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Depression at the Synaptic Level: SSRI's and their limitations

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Biology 202
2000 First Web Report
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Depression at the Synaptic Level: SSRI's and their limitations
Richard Cruz

Depression is a fairly common problem that affects as many as 1 out of 5 of us (about 1 in 10 for males and 1 in 4 for females) at some time in their lives. We all know what it is like to feel very sad, but real depression is an unshakable sadness that saps away your energy to want to do anything. Clinical depression has many different facets, and affects not only someone's mood, but often also their ability to function normally.

The DSM-IV defines a major depressive episode as depressed mood most of the day, nearly every day, markedly diminished interest or pleasure in all, or almost all, activities most of the day, significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day, large changes in psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, or indecisiveness, and recurrent thoughts of death (not just fear of dying), suicide (sometimes accompanied by attempt(s)).1

These are all markers at the behavioral or experiential levels. There are a number of proposed causes of depression ö this is due in part to the many aspects of the disease. These include early loss, inability to cope, faulty cognition, family life, and genetic predisposition.2 However, the angle that has gained popularity in recent years is viewing and treating depression as a neurological dysfunction at the synapse. It indeed is very tempting to think that depression, an incredibly complex disorder that differs from patient to patient, (because it involves personality) could be cured by taking a pill. It would certainly make things a lot easier. The often dramatic results of selective reuptake inhibitors (SSRIâs) on personality offer a link between complex workings of personality and basic cellular processes at the synapse. However, in light of all the hype and ãcure allä magic that surround the household names Zoloft, Prozac, and Paxil, how do these drugs really work, how well do they work, and what are their limitations? Are they a panacea for depression and a galaxy of other personality disorders?

In the brain, serotonin (5-HT) is a neurotransmitter involved in systems that affect mood, hunger, sleep, and aggression.3 In other parts of the body, it constricts blood vessels and inhibits gastric secretion.4 amongst other physiological functions. Serotonin can be obtained from a variety of dietary sources (including a number of on-line Îhealth-foodâ stores), most 5-HT is synthesized from tryptophan.

There are several lines of evidence that suggest that depression may have a neurochemical etiology based in levels of serotonin. This is referred to as the indoleamine hypothesis of depression.

The primary and strongest evidence in support is the effectiveness of selective serotonin reuptake inhibitors (SSRIâs) on depression. The SSRIâs available in the United States for are Fluoxetine (Prozac®), Sertraline (Zoloft®), Citalopram (Celexa®), Luvox, and Peroxetine (Paxil®). Serotonin's action in the synapses is terminated by reuptake of the neurotransmitter by the presynaptic cell. These drugs stop serotonin from being removed form the postsynaptic membrane. The removal of transmitter substance stops its effect on the postsynaptic membrane, therefore, by keeping more serotonin active, these drugs allow increased serotonin to have a greater effect.

The removal of SSRIâs decreases serotonin levels, and increases depressive symptoms.
Other manipulations of serotonin levels also can modulate the symptoms of depression. Addition or removal of serotonin precursors, usually by augmenting or restricting amounts of tryptophan in the diet, has been shown to have an effect. In a study on smokers with histories of depression, removal of tryptophan from the diet, reversed the antidepressant effects of Fluoxetine of tryptophan (Mann et al., 1996).5 Similarly, in another study, twelve normal healthy males with no history of depression were caused to display symptoms of depression when they were fed a tryptophan free amino acid mixture. To Anderton, ãThis study suggested a correlation between decreased levels of serotonin and depression and [supported] the hypothesis that low serotonin levels predispose an individual to depression.ä (We must remember, however, that correlation does NOT equal causation).

We have similar findings when we look at the other end of the life of serotonin ö its metabolites in the central nervous system. Levels of 5-hydroxyindolacetic (5-HIAA) acid, a serotonin metabolite, in the cerebral spinal fluid of depressed patients are lower than in non-depressed subjects. This difference 5-HIAA is even more pronounced in depressed patients who have exhibited suicidal behavior (Ricci et al., 1990).6

More evidence comes from genetic studies that show that implicate polymorphisms of the serotonin transporter gene. The serotonin transporter protein is the primary target of antidepressant drugs and is encoded by this single gene. Alleles of the gene were identified which contain nine, ten, and twelve copies of a certain repeated section of the gene. The presence of the allele with nine copies of the repeat was significantly associated with the risk of depression, and consequently, it may confer susceptibility to unipolar depression (Olgilvie et al., 1996). Variations in the number of repetitions in the serotonin transporter protein gene are suggested to play a role in regulating transcription (the manufacture of protein from the gene code via messenger RNA).7
This all looks like very strong and impressive evidence. Support for the indoleamine hypothesis ranges from the neurological, to the dietary, and even down to the genetics and mechanics of gene transcription. However, there are a few snags to the indoleamine hypothesis and the widespread administration of SSRIâs for depression and other serotonin related disorders.

First of all, it takes 3-6 weeks for SSRIâs to start working. This can be a dilemma with a severely depressed patient, or one close to suicide. They are getting treatment that is supposed to help them, but it will not start to take effect for a month. This can be frustrating to anyone, but simply imagine the frustration if you think that nothing will work, and that it may not be worth it anyway.
This delay also can make proper dosage administration tricky for the prescribing doctor. An inadequate or incomplete trial of an antidepressant medication is often correlated with increased suicide rate.8 The explanation for this delay in effectiveness is that it this is how much time it takes for the serotonin molecules and precursors to accumulate in the synapse. This, however, is a best guess as to why there is such a delay. Nobody really knows why.

A finer point that must be added to the genetic part of the explanation is that not everyone that gets depression has a gene for it, and not everyone that has a predisposition towards depression will get it. And then there are some people that suddenly get depression with no previous history. The right conditions must exist in order for the symptoms to appear, and the calculus for this is not understood.

Another problem is that SSRIâs are not a magic bullet. Like all drugs, they have side effects. These side effects include sexual dysfunction, weight gain, and drowsiness.9 To a depressed person, these can create more unwelcome things to be worried about.
These drugs have side effects because they affect receptor sites that cause the depressive symptoms, and some that do not. That is to say, they are selective, but not perfectly so. Even the newest and most advanced drugs have at least a little bit of interaction with some norepinephrine sites. The fact that there are at least four separate types of serotonin receptors, some of which have several distinct subtypes complicates matters further for pinpoint drug activity with fewer side effects.

Side effects are not the only serious worry. An overdose of serotonin inhibitor (serotonin syndrome) causes a variety of symptoms including hallucinations, confusion, fluctuating blood pressure, seizures, high temperatures, stiffness, and irregular heart beats.10 This can become a lethal condition very rapidly. Incidences of serotonin syndrome appear to be on the rise as more people are under regular

The largest problem with wide spread use of SSRIâs and reliance on the indoleamine hypothesis is best put in the following two statements:

[All] psychological problems have some physical manifestations, and all physical illnesses have psychological components as well. In fact, the chemical imbalances that occur during depression usually disappear when you complete psychotherapy for depression [sic], without taking any medications to correct the imbalance. This suggests that the imbalance is the body's physical response to psychological depression, rather than the other way around.11

Both psychology and drugs relieve depression in some cases, so the treatment doesn't clarify the causes.12

In light of these two statements it appears that the indoleamine hypothesis loses sight of the cause-and-effect problem of psychology. Are the depressive thought processes caused by the imbalance, or do the thought processes create the imbalance?
The hypothesis also does not address the fact that drugs in conjunction with therapy is usually
better than either treatment alone.

So why is there such a rush to Prozac, Zoloft, and Paxil? I see several possible reasons.

First, it is easier to give someone a prescription for a pill and do a rudimentary follow-up than it is to give drugs AND give therapy. Therapy takes time, commitment, and (possibly more importantly) money.

The money issue is also related to the second reason that I propose. There is a lot more weight and money in pharmacological research than there is in non-drug psychological therapy. This is because of the vast amounts of money that pharmaceutical companies put into developing new drugs. This investment must have a return, hence the immense media attention given to Zoloft, and Prozac. The push does not end with the public. An large portion of advertising and promotion is aimed at the clinicians that do the prescribing, so that they are more likely to dispense the drugs. There are multibillion-dollar machines behind the market success of SSRIâs. This is not to say that we only think that they work because Pfizer, and SmithKline-Beecham tell us that they are. These are, however, expensive treatments that can only be bought as brand names. The manufacturers can only be expected to milk their five-year patents for all that they are worth. In 1995, Eli Lilly earned 2 billion dollars from Prozac alone. Their patent on Prozac expires in 2002.

Ultimately, however, I believe that the primary reason for the emphasis on the synaptic level explanation of depression and the impulse to use drugs as the cure is the desire to have simple answers for complex problems. We often expect that the future in which every disease and disorder can be cured by a pill. With SSRIâs we have something that at least resembles that reality in our lifetime. Beyond that, it is helping thousands of people get on with their lives after being stuck in its darkest depths.

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Comments made prior to 2007

I have been taking Paroxetine to combat deppression for the past 18 months. A friend of mine who is a student doctor at Bristol University suggested i try 5-HTp. I am taking her advise and am currently in the process of stopping the Paroxetine abruptly as opposed to weaning off. I went to my GP to be sure that I wont cause myself any adverse problems by going against the reccommended weaning off period. While my GP could not give me an answer to this, she went on to say that she has never heard of 5-HT let alone wether or not they are safe. I am not convinced My GP has a clue about the side effects of Paroxetine nor studied the effects of serotonin levels to advise me on my current problem. I Wonder how can people feel safe using 5-HTp when some Doctors dont even know what it is? ... Leanne Squire, 25 September 2007


Asif Mehmood's picture

sustain relief from depression

my mother was affected by depression 5 year back, and she took zoloft from 5 years now she taper off and become enjoying her life in the age of 55years.zoloft is really a good medicine.

Samantha Watts's picture

Patients and physicians

Patients and physicians really must walk a tightrope when trying to use SSRIs to combat depression and anxiety. While the pharmaceuticals can help dampen the physical manifestations of associated with these states, therapy (most commonly CBT) helps the patient learn to cope with the destructive thought patterns. Some of the side effects, such as weight gain, can easily undermine the delicate work being done to heal the patient's mind. Since many other medications are contraindicated when taking SSRIs, preventing or reversing weight gain becomes a matter of diet, exercise and discipline, the last of which is likely in short supply to begin with. I guess the bottom line is to use such drug therapies judiciously and be prepared to have to work at recovery rather than expecting the pill to be a panacea.

I've written more about this at my blog: