Charney, 2009; Sandler, 2001). Taken together, this research highlights the need for novel approaches to treating depression (Rot, Mathew, & Charney, 2009).
As mentioned previously, research has failed to provide an adequate explanation for the frequently observed, and relatively robust, placebo effect. If all a person has to do to alleviate his/her depressive symptoms is to be told that a pill, which in reality is nothing more than sugar water, will treat his/her symptoms, and telling them does just that, then perhaps depression has more to do with personal attitudes and beliefs than genetics and molecular biology. Psychotherapy, then, which involves changing one's perceptions and attitudes, would seem to be a better approach to treating depression than antidepressants. Of course, a keen reductionist will be quick to point out that even psychological concepts, such as beliefs and attitudes, can be explained by neurological activity. After all, thoughts and emotions are just chemical reactions in the brain, right? True, but therapy does not have an inordinate amount of unpleasant and potentially lethal side effects-drugs do. Moreover, the continued use of antidepressants is based on the assumption that depression is caused by depleted MAs levels-an assumption of which many researchers have become increasingly sceptical, and rightly so.
The monamine theory of depression was developed over 50 years ago; every other theory in psychology that has been in existence for that long has either been abandoned or radically reconstructed. That physicians and psychiatrists have continued to prescribe antidepressants in exponential numbers despite the steady accumulation of research underscoring its limited effectiveness is an indication that they are either ignorant to the research or motivated to prescribe for other reasons.
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