ANNUAL REVIEWS
Annu. Rev. Med. 1990. 41:437-46
Further
Quick links to online content
SEROTONIN-SPECIFIC DRUGS FOR ANXIETY AND
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
DEPRESSIVE DISORDERS! D. S. Charney, M.D., J. H. Krystal, M.D.,
P. L. Delgado, M.D., and G. R. Heninger, M.D.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510 KEY
WORDS:
serotonin receptors, drugs, depression.
ABSTRACT
In the last few years there has been a marked increase in knowledge regarding the possible roles of serotonin neuronal dysfunction in the patho physiology and treatment of anxiety and depressive disorders. During the same time period, new drugs with specific actions on serotonin function have become available for clinical testing. This review provides an update on the efficacy of serotonin-specific drugs for anxiety and depressive disorders. INTRODUCTION
There is extensive preclinical and clinical evidence implicating dysfunction of serotonin neurons in the pathophysiology of anxiety and depressive disorders (I, 2). In addition, it has been hypothesized that the mechanism of action of certain antidepressant and antianxiety medications involves effects on serotonin neuronal function (3, 4). During the past few years, progress has been made in the development of several classes of compounds with specific actions on different aspects of serotonin function. This prom-
I
The US Government has the right to retain a nonexclusive, royalty-free license in and to
any copyright covering this paper.
437
438
CHARNEY ET AL
ises to result in improved treatment for a spectrum of anxiety and depres sive disorders. This paper briefly discusses the classification and distribution of sero tonin receptor subtypes and the hypothesized brain sites involved in the therapeutic effects of serotonin-specific antidepressant and antianxiety drugs. The therapeutic properties of these compounds are evaluated, and implications for future drug development are discussed.
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
SEROTONIN RECEPTOR SUBTYPES
There is a convincing body of evidence that several types of serotonin receptors exist in the mammalian brain and that they differ in neuro anatomical distribution and functional properties (Figure 1). These recep tors have been classified into 5-HT b 5-HT 2, and 5-HT 3 receptor subtypes, with the 5-HT I receptor further subdivided into 5-HT1A, 5-HTIB, 5-HT1C, and 5-HTID receptors (5-9).
Nucleus Accumbens
Septal Nuclei
Cerebral Cortex (5-HT1A
(5·HT2)
Globus Pallidus
& 5-HT2)
(5-tIT1C)
Substantia Nigra Amygdala (5-HT1A
&
5-HT2)
(5-HTlC
& 5-HT1 D)
�---L-_
ll_--�::::� :> --
_
Dorsal Raphe Median Raphe (5-HTIA
& 5-HT2)
ypothalamus H (S-HT1Al
ippocampus H (5-HT1A)
Figure 1
jections
Approximate anatomical representation of the main ascending serotonergic pro of the dorsal and median raphe nuclei. Many of the brain regions receiving sero
tonergic innervation have been hypothesized to be involved in the development of anxiety or fear. S-RT receptor subtypes that are present in high densities in each brain region are
indicated in parentheses. Areas containing high S-RTIA densities may be sites of action for 5-RTIA agonists such as buspirone, and regions with dense 5-RT2 localization may be sites
of action for 5-RT2 antagonists such as ritanserin.
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
SEROTONIN-SPECIFIC DRUGS
439
The 5-HT I receptors are linked to adenylate cyclase, except for the 5HT1C receptor, which is coupled to the phosphoinositide hydrolysis second messenger pathway (8, 9). The anatomical distribution of 5-HTI receptor subtypes in human postmortem brain tissue has been studied by quan titative light-microscopic autoradiography (10). 5-HTIA' 5-HTIC, and 5-HTID receptors have been found in the human brain, but sites with phar macological characteristics of 5-HTID binding sites have not been defi nitively identified. High or very high densities of 5-HT1A receptors are located in the hippocampus, raphe nuclei, layers I and II of the cortex, and nuclei of the thalamus and amygdala. Preclinical animal models of anxiety and depression have implicated these brain regions in the patho physiology of human anxiety and depressive disorders and the therapeutic actions of antianxiety and putative antidepressant drugs. Consequently, these brain sites may mediate the antianxiety and antidepressant actions of the recently developed 5-HTIA receptor agonist drugs, such as buspirone (11). High densities of 5-HT1C receptors are present in the choroid plexus, substantia nigra, globus pallidus, and the ventral medial hypothalamus. The recently identified 5-HTIlJ binding site has been found in high con centrations in the caudate, substantia nigra, and frontal cortex. The 5-HT2 receptor is linked to the phosphoinositol system (8). The anatomical distribution of 5-HT2 receptors in the human brain includes very high concentrations localized in layers TIT and V in the frontal, parietal, temporal, and occipital cortex, as well as the corpus mamillare of the hypothalamus. The claustrum, nucleus lateralis of the amygdala, and some cortical layers also have high densities of 5-HT2 receptors. Intermediate concentrations are found in the hippocampus, caudate, putamen, nucleus accumbens, and some nuclei of the amygdala, among other structures (12). It has been suggested that 5-HT2 receptors in the cortex may mediate the antianxiety and antidepressant effects of 5-HT2 receptor antagonists such as ritanserin (13). The 5-HT3 receptor has been extensively characterized in the peripheral nervous system and identified in the rat brain by using radioligand-binding techniques (14). In the rat brain, the highest levels of the receptor are found in the area postrema and limbic system. 5-HT3 receptors may be one of a family of ligand-gated ion channels. However, the existence and distribution of this receptor subtype in the human brain remains to be established (9). There is preclinical evidence that 5-HT3 antagonists may be anxiolytic (15), and confirmatory clinical studies are in progress. There is now substantial evidence that several ligands of different struc tures, including [3H]imipramine, bind with high affinity to a recognition site associated with the 5-HT transporter complex. This recognition site,
440
CHARNEY ET AL
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
which is widely distributed in the brain, mediates the inhibition of the sodium-dependent uptake of S-RT. The available evidence suggests that the binding site is not identical to the transporter recognition site for 5RT, but, rather, that an allosteric coupling exists between the two sites. Consequently, the [3H]imipramine recognition site may represent a novel type of presynaptic receptor whose function is to modulate 5-HT uptake, and it may play a role in the antidepressant and antipanic mechanisms of action of specific and potent 5-HT reuptake inhibitors such as fluoxetine and fluvoxamine (16). SEROTONIN-SPECIFIC DRUGS FOR ANXIETY AND DEPRESSIVE DISORDERS 5-HT1A Receptor Agonists
The development of the 5-HT1A receptor agonists as anxiolytics represents a new generation of nonbenzodiazepine anxiolytics. Buspirone (marketed as Buspar@), which is a prototypical drug of this class of compounds, has been established as an effective agent for generalized anxiety disorder (GAD) (17). In controlled comparison studies, buspirone and benzodiazepine drugs (e.g. diazepam) are equally effective. However, whereas benzodiazepines are effective after a single dose, buspirone requires several weeks of admin istration before clinical effects are apparent. The side-effect profile of buspirone has several advantages over that of benzodiazepines because it does not produce sedation, ataxia, or amnesia and is not associated with withdrawal reactions following abrupt discontinuation (11, 18). There is emerging evidence that other drugs of this class that are not yet generally available, such as gepirone, ipsapirone, and tandospirone, are similarly effective in the treatment of GAD (19). In contrast to its efficacy against GAD, buspirone appears to be ineffective in agoraphobic and panic disorder patients (20). It has not been systematically evaluated in patients with other anxiety disorders such as obsessive-compulsive disorder (OCD) or post-traumatic stress disorder (17). Such investigations are warranted because of the high prevalence of and morbidity associated with these disorders (21). There is preliminary evidence suggesting that 5-HTIA receptor agonists have intrinsic antidepressant properties. Controlled investigations of out patients with major depression have shown that buspirone and gepirone are superior to placebo (22). It remains to be established whether these drugs are effective for severe melancholic or psychotic depressions, which usually require inpatient treatment. The therapeutic mechanism responsible for the antianxiety and anti-
SEROTONIN-SPECIFIC DRUGS
441
depressant properties of the 5-HT lA receptor agonist drugs is currently an active area of investigation. In the short term, these drugs decrease the firing of the serotonergic cells of the dorsal raphe nucleus and reduce serotonin metabolism in the brain (23). However, determination of the long-term effects of these drugs is more important because therapeutic action occurs only with repeated administration. Similar to 5-HT reuptake inhibition and monoamine oxidase inhibitor drugs, the 5-HTIA agonists desensitize the 5-HT1A autoreceptor and down-regulate 5-HT2 receptors following chronic administration (24-26). Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
5-HT2 Receptor Antagonists
The ability of a variety of antidepressant treatments to down-regulate 5HT2 receptors has sparked an interest in the antidepressant and antianxiety properties of compounds that directly antagonize this receptor (3). Several 5-HT2 receptor antagonists are in clinical development; ritanserin is the most extensively studied of these drugs. In several double-blind active drug and placebo-controlled comparison trials, ritanscrin was effective in GAD patients (13). A recent investigation found it to be ineffective in panic disorder patients (27). There are preliminary reports that it may be effective in patients with depressive syndromes (13). 5-HT3 Antagonists
Ongoing clinical studies are identifying antianxiety properties for selective 5-HT 3 receptor antagonists (data on file, Glaxo, Inc.). This has led to increased research efforts to identify the functional properties of this recep ' tor (29). If these early clinical findings are confirmed and extended, the 5HT3 receptor antagonists may represent a new class of compounds that are effective in patients with anxiety and depressive disorders. SEROTONIN REUPTAKE INHIBITORS
The tricyclic antidepressants, which have been available since the late 1950s and early 1960s, have the ability to block the reuptake of both norepinephrine and serotonin to various degrees. During the past five years, antidepressant-drug development programs have focused on devel oping potent and selective 5-HT reuptake inhibitors based upon the assumption that these drugs would have increased efficacy in patient groups characterized by marked dysfunction of the serotonin system. Consequently, potent and selective 5-HT reuptake inhibitors, such as fiuoxetine, fiuvoxamine, and sertraline, have been investigated extensively in patients with major depression, panic disorder, and obsessive-com pulsive disorder. To date, only fiuoxetine (marketed as Prozac®) is avail-
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
442
CHARNEY ET AL
able for general use. These drugs appear to be highly effective in the treatment of major depression. However, they have not been shown to be more effective than other available antidepressants, and it has not been possible to identify a specific type of depressive illness preferentially responsive to 5-HT reuptake inhibitors. However, some patients who have not been helped by other antidepressant treatments have shown good therapeutic response to 5-HT reuptake inhibitors (30). The 5-HT reuptake inhibitors have a good side-effect profile. They are generally devoid of troublesome anticholinergic, antihistaminergic, and cardiovascular ad verse reactions. There is accumulating evidence that the 5-HT reuptake inhibitors f1u voxamine and f1uoxetine are effective in the treatment of panic disorder (31). As with major depression, it has not been demonstrated that these agents are superior in efficacy to other antipanic drug treatments, such as imipramine, phenelzine, and alprazolam. Until recently, it was believed that OCD was refractory to drug treat ments. However, the availability of the 5-HT reuptake inhibitors has markedly improved the treatment outcome. In fact, they are more effective than other available drug treatments, including the tricyclic compounds, and have less potent effects than serotonin reuptake inhibitors such as desipramine (32�34). Serotonin reuptake inhibitors are currently the drugs of choice for the treatment of OCD. They have not been evaluated in a controlled fashion for efficacy in other anxiety disorders, such as GAD and posttraumatic stress disorder. The therapeutic mechanism of action of the 5-HT reuptake inhibitors certainly involves alteration in the serotonin system function. However, because the drugs are effective after chronic but not acute administration, it is unlikely that the primary mechanism is antagonism of 5-HT reuptake, because this effect occurs after administration of a single dose. Therefore, preclinical and clinical investigations have focused on identifying the effects of chronic 5-HT reuptake inhibitor administration on serotonin function. These studies reveal a multitude of effects, with the most consistent being an enhancement of serotonin neurotransmission via a progressive desen sitization of the serotonin autoreceptor and a down-regulation of post synaptic 5-HT2 receptors (3, 35). Clinical studies have demonstrated that 5-HT reuptake inhibitors increase serotonin function more than other antidepressant drugs do (36). In addition, a recent investigation has shown that the 5-HT reuptake inhibitor-induced remission from depression is dependent upon the integrity of the serotonin neuronal system. A 90% reduction in plasma tryptophan produced by a tryptophan-free amino acid drink produces a depressive relapse in patients remitted on f1uvoxamine within eight hours (37) (Table I).
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
Table 1
Efficacy of serotonin-specific drugs in treating anxiety and depressive disorders" Major depression
OCD
GAD
Panic disorder
Proposed mechanism Drug class 5-HT1A agonists
Efficacy Replication
++
+
Efficacy
Replication
Efficacy
Replication
o
+
++/+++
+++
Efficacy Replication NT
NT
of action Chronic treatment results in 5-HT1A autoreceptor and 5-
(e.g. buspirone)
HT2 receptor down
regulation 5-HT2 antagonists
+/++
+
0
+
++
+
NT
NT
Decreased 5-HT2
NT
NT
NT
NT
++
+
NT
NT
Decreased 5-HT3
receptor function
(e.g. ritanserin) 5-HT3 antagonists
receptor function
(e.g. odansetron) 5-HT reuptake
+++
+++
++ +
+
NT
NT
++
+++
Enhanced serotonin
inhibitors
neurotransmission
(e.g. fluoxetine,
via 5-HT auto
fiuvoxamine)
receptor subsensi
aEfficacy was rated as follows:
NT, not
tested;
0, ineffective;
�
� f
Annu. Rev. Med. 1990. 41:437-46
Further
Quick links to online content
SEROTONIN-SPECIFIC DRUGS FOR ANXIETY AND
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
DEPRESSIVE DISORDERS! D. S. Charney, M.D., J. H. Krystal, M.D.,
P. L. Delgado, M.D., and G. R. Heninger, M.D.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510 KEY
WORDS:
serotonin receptors, drugs, depression.
ABSTRACT
In the last few years there has been a marked increase in knowledge regarding the possible roles of serotonin neuronal dysfunction in the patho physiology and treatment of anxiety and depressive disorders. During the same time period, new drugs with specific actions on serotonin function have become available for clinical testing. This review provides an update on the efficacy of serotonin-specific drugs for anxiety and depressive disorders. INTRODUCTION
There is extensive preclinical and clinical evidence implicating dysfunction of serotonin neurons in the pathophysiology of anxiety and depressive disorders (I, 2). In addition, it has been hypothesized that the mechanism of action of certain antidepressant and antianxiety medications involves effects on serotonin neuronal function (3, 4). During the past few years, progress has been made in the development of several classes of compounds with specific actions on different aspects of serotonin function. This prom-
I
The US Government has the right to retain a nonexclusive, royalty-free license in and to
any copyright covering this paper.
437
438
CHARNEY ET AL
ises to result in improved treatment for a spectrum of anxiety and depres sive disorders. This paper briefly discusses the classification and distribution of sero tonin receptor subtypes and the hypothesized brain sites involved in the therapeutic effects of serotonin-specific antidepressant and antianxiety drugs. The therapeutic properties of these compounds are evaluated, and implications for future drug development are discussed.
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
SEROTONIN RECEPTOR SUBTYPES
There is a convincing body of evidence that several types of serotonin receptors exist in the mammalian brain and that they differ in neuro anatomical distribution and functional properties (Figure 1). These recep tors have been classified into 5-HT b 5-HT 2, and 5-HT 3 receptor subtypes, with the 5-HT I receptor further subdivided into 5-HT1A, 5-HTIB, 5-HT1C, and 5-HTID receptors (5-9).
Nucleus Accumbens
Septal Nuclei
Cerebral Cortex (5-HT1A
(5·HT2)
Globus Pallidus
& 5-HT2)
(5-tIT1C)
Substantia Nigra Amygdala (5-HT1A
&
5-HT2)
(5-HTlC
& 5-HT1 D)
�---L-_
ll_--�::::� :> --
_
Dorsal Raphe Median Raphe (5-HTIA
& 5-HT2)
ypothalamus H (S-HT1Al
ippocampus H (5-HT1A)
Figure 1
jections
Approximate anatomical representation of the main ascending serotonergic pro of the dorsal and median raphe nuclei. Many of the brain regions receiving sero
tonergic innervation have been hypothesized to be involved in the development of anxiety or fear. S-RT receptor subtypes that are present in high densities in each brain region are
indicated in parentheses. Areas containing high S-RTIA densities may be sites of action for 5-RTIA agonists such as buspirone, and regions with dense 5-RT2 localization may be sites
of action for 5-RT2 antagonists such as ritanserin.
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
SEROTONIN-SPECIFIC DRUGS
439
The 5-HT I receptors are linked to adenylate cyclase, except for the 5HT1C receptor, which is coupled to the phosphoinositide hydrolysis second messenger pathway (8, 9). The anatomical distribution of 5-HTI receptor subtypes in human postmortem brain tissue has been studied by quan titative light-microscopic autoradiography (10). 5-HTIA' 5-HTIC, and 5-HTID receptors have been found in the human brain, but sites with phar macological characteristics of 5-HTID binding sites have not been defi nitively identified. High or very high densities of 5-HT1A receptors are located in the hippocampus, raphe nuclei, layers I and II of the cortex, and nuclei of the thalamus and amygdala. Preclinical animal models of anxiety and depression have implicated these brain regions in the patho physiology of human anxiety and depressive disorders and the therapeutic actions of antianxiety and putative antidepressant drugs. Consequently, these brain sites may mediate the antianxiety and antidepressant actions of the recently developed 5-HTIA receptor agonist drugs, such as buspirone (11). High densities of 5-HT1C receptors are present in the choroid plexus, substantia nigra, globus pallidus, and the ventral medial hypothalamus. The recently identified 5-HTIlJ binding site has been found in high con centrations in the caudate, substantia nigra, and frontal cortex. The 5-HT2 receptor is linked to the phosphoinositol system (8). The anatomical distribution of 5-HT2 receptors in the human brain includes very high concentrations localized in layers TIT and V in the frontal, parietal, temporal, and occipital cortex, as well as the corpus mamillare of the hypothalamus. The claustrum, nucleus lateralis of the amygdala, and some cortical layers also have high densities of 5-HT2 receptors. Intermediate concentrations are found in the hippocampus, caudate, putamen, nucleus accumbens, and some nuclei of the amygdala, among other structures (12). It has been suggested that 5-HT2 receptors in the cortex may mediate the antianxiety and antidepressant effects of 5-HT2 receptor antagonists such as ritanserin (13). The 5-HT3 receptor has been extensively characterized in the peripheral nervous system and identified in the rat brain by using radioligand-binding techniques (14). In the rat brain, the highest levels of the receptor are found in the area postrema and limbic system. 5-HT3 receptors may be one of a family of ligand-gated ion channels. However, the existence and distribution of this receptor subtype in the human brain remains to be established (9). There is preclinical evidence that 5-HT3 antagonists may be anxiolytic (15), and confirmatory clinical studies are in progress. There is now substantial evidence that several ligands of different struc tures, including [3H]imipramine, bind with high affinity to a recognition site associated with the 5-HT transporter complex. This recognition site,
440
CHARNEY ET AL
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
which is widely distributed in the brain, mediates the inhibition of the sodium-dependent uptake of S-RT. The available evidence suggests that the binding site is not identical to the transporter recognition site for 5RT, but, rather, that an allosteric coupling exists between the two sites. Consequently, the [3H]imipramine recognition site may represent a novel type of presynaptic receptor whose function is to modulate 5-HT uptake, and it may play a role in the antidepressant and antipanic mechanisms of action of specific and potent 5-HT reuptake inhibitors such as fluoxetine and fluvoxamine (16). SEROTONIN-SPECIFIC DRUGS FOR ANXIETY AND DEPRESSIVE DISORDERS 5-HT1A Receptor Agonists
The development of the 5-HT1A receptor agonists as anxiolytics represents a new generation of nonbenzodiazepine anxiolytics. Buspirone (marketed as Buspar@), which is a prototypical drug of this class of compounds, has been established as an effective agent for generalized anxiety disorder (GAD) (17). In controlled comparison studies, buspirone and benzodiazepine drugs (e.g. diazepam) are equally effective. However, whereas benzodiazepines are effective after a single dose, buspirone requires several weeks of admin istration before clinical effects are apparent. The side-effect profile of buspirone has several advantages over that of benzodiazepines because it does not produce sedation, ataxia, or amnesia and is not associated with withdrawal reactions following abrupt discontinuation (11, 18). There is emerging evidence that other drugs of this class that are not yet generally available, such as gepirone, ipsapirone, and tandospirone, are similarly effective in the treatment of GAD (19). In contrast to its efficacy against GAD, buspirone appears to be ineffective in agoraphobic and panic disorder patients (20). It has not been systematically evaluated in patients with other anxiety disorders such as obsessive-compulsive disorder (OCD) or post-traumatic stress disorder (17). Such investigations are warranted because of the high prevalence of and morbidity associated with these disorders (21). There is preliminary evidence suggesting that 5-HTIA receptor agonists have intrinsic antidepressant properties. Controlled investigations of out patients with major depression have shown that buspirone and gepirone are superior to placebo (22). It remains to be established whether these drugs are effective for severe melancholic or psychotic depressions, which usually require inpatient treatment. The therapeutic mechanism responsible for the antianxiety and anti-
SEROTONIN-SPECIFIC DRUGS
441
depressant properties of the 5-HT lA receptor agonist drugs is currently an active area of investigation. In the short term, these drugs decrease the firing of the serotonergic cells of the dorsal raphe nucleus and reduce serotonin metabolism in the brain (23). However, determination of the long-term effects of these drugs is more important because therapeutic action occurs only with repeated administration. Similar to 5-HT reuptake inhibition and monoamine oxidase inhibitor drugs, the 5-HTIA agonists desensitize the 5-HT1A autoreceptor and down-regulate 5-HT2 receptors following chronic administration (24-26). Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
5-HT2 Receptor Antagonists
The ability of a variety of antidepressant treatments to down-regulate 5HT2 receptors has sparked an interest in the antidepressant and antianxiety properties of compounds that directly antagonize this receptor (3). Several 5-HT2 receptor antagonists are in clinical development; ritanserin is the most extensively studied of these drugs. In several double-blind active drug and placebo-controlled comparison trials, ritanscrin was effective in GAD patients (13). A recent investigation found it to be ineffective in panic disorder patients (27). There are preliminary reports that it may be effective in patients with depressive syndromes (13). 5-HT3 Antagonists
Ongoing clinical studies are identifying antianxiety properties for selective 5-HT 3 receptor antagonists (data on file, Glaxo, Inc.). This has led to increased research efforts to identify the functional properties of this recep ' tor (29). If these early clinical findings are confirmed and extended, the 5HT3 receptor antagonists may represent a new class of compounds that are effective in patients with anxiety and depressive disorders. SEROTONIN REUPTAKE INHIBITORS
The tricyclic antidepressants, which have been available since the late 1950s and early 1960s, have the ability to block the reuptake of both norepinephrine and serotonin to various degrees. During the past five years, antidepressant-drug development programs have focused on devel oping potent and selective 5-HT reuptake inhibitors based upon the assumption that these drugs would have increased efficacy in patient groups characterized by marked dysfunction of the serotonin system. Consequently, potent and selective 5-HT reuptake inhibitors, such as fiuoxetine, fiuvoxamine, and sertraline, have been investigated extensively in patients with major depression, panic disorder, and obsessive-com pulsive disorder. To date, only fiuoxetine (marketed as Prozac®) is avail-
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
442
CHARNEY ET AL
able for general use. These drugs appear to be highly effective in the treatment of major depression. However, they have not been shown to be more effective than other available antidepressants, and it has not been possible to identify a specific type of depressive illness preferentially responsive to 5-HT reuptake inhibitors. However, some patients who have not been helped by other antidepressant treatments have shown good therapeutic response to 5-HT reuptake inhibitors (30). The 5-HT reuptake inhibitors have a good side-effect profile. They are generally devoid of troublesome anticholinergic, antihistaminergic, and cardiovascular ad verse reactions. There is accumulating evidence that the 5-HT reuptake inhibitors f1u voxamine and f1uoxetine are effective in the treatment of panic disorder (31). As with major depression, it has not been demonstrated that these agents are superior in efficacy to other antipanic drug treatments, such as imipramine, phenelzine, and alprazolam. Until recently, it was believed that OCD was refractory to drug treat ments. However, the availability of the 5-HT reuptake inhibitors has markedly improved the treatment outcome. In fact, they are more effective than other available drug treatments, including the tricyclic compounds, and have less potent effects than serotonin reuptake inhibitors such as desipramine (32�34). Serotonin reuptake inhibitors are currently the drugs of choice for the treatment of OCD. They have not been evaluated in a controlled fashion for efficacy in other anxiety disorders, such as GAD and posttraumatic stress disorder. The therapeutic mechanism of action of the 5-HT reuptake inhibitors certainly involves alteration in the serotonin system function. However, because the drugs are effective after chronic but not acute administration, it is unlikely that the primary mechanism is antagonism of 5-HT reuptake, because this effect occurs after administration of a single dose. Therefore, preclinical and clinical investigations have focused on identifying the effects of chronic 5-HT reuptake inhibitor administration on serotonin function. These studies reveal a multitude of effects, with the most consistent being an enhancement of serotonin neurotransmission via a progressive desen sitization of the serotonin autoreceptor and a down-regulation of post synaptic 5-HT2 receptors (3, 35). Clinical studies have demonstrated that 5-HT reuptake inhibitors increase serotonin function more than other antidepressant drugs do (36). In addition, a recent investigation has shown that the 5-HT reuptake inhibitor-induced remission from depression is dependent upon the integrity of the serotonin neuronal system. A 90% reduction in plasma tryptophan produced by a tryptophan-free amino acid drink produces a depressive relapse in patients remitted on f1uvoxamine within eight hours (37) (Table I).
Annu. Rev. Med. 1990.41:437-446. Downloaded from www.annualreviews.org Access provided by University of Aberdeen on 02/15/15. For personal use only.
Table 1
Efficacy of serotonin-specific drugs in treating anxiety and depressive disorders" Major depression
OCD
GAD
Panic disorder
Proposed mechanism Drug class 5-HT1A agonists
Efficacy Replication
++
+
Efficacy
Replication
Efficacy
Replication
o
+
++/+++
+++
Efficacy Replication NT
NT
of action Chronic treatment results in 5-HT1A autoreceptor and 5-
(e.g. buspirone)
HT2 receptor down
regulation 5-HT2 antagonists
+/++
+
0
+
++
+
NT
NT
Decreased 5-HT2
NT
NT
NT
NT
++
+
NT
NT
Decreased 5-HT3
receptor function
(e.g. ritanserin) 5-HT3 antagonists
receptor function
(e.g. odansetron) 5-HT reuptake
+++
+++
++ +
+
NT
NT
++
+++
Enhanced serotonin
inhibitors
neurotransmission
(e.g. fluoxetine,
via 5-HT auto
fiuvoxamine)
receptor subsensi
aEfficacy was rated as follows:
NT, not
tested;
0, ineffective;
�
� f
