SSRI's: Successes and Questions

Biology 202
2004 Second Web Paper
On Serendip

SSRI's: Successes and Questions

Mariya Simakova

If you go to any pharmacy on the Main Line and look behind the counter, where they have the frequently-asked-for drugs, you will see that, apart from one or two birth control brands, all dispenser labels read "Amitril," "Prozac," "Zoloft," "Paxil," "Lexapro," etc. There is nothing special about the Main Line, it does not have an uncanny ability to attract emotionally imbalanced people; its pharmacies, in fact, simply reflect a worldwide and perpetually worsening epidemic called depression. Called by some "the cancer of emotions," depression affects approximately twelve percent of American women and eight percent of American men in their lifetime (1). Although the causes of depression are unknown, a range of effective antidepressants is available and is widely used by psychiatrists to treat various subtypes of depression. Moreover, it is frequently said that pharmacological treatment of depression has a great advantage over mere psychotherapeutical approach, and that any lasting effect and remission can only be achieved, if the patient combines an antidepressant with therapy (2).

There are several classes of antidepressants, but I would like to focus on selective serotonin uptake inhibitors (SSRI's), which have been developed in late 1980's (3) and which are, perhaps, the most popular antidepressants currently used. The reason for this popularity is not so much their effectiveness as compared with other drugs (for example, with monoamine oxidase inhibitors or tricyclic antidepressants) – studies show that their efficacies are similar (4) – but, rather, SSRIs' significantly smaller range of side effects (5). Patients taking SSRI's are more likely to complete the full course of treatment and, therefore, are more likely to reach remission.

This relative safety and tolerability of SSRI's are due to their selective action. Most antidepressants work by reestablishing communication between neurons through increasing the available level of neurotransmitters in the synaptic cleft. While other antidepressants affect several factors of the communication process (and some of their actions are unclear to the researchers), SSRI's action is focused strictly on the reuptake of serotonin by the presynaptic neuron, providing less leeway for possible side effects. By inhibiting the work of the serotonin reuptake transporter of the presynaptic cell, SSRI's increase the level of serotonin in the synaptic cleft, thus increasing the time in which serotonin can bind to the post-synaptic cell's receptors and the quantity of serotonin molecules in the cleft. (3)

Although patients treated with SSRI's often reach recovery, the assertion that serotonin deficiency is at the root of depression is not only arguable but most likely false. Several researches have shown that, although the connection between serotonin and depression is evident, it is by no means clear how the level of this neurotransmitter affects the condition, or whether it is even an important factor for all patients. Thus, the tryptophan depletion test, which allows researchers to reduce the level of serotonin in test subjects, shows that only 50 percent of healthy subjects with prior history of depression suffered from a relapse after their level of serotonin dropped. Evidently, this parameter is essential only for about half of depressed patients. Moreover, depression was not induced in the healthy subjects who never had depression prior to the test, which shows that serotonin deficiency is not the cause, but, most likely, itself one of the effects of depression. (1)

Another interesting dilemma is the fact that symptoms of depression can be alleviated not only by inhibiting the reuptake of serotonin, thus increasing its level in the synaptic cleft, but also by enhancing it, thus lowering the level of the neurotransmitter. For instance, tianeptine, a drug available in Europe, is as effective as most antidepressants, but its mechanism of action is the opposite of SSRI's. (1), (9) This once again highlights our current ignorance both of the cause of depression and of exact pathways of effective treatments.

Yet another SSRI's mystery is the time that is needed for them to take effect. In vitro studies show that they stop the uptake of serotonin into presynaptic neurons as soon as their level in plasma reaches the needed mark (which should take 2-8 hours) (4), but the actual therapeutic effect of alleviating depressive symptoms does not show until 2-6 weeks after the start of the treatment. (7), (8) This discrepancy may, in fact, provide an insight into various possible causes of depression that either stem from or influence the level of serotonin in the synaptic cleft.

One hypothesis that attempts to account for this time discrepancy proposes that the increased amount of serotonin in the synaptic cleft activates both the postsynaptic receptors and the autoreceptors of the presynaptic cell. The latter decrease the level of serotonin released by the presynaptic cell, not allowing serotonin to build up in the cleft. Over time, the autoreceptors become desensitized, the serotonin release is increased, and the therapeutic effect of the drug is noticeable. (11)

Another way proposed to account for this is that the therapeutic lag may be related to the number and sensitivity of postsynaptic receptors. In depressed patients, 5-HT (serotonin) receptors in the postsynaptic cell are up-regulated to compensate for the lack of serotonin. Studies show that SSRI's treatment causes down-regulation of the receptors at first, and then their activity is finally balanced. It is interesting that the time that it takes for the receptors to begin functioning normally is consistent with the time of the therapeutic lag. (11) This hypothesis suggests that the causes of depression are connected not to the level of serotonin but, rather, to receptor activity.

But perhaps the most interesting story that is currently used to account for SSRI's therapeutic lag is the connection between serotonin and hypothalamic pituitary adrenal system, which is involved in human stress response. Stressful events cause the neurons in hypothalamus to release corticotrophin releasing factor (CRF), a 41-amino acid containing neuropeptide, into blood. CRF affects the anterior pituitary, which responds by releasing adrenocorticotrophic hormone (ACTH), which is then transported to the adrenalin gland that produces glucocorticoids (cortisol in humans). Cortisol, in its turn, influences the anterior pituitary, hypothalamus, and the hippocampus through glucocorticoid receptors – a negative feedback process which maintains normal level of cortisol in the nervous system. In response to stressful events, cortisol levels rise, providing the organism with extra energy and increasing alertness. CRF-producing neurons are found not only in hippocampus, but also throughout the central nervous system – in the cerebral cortex, amygdala, and the brain stem (including the locus ceruleus and raphe nuclei – the sites of origin for norepinephrine and serotonin neurons). In addition to regulating the release of ACTH, CRF appears to have the functions of neurotransmitter, mediating the endocrinal, immune, autonomic, emotional, and cognitive responses to stress. (1), (10)

Studies document that there is a substantial increase of the levels of CRF, ACTH, and cortisol in depressed patients and the anatomical increase in the number of CRF-producing neurons. These constant high levels cause the downregulation of the glucocorticoid receptors ("glucocorticoid resistance"), and this imbalance may lead to the development of depressive symptoms, although the exact reasons for that are not clear. (1), (10) The imbalanced glucocorticoid receptors activity is also thought to decrease cell resilience, increase cellular death, and decrease neurogenesis, ultimately leading to decreased hippocampal volume (8). Laboratory animal studies show that antidepressants, including SSRI's normalize glucocorticoid receptors activity and indirectly influence cell survival and cell plasticity. These effects of antidepressants take about 2 weeks, which may explain their therapeutic lag in humans. (1), (8), (10) Antidepressants, including SSRI's, may not only eliminate depressive symptoms, but also help reduce stress vulnerability. However, studies suggest that chronic antidepressant treatment is needed in order for these effects to be stable. (1), (8)

Several important lessons can be drawn from the history of the use of SSRI's. First of all, contrary to popular assumptions, the existence of a successful (or partially successful) drug does not imply that medical researchers are clear on the origin of the disease. It is far more likely, as the case is with antidepressants, that effective treatments will be developed as a result of chance observation, and that the existence of appropriate drugs and the ability to monitor their effect on the patient will ultimately lead to the understanding of the causes of the illness. Secondly, the widespread prejudice against "dirty drugs," the drugs that affect not only one or two, but several biological processes (which often include unclear ones as well) are not necessarily better that "clean drugs," which exert influence over much smaller range of biological processes. It is clear that the more "dirty" tryciclic antidepressants may be more effective in some cases than the "clean" SSRI's. Thirdly, the inability of SSRI's to effectively cure about half of patients suggests that there cannot exist a single possible medication, whether for depression or for other illnesses, due to biological differences between humans. Fourthly, the study of the successes and, more importantly, of the failures of SSRI's have led the researchers to surmise that what we term depression may be not one, but, in fact, multiple disorders, having distinct paths of origin and, consequently, necessitating different treatments. The popular assumption that SSRI's may be a cure-all for depression is thus challenged. Fifthly, and most provocatively, the inquiries into SSRI's actions suggest that there is no single cause even for individual subtypes of depression, but, rather, that multiple processes – environmental, genetic, intracellular – in multiple parts of the brain are combined (and this combination may be different in individuals), producing depressive symptoms. Overall, serotonin imbalances may be just one of the "final pathways" (1) that multiple causes of depression take, and it is lucky that modifying secondary serotonin imbalances may affect primary processes involved in depression. All of this taken into account, there is a need to continue searching for new understandings of the causes of depression and to develop new medications that will include serotonin-regulating effects, but whose mechanisms of action will also include directly modifying other imbalances involved in depressive disorders.

References

Web Sources:
1) Noha Sadek, MD, Charles B. Nemeroff, MD, PhD. "Update on the Neurobiology of Depression.", on MedScape site (from a collection of articles from Clinical Update, an online journal for continuing education of medical professionals).
2) All About Depression, a website with a general review of the causes and treatments of depression.
3) Charles B. Nemeroff, MD. "Neurobiology of Depression." Scientific American, June 1998. Web access to the archived article available from BMC campus.
4) Stuart A Montgomery. "Selective Serotonin Reuptake Inhibitors in the Acute Treatment of Depression.", on The American College of Neuropsychopharmacology site.
5) Barbui C. et al. "Treatment discontinuation with selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs).", on MedScape site (from a collection of articles from WebMD Scientific American® Medicine online textbook for continuing education of medical professionals).
6) Thomas AM Kramer, MD. "Mechanisms of Action.", on MedScape site (from a collection of articles from Medscape General Medicine online journal for continuing education of medical professionals).
7) "Depression: Beyond the Catecholamine Theory of Mood.", a comprehensive site developed for a University of Plymouth psychology course.
8) Husseini K. Manji et al. "The Cellular Neurobiology of Depression.", from Nature Medicine online.
9) David Gutman, BS, Charles B. Nemeroff, ND, PhD. "The Neurobiology of Depression: Unmet Needs.", on MedScape site (from a collection of articles from Clinical Update, an online journal for continuing education of medical professionals).
10) Juan F. Lopez, MD. "The Neurobiology of Depression.", on The Doctor Will See You Now website.
11) "Neurobiology of Depression.", a handout for a San Diego State University psychology course with a comprehensive discussion on neurobiology of depression.

Comments made prior to 2007

Hi, I read your page about SSRI'S and want to say I am a sucess story in relation to Lexapro. I believe that it saved my life and my marriage. I have been taking it about a year now and it has made me a person I like to be with and others do too. I am no longer depressed, suicidal or emotionally unstable, Thank God for Lexapro and the Doctor who prescribed it. If it weren't for him I may be dead right now ... Sandra Mannaravalappil, 19 February 2006