Serotonin And Suicide

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In 2001, a researcher named Victoria Arango found that depressed people who committed suicide had fewer neurons in the orbital prefrontal cortex. She also reported that the brains of people who commit suicide had one-third the number of serotonin transporters than control brains. Arango concluded that perhaps depressed people had less serotonin than normal, and, in an attempt to compensate, made fewer transporters. In other words, these brains were trying to make the most of what little serotonin they had. Yet these compensations did not seem enough to prevent suicide attempts. Arango commented on the individuals who committed suicide, saying, "They can be so sick Prozac can't help them." Inhibiting the reuptake of serotonin is not always enough to prevent suicide. These findings may explain why some people commit suicide even while taking SSRIs.

In fact, Fred ("Rusty") Gage, of the Salk Insitute, along with members of his lab, has found many kinds of activities, such as exercise or doing puzzles, seem to enhance the growth of new neurons. Gage was one of the first scientists who recognized that adults had self-renewing brain cells. Although exercise has long been touted as a mood booster by those who regularily work out, Gage's work was one of the first to prove that exercise actually helps the brain grow and adapt to stress. Dozens of studies published since Gage's early findings indicate that there are different ways to make neurons grow. These findings may eventually lead to other effective ways to combat depression.

HOW SSRIs FEEL

Despite the hype of Prozac being the "happy" drug, people taking SSRIs do not feel "high" or especially jubilant. As with older antidepressants (TCAs and MAOIs), the most commonly reported side effect of SSRIs is jitteriness (Figure 3.2). People have likened the short-term effects of Prozac to that of highly caffeinated beverages. Indeed, as with too much caffeine, nausea and slight headache are associated with these drugs. However, it must be noted that caffeine has an undefined and most likely negligible effect on the serotonin system.

Jitteriness is a side effect that appears during the first week after taking SSRIs (some have noted that taking Prozac with food helps relieve the problem). Sometimes this feeling of agitation is so strong that some people starting on Prozac initially lose a few pounds. Subsequent weight loss may also be due to decreased appetite and increased activity, such as knee jiggling and finger-tapping. Another common side effect is teeth grinding. Although many of the side effects described above are also those of amphetamine, a drug with intense serotonin uptake inhibition, SSRIs do not give a "speedy" type of feeling. For the most part, people using SSRIs feel quite normal.

One side effect that may interfere with daily life is insomnia, which occurs in up to 14 percent of people who

Antide

pressants

Side Effects

Class

Drug name

Usual Adult Daily dosage

I l

1

Orthostatic hypotension

1 11

3

Agitation/ insomnia

SSRI

Citralopram (Celexa)

20-60mg/d

none

Sow

none

very high

high

low

SSR1

Fluoxetine (Prozac, Sarafcm)

I0-80mgfd

none

none

none

very high

high

very high

SSRI

300mg/d

none

moderate

none

very high

high

low

SSRI

Paroxetine (Paxil)

20-60mg/d

low

low

none

very high

high

low

SSRI

Sertraline (Zoloft)

200mg/d

none

very low

none

very high

very high

moderate

Figure 3.2 Like TCAs, SSRIs have a high probability of causing sexual dysfunction. Other side effects, listed here, include agitation, insomnia, and sedation, although they occur less frequently.

take SSRIs, but only 2 percent actually have to drop out of treatment because of the effect. Sometimes patients are counseled on taking SSRIs only in the morning, so that their sleep is not disrupted. Or, less commonly, a sleeping aid can be prescribed.

Over time the initial feeling of agitation tends to dissipate, and usually after 4-6 weeks the beneficial effects kick in. During this time, a patient must be encouraged to stay on the drug since the SSRI time frame of effect can be different for everyone. However, when improvement in mood does occur, in most cases there is no miraculous personality change. Sometimes when people with long-term, chronic depression begin to feel better, it may seem as if there has been a complete transformation in character. But the more typical response reported is the feeling that one's old self is back. Most patients on Prozac do not feel "better than well" (to use the phrase coined by Brown University psychiatrist Peter Kramer). Prozac, or any SSRI, simply makes it possible to enjoy life again, changing brain chemistry so that negative thinking is no longer the norm.

PROZAC PERSONALITY?

Some people, however, find that Prozac seems to numb their ability to feel emotion. Patients have reported feeling "flat" or "baseless." Creative types such as artists and writers sometimes complain that their thoughts are more mundane while taking Prozac, that it is more difficult to have flashes of creative insight. Since creativity is such a subjective quality, there is no way to tell whether or not Prozac has an effect on innovative thought. Obviously, if depression offered insight for some artistic types of expression, Prozac might hinder such inspiration. Nonetheless, there is no doubt that some people who experience depression are willing to trade misery for a more balanced life. In most cases, Prozac increases productivity and innovation, due to the cessation of depression.

Even if Prozac is not a "personality cosmetic," the fact that people's outlook can be changed from one of hopelessness to one of contentment is astounding. The therapeutic potential of SSRIs has led to interesting philosophical questions on the nature of happiness, the origin of personality, and the role of melancholy in life experience. SSRIs have also stimulated new interest in how the brain generates mood. Researchers interested in the basis of human emotion can now map the brains of patients taking SSRIs to see what areas of the brain generate pessimistic thoughts.

One study found that key changes from SSRI treatment occurred in the hippocampus, a region important for memory processing. Helen Mayberg, a professor at the University of Toronto and lead author of the study, also found increased connectivity in the amygdala (a region associated with emotion) and the cortex (an area of higher thought processes)

Easy Brain Diagram

Figure 3.3 Diagram of the limbic system. The limbic system is a set of brain regions that regulate emotion and have special connections to each other. The amygdala is the region where the brain processes emotions such as fear and anger. The hippocampus processes memories while the cortex is involved with higher cognitive functions such as logic and problem solving. Often these structures will regulate each other (such as when the higher reasoning cortex quells an irrational fear generating from the amygdala.

Figure 3.3 Diagram of the limbic system. The limbic system is a set of brain regions that regulate emotion and have special connections to each other. The amygdala is the region where the brain processes emotions such as fear and anger. The hippocampus processes memories while the cortex is involved with higher cognitive functions such as logic and problem solving. Often these structures will regulate each other (such as when the higher reasoning cortex quells an irrational fear generating from the amygdala.

after chronic Prozac treatment (Figure 3.3). In fact, Mayberg found that the increasing brain connectivity improved the the patient's chance of sustaining the effects of the antidepres-sant, thereby preventing relapse. Another interesting finding from this same study was that Prozac has gender-specific benefits. When researchers tracked how patients responded to stress, they found that Prozac increased neuronal connectivity in the hippocampus of males but reduced it in females, as well as in several other regions.

Yet Mayberg's finding does not imply that females are not receiving the same benefits from Prozac as males. On the contrary, Eli Lilly was recently given FDA approval to sell Prozac as a cure for premenstrual dysphoric disorder (PMDD) under a new name: Sarafem. This marketing move was done partially to license a new patent for Prozac, whose license as an antidepressant had expired. However, studies have shown that Prozac does appear to relieve some of the distressed feelings certain women get before menstruating. In some cases, these short periods of depression prevent women from going to work or enjoying everyday activities. However, many clinicians feel that the incidence of this disorder is very rare (3-5 percent) and that it should not be necessary to medicate someone for a very brief depression, despite its recurrence. At the same time, women have been shown to experience more depressive episodes than men and this may be linked to hormonal differences that contribute to PMDD.

BEYOND DEPRESSION: OTHER USES OF SSRIs

PMDD is not the only mental disorder that can be treated with SSRIs. There are many kinds of syndromes that SSRIs have been approved to treat. These syndromes include eating disorders, obsessive-compulsive disorder, post-traumatic stress disorder, panic disorder, and generalized anxiety disorder. Although each SSRI would probably be just as effective in treating these syndromes, the companies that own them have done extensive research to find a niche for their drug. Thus some SSRIs, such as Paxil (paroxetine), are approved for social phobia simply because the company that owns them has done the clinical studies proving it is effective and therefore should be licensed for it. Indeed, there seems to be no end to syndrome niche markets in which SSRIs can be effective. There are now efforts to market some SSRIs as treatments for kleptomania (strong desire to shoplift), addiction,and even weight loss.

How can SSRIs be taken for so many different disorders? The most likely reason is because all of these syndromes stem from similar mood imbalances. People who are depressed often begin behaving in a certain way in an effort to control their feelings of unhappiness. For instance, kleptomania is characterized as an impulse control disorder, where someone feels the need to steal to subjugate (win control over) feelings of anxiety. Many eating disorders also stem from anxiety and depression, which are funneled into obsessions about eating and thinness. Another odd syndrome that has roots in depression is trichotillomania, the compulsion to pull one's hair out until the affected person has bald spots on his or her head. The hair-pulling behavior is a manifestation of anxiety and depression, a bizarre habit that can distract and

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