Indoleamines:  The Role of Serotonin in Clinical Disorders

George R. Heninger

Since 1948 when serotonin, 5-hydroxytryptamine, (5-HT) was first isolated, identified, and synthesized, there has been an exponential growth in the information available on its biochemical, physiologic, and behavioral effects.  The body of information on 5H-T is now so large that a 4 year medline search covering 1995-1998 will identify over 10,000 articles on 5H-T, and over 1/2 of these are related to 5-HT based treatments.  5-HT is now known to modulate numerous physiologic and behavioral systems which explains the many 5-HT based drugs used as treatments in very different clinical conditions.   Even though alterations in 5-HT system function are observed in many of these clinical conditions, definitive evidence of a "serotonin disease" (aside from carcinoid tumors) that demonstrates clear abnormalities at the genetic, anatomic, and biochemical levels, remains to be demonstrated.  Thus, at the present time, even though there is extensive therapeutics directed at increasing or decreasing 5-HT function at selected sites, considerable additional research will be necessary to clarify the causative pathogenic role of the many 5-HT dependent mechanisms involved in the widely different clinical conditions where 5-HT based treatments are used. (See also Signal Transduction Pathways for Catecholamine Receptors, Norepinephrine and Serotonin Transporters: Molecular Targets of Antidepressant Drugs and Selective Serotonin Reuptake Inhibitors in the Acute Treatment of Depression this volume).

Historically, initial research focused on defining the pathways for synthesis and degradation of 5-HT and the discovery of drugs interacting with these processes.  One of the first clinical applications of this new understanding was the use of the 5-HT synthesis inhibitor, parachorophenylalanine (PCPA) as a treatment to reduce the excessive 5-HT secretion from carcinoid tumors (78).  The development of monoamine oxidase inhibitors and their effectiveness in the treatment of depression provided the initial evidence of the importance of 5-HT in these disorders, and the psychometimetic effects of lysergic acid diethylmide (LSD) pointed to the involvement of 5-HT in psychosis and schizophrenia (78).  Early studies attempting to demonstrate the efficacy of 5-HT precursors as treatments provided some additional evidence of 5-HT involvement in affective disorders and in the control of myoclonus (798,86).  In more recent times, the development and widespread clinical use of selective 5-HT reuptake inhibitors (SSRI), and the preclinical delineation of the multiple 5-HT receptor subtypes and their coupling to intracellular messenger systems and the development of drugs selectively acting on these systems, have catalyzed an explosion of new research information in this field.  At present there is a great deal of new information on the molecular biology, physiology and pharmacology of the 5-HT receptor subtypes, (see preceding chapters).  The role of the 5-HT system in the normal regulation of physiologic and behavioral processes is increasingly better understood.  It is now clear that the 5-HT systems are extremely diverse, and that they are involved in a multitude of physiologic and behavorial processes. 

The information reviewed in the six preceding chapters covering the molecular, biochemical, anatomical, physiological, pharmacologic and behavioral dimensions of the 5-HT system clearly documents the diversity of this predominantly modulatory system.  Table 1 lists a number of the clinically relevant areas where the involvement of the 5-HT system has been demonstrated (48).  Because of the difficulties of precisely specifying the function of such a diverse modulatory system in humans, it has not been possible to definitively prove that there is a primary abnormality in 5-HT function in any of these clinically related areas.  Certainly many alterations in 5-HT function have been demonstrated, but because of the complicated inter-dependency of the 5-HT system with other neurotransmitter and biochemical systems, these changes may easily be secondary to more primary abnormalities in other systems.  In many instances, active treatments that alter 5-HT function are known to produce beneficial therapeutic effects even though abnormalities in the 5-HT system have not been clearly demonstrated for that clinical condition (e.g., diabetic neuropathy) (52).   

A schematical drawing delineating several of the steps involved in 5-HT neurotransmission is illustrated in figure 1.  It can be seen that there are a large number of cellular processes involved in 5-HT metabolism which could be altered in clinical conditions or altered by pharmacologic treatment.  Over the history of research in the field, initial understanding was obtained regarding the overall 5-HT metabolic pathways such as synthesis and degradation and reuptake inhibition.  Only more recently have the details of 5-HT receptor pharmacology, receptor effector coupling, and short and long term effects of 5-HT receptor stimulation on intracelluar processes begun to be understood.  In addition to the biochemical diversity of the different 5-HT cellular systems, the numerous 5-HT receptor subtypes, the anatomic location of the different receptors (e.g. pre vs. postsynaptic, etc.), the different neural circuits involved and the interaction with other neurotransmitter systems, all add additional layers of complexity.  At present, even though a great deal is known regarding postsynaptic cellular mechanisms, their investigation at the clinical level is very difficult and their elucidation in a variety of clinical states and the effect of modification of 5-HT neurotransmission on them are only now beginning to be understood (60).

The major evidence for 5-HT alterations in clinical disease states derives from the symptomatic change following treatments that alter the 5-HT system.  The manipulation of 5-HT precursors and the use of 5-HT receptor agonists and antagonists has provided some evidence that 5-HT function may be altered in some clinical conditions.  However, the direct assessment of the anatomic integrity of the 5-HT systems and 5-HT synthesis and turnover in different brain areas has been difficult to achieve. 

Diversity of 5-HT Involvement at the Clinical Level:

As indicated in Table 1, 5-HT plays an important modulatory role in many important behavioral and physiologic systems.

The diverse and complex nature of 5-HT involvement in different clinical conditions can be illustrated with 5 clinical examples where the variability in the clinical response to 5-HT based treatments across widely different clinical conditions reflects the complexity of the underlying 5-HT systems.

They include:

1.  Treatment response to SSRI's across diverse clinical conditions.
2.  Behavioral effects of 5-HT specific neurotoxins.
3.  Differential sensitivity of diagnostic groups and treatments to 5-HT precursor levels.
4.  Influence of 5-HT receptor subtype and location.
5.  Interactions with other neurotransmitter systems.

The more specific details on the biochemical abnormalities, the response to 5-HT agonist or antagonist challenge, and the details of response to 5-HT based treatments can be found in subsequent chapters dealing with the specific clinical conditions such as depression, schizophrenia, eating disorders, etc.

1.  There is a wide spectrum of symptomatic response to SSRI treatments in different disorders.

The increased availability of a number of SSRI's for clinical use has led to treatment trials in a wide variety of different clinical conditions.  Even though the availability of new drug treatments often stimulate overly optimistic published case reports of beneficial treatment response, in the case of SSRI's, a number of randomized placebo controlled studies have been conducted in several disorders other than depression, the primary indication for SSRI treatment.  Placebo controlled studies have demonstrated positive results of SSRI treatment in:  OCD, panic disorder, premenstrual syndrome, bulimia nervousa, autistic disorder, diabetic neuropathy, and diabetic obesity (see Introduction to Clinical Neuropsychopharmacology, Selective Serotonin Reputake Inhibitors in the Acute Treatment of Depression, Novel Pharmacological Approachews to the Treatment of Depression, The Neurobiology of Treatment-Resistant Mood Disorders, Physiological Indicators of the Schizophrenia Phenotype, and Parkinson's Disease this volume.  The nature and magnitude of the symptomatic responses reported in several other clinical conditions suggests that they will eventually be found to be reliable also.  Table 2 lists the wide spectrum of different clinical conditions that have been reported to demonstrate a beneficial symptomatic response following SSRI treatment.  It can be seen that even though a common factor such as anxiety may underlie some disorders (e.g panic disorder, social phobia, and post-traumatic stress disorder) or a repetitive behavior in others (e.g. OCD, trichotillomania, and onychlphagia), it is not possible to reduce the divergence of the clinical effects of SSRI treatment to any simple holistic scheme.  Instead, the diversity of treatment responses to SSRI's suggests that the overall 5H-T system is more like a chameleon, - i.e. in each instance 5-HT based treatments effect different symptom dimensions depending on the disease background. 

The wide diversity of effects following SSRI treatment would be consistent with the complexity of the 5-HT system.  This includes:   the multiple 5-HT receptor subtypes, the different cellular groups containing 5-HT that project widely throughout the CNS, the relative abundance of nonjunctional vericosities containing secretory vesicles, the complex micro circuits involving different 5-HT receptors on pre- and post-synaptic elements and the predominantly modulatory nature of the 5-HT systems relative to other neurotransmitter systems.  This relative lack of specificity has major implications for the evaluation of new 5-HT based treatments.  On the positive side, the widespread involvement of 5-HT in many physiologic systems offers many opportunities for the development of new treatments.  However, because of the complexity, it will not be possible to predict the clinical conditions and the quality of response to the new treatments with reasonable consistency.

The degree of clinical improvement may be limited in many instances, and 5-HT based treatments may work best when combined with other treatments due to the predominantly modulatory nature of the 5-HT systems.  An example of this is the synergistic benefits of 5-HT and NE reuptake inhibition in the treatment of depression (59).  An area of considerable promise involves the development of more specific 5-HT receptor agonists and antagonists and this will allow more targeted and effective therapies as exemplified by the use of sumatriptin in migraine (7).

2.  Behavioral Effects of 5-HT specific neurotoxins - Consequences of MDMA (Ecstasy - 3,4 methylenedioxymethamphetamine) use.

An additional area where understanding the properties of the 5-HT systems might help clarify 5-HT effects at the clinical level, involves the dual 5-HT projections to the forebrain and their differential sensitivity to neurotoxic amphetamine derivatives.  The cerebral cortex in many mammals is innervated by two morphologically distinct classes of 5-HT axon terminals.  Fine axons with small varicosities arise from the dorsal raphe nuclei and beaded axons with large spherical varicosities arise from the median raphe nuclei.  These two types of axons have different regional and laminar distributions and are differentially sensitive to neurotoxic effects of certain amphetamine derivatives, which include 3,4 methylenedioxymethamphetamine (Ecstasy) (MDMA).  The fine axons are much more sensitive to neurotaxic effects than the beaded axons, and the loss of fine axons lasts for months while the beaded axons remain unaffected following neurotoxic drug treatment (50).

Individuals using MDMA utilize doses approaching those shown to be neurotoxic in non human primates. Indeed a 26% decrease in cerebrospinal fluid, 5-hydroxy indoleacetic acid (5-HIAA) was found in MDMA users (74), providing evidence of lowered 5-HT turnover - presumably in the fine axon system.  This has been independently supported by the finding of an approximately 30% decrease in 5-HT transporter binding in MDMA users compared to controls as measured by PET (54).  The behavioral effect of the presumed neurotoxic 5-HT lesions has been more difficult to assess because of the difficulty in controlling for other drug use and subject selection bias.  However, it is of interest that MDMA users have been found to be more impulsive and have more memory problems than controls (24, 42, 56, 68).  MDMA users were also found to have incurred increased depressive symptoms 5 days after use (16).  When subjects retrospectively compared their MDMA experience after taking fluoxetine, which is known to block the neurotoxic effects of MDMA to their experience before taking fluoxetine, the euphoric and positive interpersonal effects of MDMA were reported to be unchanged (53).  Although this might suggest a differential role for the fine and beaded axon systems in explaining the effects of MDMA and the role of 5-HT in reward systems, additional data will clearly be needed to clarify this interesting question.  It is of considerable importance that even tough MDMA users have a 20-30% reduction in 5-HT function, they do not have a clear increased incidence of syndromes like major depression - a condition where 5-HT abnormalities have been demonstrated and where 5-HT based treatments (SSRI) are therapeutic.  The diversity of clinical finding following MDMA use again illustrates the multi faceted aspects of the 5-HT system at the clinical level.

3.  Differential sensitivity of clinical syndromes and the effect of treatment status on symptom expression during rapid 5-HT depletion.

One of the more compelling lines of evidence for the involvement of 5-HT in affective disorders was reported in the mid-1970's when Shopsin and colleagues administered the tryptophan hydroxylase inhibitor, parachloraphenalanine (PCPA) to patients who, while being treated with imipramine or tranylcypromine, had recently recovered from depression (76).  In two patients who recovered following imipramine treatment and four patients who recovered following tranylcypromine treatment, there was a rapid and very robust return of depressive symptoms within one to four days after starting the PCPA.  All patients recovered from the increase in symptoms 2-7 days after the PCPA was stopped. 

Another method for producing a short-term alteration in 5-HT synthesis has been utilized by Young and colleagues (91).  Since synthesis of 5-HT is dependent on brain levels of tryptophan and depletion of plasma tryptophan results in reduction in brain tryptophan, a method was developed to reduce plasma tryptophan levels and consequently produce a reduction in brain 5-HT turnover.  The ingestion of a high amino acid load stimulates protein synthesis.  Following the ingestion of a high amino acid load that does not include tryptophan, there is a marked drop in plasma free and total tryptophan levels.  The lowered tryptophan levels in conjunction with the higher neutral amino acid levels which compete with tryptophan for uptake into brain has been shown to lower brain tryptophan, serotonin and 5-HIAA in non human primates (90).

When this procedure is used in healthy subjects, small but significant increases in self ratings of depression are produced, but the magnitude of the changes do not approach those seen in clinical depression.  This method has been utilized by Delgado and colleagues to extend the prior studies on the role of 5-HT in depression (18).  The method was modified by utilizing a low tryptophan diet preceding the ingestion of the large amino acid load without tryptophan.  A control test was accomplished utilizing a large amino acid load with tryptophan present.  Utilizing this methodology there is approximately a mean drop of 80% in free or total plasma tryptophan levels 5 hours following the amino acid ingestion.  When this method has been applied to the study of previously depressed patients who had recently recovered on a variety of antidepressant treatments, it was found that 60% of them had a symptomatic relapse equal to or greater than a 50% increase in their Hamilton Depression Rating Scale Scores at 5 or 7 hours following the amino acid drink (18).  In contrast, when this same procedure was utilized in highly symptomatic depressed patients not on medication, there was no consistent increase in depressive symptoms following the amino acid drink (21).  These results are illustrated in Figure 2 where it can be seen that the patients recently improved on antidepressant treatment had a mean increase of almost 12 points in the Hamilton Ratings Scale.  In contrast, the much more symptomatic patients who were off medication only had a mean change of 3 points which was not statistically significant.  Thus, the consistency of the results across the PCPA study and the tryptophan depletion study indicate that short term maintenance of the clinical response to antidepressants is dependent on adequate 5-HT function.  However, the lack of effect of the tryptophan depletion in symptomatic drug-free patients remains unexplained.  It is of interest also that PCPA does not produce depression in patients who are treated for carcinoid tumors (78). 

The initial tryptophan depletion study suggested that patients on SSRI's and monoamine oxidase inhibitors were more vulnerable to the tryptophan depletion effects (18,22).  However, patients had not been randomly assigned to the treatments and this could have confounded the differences between treatments.  In order to more objectively evaluate this possibility a subsequent a study was conducted where patients were randomly assigned to the SSRI  fluoxetine or to the selective NE uptake inhibitor desipramine (20).  In the left side of Figure 3, the interaction of drug treatment with the tryptophan depletion effect is illustrated and it can be seen that recently recovered patients on fluoxetine are significantly more vulnerable to relapse than similar recently recovered patients on desipramine.  In order to assess the specificity of this effect relative to 5-HT depletion versus catecholamine depletion, a second study was conducted utilizing alpha methylparatyrosine to deplete catecholamine levels (19).  The right half of Figure 3 illustrates the findings from this study.  It can be seen that all 5 recently recovered patients receiving the selective catecholamine uptake inhibitors desipramine or mazindol had a relapse but that only one of 12 recently recovered patients receiving a SSRI did.  Thus, not only do these data indicate that maintaining an antidepressant response is dependent on adequate 5-HT function, there is also specificity as to the drug treatment utilized, since patients recovering on SSRI's are more vulnerable to tryptophan depletion than patients on desipramine.  This finding in conjunction with the specificity of the catecholamine depletion to produce relapse predominantly in patients treated with catecholamine uptake inhibiting drugs points to a specific role for the 5-HT system in effecting the antidepressant response to 5-HT based treatments in depression. 

Subsequent to these initial studies many other studies have been conducted utilizing the method to deplete tryptophan in a number of other clinical situations (73), some of these are listed in Table 3.  Healthy subjects do not have major depressive symptoms following tryptophan depletion and healthy subjects given the tryptophan depletion during catecholamine depletion also show no increase in depression.  Since symptomatic patients with major depression were not vulnerable to tryptophan depletion but recovered patients on SSRI treatment were, healthy subjects were treated with an SSRI for 3 weeks to see if this made them vulnerable.  The healthy subjects treated with SSRI's did not show an increased symptomatic response following tryptophan depletion.

The question arises as to the specificity of the symptomatic relapse following SSRI treatment since only patients responding to SSRI treatment were vulnerable.  It can be seen in Table 3 that patients with major depression who have responded to sleep deprivation also do not show a relapse with tryptophan depletion.  (It is  of interest in this study, that tryptophan depletion prevented the symptomatic relapse usually seen after the make-up night of sleep (64)   Patients treated with ECT also do not show a symptom relapse with tryptophan depletion.  Thus, the lack of tryptophan depletion induced relapse following recovery with CRI, sleep deprivation and ECT suggests that these 3 treatments are different systems than those utilized by SSRI's.

A major question is whether the tryptophan depletion method could be used as a marker for vulnerability.  Patients who had a prior depressive episode but who were currently medication free had a significant return of symptoms following the tryptophan depletion (81).  This was not found in another study, however (47).

 Patients with seasonal affective disorder who were symptomatic at the time of tryptophan depletion similar to the symptomatic patients for major depression disorder do not a show a symptom increase with tryptophan depletion.   However, patients with seasonal affective disorder remitted with light therapy or who had had winter depression but remitted in the summer do show a vulnerability to symptom return following tryptophan depletion.  The findings in seasonal affective disorder and major depression are similar in that the symptomatic patients off medications do not have a worsening but that treatment with an SSRI or light therapy or eventual long term recovery off drugs somehow confers vulnerability to the depletion.

There is some evidence that lithium may augment serotonergic function and it was of interest of whether tryptophan depletion would lead to symptom worsening in bipolar patients who were remitted on lithium treatment.  The studies that have evaluated this question have not found a return of symptoms within the first 24 hrs. (10,11 although one study did report a small increase in manic type symptoms in some patients 72 hrs. following the tryptophan depletion at a time that tryptophan levels were back to normal (10). 

Tryptophan depletion has been administered in many other diagnostic groups and situations.  Two of these include bulimia nervosa and OCD, both of which have been shown to be responsive to SSRI treatment (2,31).  Both symptomatic drug-free bulimic patients and recovered medication free bulimic patients have changes following tryptophan depletion that are indicative of a worsening of their clinical symptomatology.  The worsening of drug free symptomatic patients, bulimic patients, is different than the lack of symptom increase in patients with major depression or seasonal affective disorder when they are off treatment, but the exacerbation when medication free is similar to that seen in depressive disorder and seasonal affective disorder.  In contrast to bulimia nervosa, patients with symptomatic OCD or OCD improved on SSRI's do not show a return of OCD type symptoms with tryptophan depletion.  In one study where OCD patients were improved on SSRI treatment, even though the OCD symptoms did not increase, there was an increase in depressive symptoms following the tryptophan depletion (4).  This is illustrated in figure 4. 

The main finding illustrated in Table 3 is the heterogeneity of the clinical response following tryptophan depletion depending on the diagnostic subgroup and the type of treatment and drug free recovered state.  Thus, even though major depression, seasonal affective disorder, bulimia nervosa and OCD are all SSRI responsive, these four clinical conditions do not shown the same vulnerability to symptom exacerbation when symptomatic and medication free, they also do not shown the same symptomatic exacerbation when recovered and on SSRI treatment or when recovered off all medication.  This is clear clinical evidence of strong heterogeneity in the role of the 5-HT system in these syndromes. Any concept of a unitary 5-HT system cannot account for the heterogeneity in this type of data. 

Taken together, these data indicate considerable differential specificity for aspects of the 5-HT system involved in SSRI induced recovery from depression, seasonal affective disorder, bulimia, and OCD.  The lack of depressive symptom relapse in SSRI treated patients during catecholamine depletion in contrast to the extreme sensitivity of NE uptake inhibitor treatments, indicates that there is significant specificity of the type of treatment and the monoamine system affected.  More importantly within the 5-HT system it appears that maintenance of SSRI induced recovery for depressive symptoms is dependent on immediate availability of 5-HT but this is not the case for SSRI induced recovery from OCD symptoms.  Clearly more complex different and specific 5-HT mechanisms are involved in SSRI treatment of depression and OCD than just a simple model where deficient 5-HT function is augmented equally by SSRI treatment in both conditions.

4.  Serotonin effects on the vascular wall depend on the 5-HT receptor subtype and location.  

Serotonin ("serum tonic factor") was initially discovered through its vasoconstrictor actions (78).  It has since been shown that 5-HT possess both vasoconstrictor and vasodilator properties. In table 4, some of the mechanisms involved in the vasconstrictor and vasodilator  actions of 5-HT are listed.  The vasodilator properties of 5-HT are often unmasked following the use of 5-HT2 antagonists and the net effect of 5-HT on the blood vessel wall can depend on 1) location of vessel studied, 2) the degree of activation of the vascular smooth muscle, 3) the integrity of the endothelium and, 4) many other modulating factors such as local temperature, oxygen tension, blood pressure, etc. (87). 

Exactly how these factors modify the complex array of the different types and diversity of 5-HT receptors on the vascular smooth muscle cells, the endothelial cells, and the adrenergic nerves is not precisely known.  It is clear, however, that the known mechanisms are sufficient to account for the apparent discrepancies in 5-HT effects such as the observation that excess 5-HT is released only in painful areas during cluster headache attacks (3), while the 5-HT agonist, sumatriptin, is at the same time an effective treatment for cluster headaches (7,57,84).

Sumatriptin is active at the "5-HT1 like" receptor sites and it binds with high affinity to those receptor sites that most closely resemble the 5HT1D receptor.  It also binds with lower affinity to 5-HT-1a and 5-HT1B recognition sites.  Sumatriptin does not significantly cross the blood brain barrier.  It produces vascular smooth muscle constriction within intracranial vessels and some extra cranial ones also.  It also reduces neurogenic inflammation thought to be important in the pathogenesis of migraine and, it has effects on the trigeminovascular nerves that transmit nociceptive information from the meninges, and it may be involved in blocking the effects of more central events on trigeminal nerve function (7,57,84).

Figure 5 illustrates the robust positive results from 4 studies of sumatriplin in headache (7).  Its equal efficacy in cluster headache and migraine is illustrated and the superiority of the subcutaneous administration over oral administration can also be seen.  The 70% improvement rate following subcutaneous administration when the placebo response is 20% demonstrates a net 50% improvement.  Thus, it is one of the most specific and efficacious of the available 5-HT based treatments.

The specificity and efficacy of sumatriptin in the treatment of headache emphasizes the importance of the receptor location and the receptor subtype effected by the 5-HT based treatments.  Even though sumatriptin may be acting on several mechanisms at once (i.e. vascular smooth muscle contraction, reducing neurogenic inflammation, and reducing trigeminovascular nociceptine information), it is still one of the best examples of the importance of directing 5-HT based treatments to specific locations and 5-HT subtypes.  The strong positive clinical utility of sumatriptin in the treatment of headache illustrates how the development of drugs acting on specific 5-HT receptors can not only provide important new clinical treatments but that by  understanding the drug mechanism of action, we can also add considerably to our understanding of the role of the 5-HT systems in general.

5.  The role of 5-HT interactions with other neurotransmitter systems:  Ondansetron in the treatment of nausea and emesis. 

The preclinical data on 5-HT indicate that the 5-HT systems are predominately modulatory and that most 5-HT effects interact with the ongoing status of the other involved neurotransmitter systems.  At the clinical level, it is difficult if not impossible to ascribe an effect to a single mechanism because of these interactions.  As a consequence of this highly interdependent interaction with other systems,  the clinical effects of 5-HT treatments usually only result in partial symptomatic improvement.  This contrasts with some other clinical conditions where the clinical biochemical abnormality is primarily a deficiency of a single molecule that can be replaced.  In these instances,  a nearly complete symptomatic remission is seen (e.g. vitamin deficiencies, diabetes, hypothyroidism, etc.).

One of the systems involving 5-HT where some of the neurotransmitters and receptors are better understood involves the systems regulating the control of nausea and emesis (83).  Table 5 lists four of the neurotransmitter systems where agonists produce nausea and emesis and antagonists prevent it.  This system is one of the better examples of the interaction of 5-HT with other systems even though the neural circuits involved are complex in that the same receptors  may be located at different points in the circuit and the interrelationships between the circuits of the neurotransmitter systems are not precisely known (83).  Ondansetron is a 5-HT₃ receptor antagonist that appears to act on the 5-HT3 receptors located in the area posterior and in the gastrointestinal tract (37,40,83).  Ondansetron by itself has a moderate efficacy in reducing nausea and emesis (left half of figure 6.)  However, when a D₂ receptor blocking drug metopimazine is added to the treatment, significant improvement in efficacy is observed (right half of Figure 6).  This illustrates an additive effect of other treatments with 5-HT drug action that is also seen in many other clinical situations.  It is important to note that in the same type of patients and with the same type of chemotherapy where ondansetron and metopimazine were additive, ondansetron alone was less effective than a combination of dexamethasone and metoclopramide (46).  Thus, in the clinical situation considerable testing will be necessary before optimal combinations and doses can be arrived at.  In those instances where the pathophysiologic role of 5-HT is more direct, specific targeted treatments should be more effective.  It is of interest in this regard that ondansetron produced an "impressive response" in the treatment of symptoms of the carcinoid syndrome (71).

Given the prevailing view that the 5-HT systems are primarily modulatory, it is not surprising that in the clinical situation, most 5-HT based treatments result in only a partial symptomatic improvement and that there are strong interactive effects with other treatments.  The neuroanatomy of the 5-HT system suggest that up to 60% or more of 5-HT released may not be at synapses.  Thus, 5-HT effects would not be expected to be highly anatomically localized or demonstrate the properties associated with systems that more directly mediate neurotransmission.  The modulatory nature of the 5-HT systems can be seen at the clinical level through interactions with other neurotransmitter systems. 

Summary:  Following the discovery of the "serum tonic" factor, 5-HT, in 1948, the exponentially increasing amount of information on the molecular biology, biochemistry, pharmacology, anatomy, physiology and behavior of the 5-HT system have led to a wide array of clinical applications.  Probes of 5-HT turnover in CNS and peripheral tissue have demonstrated alterations in 5-HT metabolism to be associated with a wide number of clinical conditions, and many drugs such as antidepressants, antipsychotics, and anxiolytics have been shown to alter 5-HT function in several disorders.  The development and widespread use of SSRI's has demonstrated that the 5-HT systems are involved is a diverse array of very different clinical conditions .  In contrast, the development of specific 5-HT receptor agonists and antagonists has led to more specific targeted therapeutic interventions such as the use of the 5-HT agonist, sumatriptin, in migraine and cluster headache, and the 5-HT3 antagonist ondansetron in the control of nausea and emesis. 

At present, a simple holistic view of the 5-HT systems role in clinical disorders cannot be advocated.  Rather, a more empirical experimental but optimistic approach would be proposed.  The widespread involvement of the 5-HT systems in modulating the physiologic functions of a large number of different and important biologic systems, coupled with the rapid progress of the molecular biologic approach in discovering new 5-HT receptor subtypes, should foster increased research activity directed at the development of  clinically applicable and specific 5-HT receptor subtype agonists and antagonists.  These can be utilized in neuroimaging of clinical populations to identify specific abnormalities in 5-HT systems.  In addition, these new drugs can then be studied alone and in combination with other treatments in order to clarify the parameters of drug use for the clinical effect.  By comparing and contrasting the optimal clinical effect of a drug to the proven effects of the drug on the specific 5-HT system involved, it will be possible in the future to more clearly specify the role of the specific 5-HT system in the pathogenesis and treatment of the particular clinical disorder.

Acknowledgments:  Supported in Part by USPHS Grant MH25642 and a NARSDA award.

published 2000