Serotonin activity

As noted earlier, the only other method presently available for detecting serotonergic dysfunction in living humans involves neuroendocrine challenge with serotonin-active drugs (Cowen and Anderson 1976). One such... 

Serotonergic function has been investigated by using multiple methods. Assaying the major metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) has been widely used (Ch. 13). This method assumes that CSF 5-HIAA is related to brain serotonin activity. This premise is supported by the rostral-caudal concentration gradient of CSF 5-HIAA and the observation in postmortem studies that CSF 5-HIAA correlates with levels of 5-HIAA in prefrontal cortex [16], both of which suggest that CSF 5-HIAA is a reasonable index of prefrontal serotonin turnover. ... 

Sleep is reduced when there is decreased serotonin activity or destruction of the dorsal raphe nucleus. 

Mirtazapine (Remeron). Mirtazapine is the newest of the atypical antidepressants. It mainly works by blocking the alpha-2 negative feedback receptor and thus increases norepinephrine and serotonin activity. In addition, mirtazapine blocks serotonin-2 and serotonin-3 receptors to produce a specific serotonin action like nefazodone. Mirtazapine is approved for the treatment of depression. Its use in the anxiety disorders is being studied. 

Buspirone (Buspar). Buspirone is an anxiety-relieving medication that alters serotonin activity. When added to an antidepressant, buspirone may help treat the depression. It will also relieve anxiety and may reverse sexual side effects of a SSRl. Please refer to Chapter 5 Anxiety Disorders for more information regarding buspirone. 

Pindolol (Visken). Pindolol is a blood pressure medicine that also alters serotonin activity. Some believe that it helps speed the response to antidepressants, but more study is needed. It is generally well tolerated. 

When switching between a MAOl and other antidepressants that affects serotonin activity, the first medication must be allowed to wash out of the patient s system before the new antidepressant is started. The duration of this washout period is determined by the half-life of the antidepressant that is being discontinued. If a washout is neglected, then a potentially dangerous serotonin syndrome may result. 

Pindolol (Visken). A beta blocker known to potentiate serotonin activity via a distinct action on serotonin autoreceptors, pindolol has been reported in a controlled study to augment SSRl treatment in OCD patients who are partial responders. Pindolol is administered at a dose of 2.5 mg three times daily. It is generally well tolerated but low blood pressure, dizziness, and sedation can occur. 

Serotonin-Boosting Antidepressants. Antidepressants that enhance serotonin activity in the brain have also been studied in ADHD. In particular, fluoxetine (Prozac) and the serotonin-selective TCA clomipramine (Anafranil) have been the most extensively evaluated, with mixed success. They provide some benefit for aggression and impulsivity but don t significantly improve the poor attention of ADHD. As a result, the SSRls and other serotonin-boosting antidepressants do not appear to be effective first-line treatments for ADHD. Conversely, depressed patients without ADHD often show improvements in symptoms of concentration and attention when treated with a SSRI. Although SSRls are not widely used in the treatment of ADHD, they may be worthy of consideration in ADHD patients whose impulsivity is not controlled by stimulants alone. Those with comorbid conduct disorder or ODD who are prone to agitation and at times violent outbursts may be helped by the addition of a SSRI. 

Antidepressants. The most widely used psychiatric medicines with the broadest range of application in TBI patients are undoubtedly the SSRI antidepressants. They are well tolerated, unlikely to worsen any of the preexisting deficits associated with TBI, and offer relief from not only depression but also impulsivity and virtually all variants of anxiety in these patients. As such, SSRIs are the preferred first-line treatment for all anxiety disorders after TBI. Other newer antidepressants that also work (at least in part) by boosting serotonin activity, namely, mirtazapine (Remeron), nefazodone (Serzone), venlafaxine (Effexor XR), and duloxetine (Cymbalta) can also be considered, but they have not been well studied in patients with TBI. In... 

Antidepressants that increase serotonin activity can also indirectly decrease dopamine activity by inhibiting the activity of dopamine-secreting nerve cells. This effect on dopamine nerve cells is generally not of sufficient magnitude to treat psychosis, but it may explain why patients taking these antidepressants on rare occasions experience akathisia and other extrapyramidal side effects. 

Probably the greatest advances in psychiatric medications of the last 15 years have involved the neurotransmitter serotonin. First was the arrival of serotonin-specific antidepressants with fewer side effects and greater safety than their predecessors. More recently, atypical antipsychotics have highlighted the importance of serotonin-dopamine interactions in the optimal treatment of schizophrenia and other psychotic disorders. While these are indeed significant advances, medications that alter serotonin activity are not without their own side effect burden. 

TABLE 13.6. Medications that Enhance Serotonin Activity... 

Medication Serotonin Activity Transmitters Clinical Uses... 

When we talk about serotonin-blocking medications, a point of clarification must be made. In most cases, medications do not block overall serotonin activity but instead block the activity at one of the many serotonin receptor types. For example, the antidepressants trazodone, nefazodone, and mirtazapine increase total serotonin activity yet they block certain of the serotonin receptors. Mirtazapine increases both serotonin and norepinephrine activity by interfering with the alpha-2 receptor. By also blocking the serotonin-2 and serotonin-3 receptors, mirtazapine avoids the sexual dysfunction and GI side effects commonly experienced with other serotoninboosting medications. We cannot truly call these serotonin-blocking medications, because they are serotonin-boosting medications that selectively block certain serotonin receptors. 

As noted in the previous section, buspirone produces both serotonin-boosting and serotonin-blocking effects by stimulating the serotonin-lA receptor. These mixed effects produce an overall milder serotonin-boosting effect that limits it potential side effects but also results in a more limited range of clinical uses than is available to other serotonin-boosting medications. Clearly, we cannot really say that buspirone blocks serotonin activity in the same way that antipsychotics block dopamine activity. 

Figure 7. A serotonergic synapse including a depiction of the acute tryptophan depletion method discussed in the text. All large neutral amino acids (SLNAAs) share a common blood-brain barrier transporter. The serotonergic precursor, tryptophan, essentially competes with the other LNAAs for transport. Thus tryptophan is uniquely susceptible to acute dietary manipulation. Numerous serotonergic receptor types exist, including presynaptic S-HTm and (somatodendritic) 5-HTia autoreceptors and postsynaptic 5-HTia, 5-HTid, 5-HT2a 5-HT2c 5-HT3 and 5-HT4 receptors. Additional modulation of serotonin activity can occur via the action of selective serotonin re-uptake inhibitors (SSRls) including fluoxetine, fluvoxamine, and citalopram.

There is as yet little evidence of specific association between abnormal serotonin activity and any of the key cognitive features of autism. More circumscribed study of particular cognitive functions of autism may yet yield new insights. Perhaps most promisingly, the findings of associations between serotonin functioning and obsessional behaviour indicate the need for further investigation. 

Inoue T, Koyama T, Yamashita I (1993) Effect of conditioned fear stress on serotonin metabolism in the rat brain. Pharmacol Biochem Behav 44 371-374 Inoue T, Tsuchiya K, Koyama T (1994) Regional changes in dopamine and serotonin activation with various intensity of physical and psychological stress in the rat brain. Pharmacol Biochem Behav 49 911-920... 

Use with caution in oider patients with Narrow-angle glaucoma, overflow incontinence, orthostatic hypotension, taking drugs that increase serotonin activity. 

Kaye, W.H., Greeno, C.G., Moss, H., Fernstrom, J., Fernstrom, M., Lilenfeld, L.R., Weltzin, T.E., and Mann, J. (1998) Alterations in serotonin activity and psychiatric symptomatology after recovery from bulimia nervosa. Arch Gen Psychiatry 55 927— 935. 

Kaye, W.H., Gwlrtsman, H.E., George, D.T., and Ebert, M.H. (1991) Altered serotonin activity in anorexia nervosa after long-term weight restoration does elevated cerebrospinal fluid 5-hydroxyindoleacetlc acid level correlate with rigid and obsessive behavior Arch Gen Psychiatry 48 556-562. 

Porsolt RD, Bertin A, Blavet N Immobility induced by swimming in rats effects of agents which modify central catecholamine and serotonin activity. Eur J Pharmacol 57 201-220, 1979... 

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