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LEADING ARTICLE
Drugs 41 (I): 11-18. 1991 0012-6667/9 1/0001-00 II /$04.00/0 © Adis International Limited. All rights reserved.
DRU1417
5-HT 1 A Partial Agonists What is Their Future?
Debra A. Glitz and Robert Pohl Wayne State University, Detroit, Michigan, USA
Drugs that act selectively on the serotonergic system (e.g. fluvoxamine) are effective in a variety of psychiatric disorders including depression, panic disorder and obsessive compulsive disorder (OCD) [Den Boer et al. 1987; Goodman et al. 1989; Schatzberg et al. 1987]. Recently, multiple subtypes of serotonin (5-hydroxytryptamine, 5-HT) receptors have been identified, along~ith agents that act relatively selectively at the vai'iou's 5-HT receptor subtypes. Increasingly, selectiv~ and specific psychotropic agents are of clinical! :ht~rest because they generally have fewer side erte~fs . Such agents may help determine whether theh{ is any diagnostic specificity for abnormalities ih~olving 5-HT receptor subtypes.
At present, 31l1ain classes of 5-HT r~Wle'~I~or subtypes ha.ve. been identified: 5-HTI, 5-~~21 ! and 5-HT3. WithIn the 5-HTI class of recept~rs, jat least 4 different receptor subtypes have beel1l jlddntified:
i l li I' : ; !
5-HTIA, 5-HTIB, 5-HTlc and 5-HTrdli(peroutka & Snyder 1979; Peroutka et al. 1989).
Early studies with buspirone, a partiM$-HTIA receptor agonist, suggested apossible~(}l~ fOIl this receptor in the pathophysiology of anxiet&!disQrd
ers. Several other ~nvestigational dr~g~l l ij~~~ ~Iso been developed which demonstrate hlg~ i ~mll1ty for the 5-HTIA receptor, including 8-hYdr#*~~~-(di-npropylamino)tetralin (8-0H-DPAT), ~ l lhiJhIYSelective 5-HT IA receptor agonist, gePiron~i l~n~ BMY 7378, ipsapirone, SM3997, WY478461 IH~. : MDL 72832. In this article the potential cli~~d~I ' appli-
cations of 5-HT I A partial agonists in the treatment of neuropsychiatric disorders are discussed.
1. Anxiety Disorders 1.1 Generalised Anxiety Disorder
The discovery that buspirone inhibited aggressive behaviour in rhesus monkeys (Tompkins et al. 1980) led to clinical trials in the treatment of anxiety. Several controlled studies in anxious patients have found buspirone to be superior to placebo and to have a similar therapeutic effectiveness in comparison with diazepam and chlordiazepate (B6hm et al. 1990; Feighner & Cohn 1989; Goa & Ward 1986; Goldberg & Finnerty 1979, 1982; Murphy et at 1989; Pecknold et al. 1989; Rickels et al. 1982; Wheatley 1982). Gepirone has also been reported to be an effective anxiolytic agent (Casanolosi et a1.1987; Cott et al. 1988; Harto et al. 1988). Unlike benzodiazepines, but similar to antidepressants, the anxiolytic effects of 5-HT IA partial agonists may deveJop gradually over several weeks (Harto et al. 1988). This suggests that chronic modulation of 5-
.! ... . • HT!receptors may be necessary for their therapeu-tiC activity.
:yhe mechanism of the anxiolytic effects of these corripounds is unclear. Although buspirone affects bot'cl dopaminergic (Taylor et al. 1982) and norad~~nergic activity (Gower & Tricklebank 1988), thdr~ is evidence to suggest that the anxiolytic actiy\t~ of 5-HTIA partial agonists is related to their eff~dt on 5-HT neurotransmission (Eison et al.
LEADING ARTICLE
Drugs 41 (I): 11-18. 1991 0012-6667/9 1/0001-00 II /$04.00/0 © Adis International Limited. All rights reserved.
DRU1417
5-HT 1 A Partial Agonists What is Their Future?
Debra A. Glitz and Robert Pohl Wayne State University, Detroit, Michigan, USA
Drugs that act selectively on the serotonergic system (e.g. fluvoxamine) are effective in a variety of psychiatric disorders including depression, panic disorder and obsessive compulsive disorder (OCD) [Den Boer et al. 1987; Goodman et al. 1989; Schatzberg et al. 1987]. Recently, multiple subtypes of serotonin (5-hydroxytryptamine, 5-HT) receptors have been identified, along~ith agents that act relatively selectively at the vai'iou's 5-HT receptor subtypes. Increasingly, selectiv~ and specific psychotropic agents are of clinical! :ht~rest because they generally have fewer side erte~fs . Such agents may help determine whether theh{ is any diagnostic specificity for abnormalities ih~olving 5-HT receptor subtypes.
At present, 31l1ain classes of 5-HT r~Wle'~I~or subtypes ha.ve. been identified: 5-HTI, 5-~~21 ! and 5-HT3. WithIn the 5-HTI class of recept~rs, jat least 4 different receptor subtypes have beel1l jlddntified:
i l li I' : ; !
5-HTIA, 5-HTIB, 5-HTlc and 5-HTrdli(peroutka & Snyder 1979; Peroutka et al. 1989).
Early studies with buspirone, a partiM$-HTIA receptor agonist, suggested apossible~(}l~ fOIl this receptor in the pathophysiology of anxiet&!disQrd
ers. Several other ~nvestigational dr~g~l l ij~~~ ~Iso been developed which demonstrate hlg~ i ~mll1ty for the 5-HTIA receptor, including 8-hYdr#*~~~-(di-npropylamino)tetralin (8-0H-DPAT), ~ l lhiJhIYSelective 5-HT IA receptor agonist, gePiron~i l~n~ BMY 7378, ipsapirone, SM3997, WY478461 IH~. : MDL 72832. In this article the potential cli~~d~I ' appli-
cations of 5-HT I A partial agonists in the treatment of neuropsychiatric disorders are discussed.
1. Anxiety Disorders 1.1 Generalised Anxiety Disorder
The discovery that buspirone inhibited aggressive behaviour in rhesus monkeys (Tompkins et al. 1980) led to clinical trials in the treatment of anxiety. Several controlled studies in anxious patients have found buspirone to be superior to placebo and to have a similar therapeutic effectiveness in comparison with diazepam and chlordiazepate (B6hm et al. 1990; Feighner & Cohn 1989; Goa & Ward 1986; Goldberg & Finnerty 1979, 1982; Murphy et at 1989; Pecknold et al. 1989; Rickels et al. 1982; Wheatley 1982). Gepirone has also been reported to be an effective anxiolytic agent (Casanolosi et a1.1987; Cott et al. 1988; Harto et al. 1988). Unlike benzodiazepines, but similar to antidepressants, the anxiolytic effects of 5-HT IA partial agonists may deveJop gradually over several weeks (Harto et al. 1988). This suggests that chronic modulation of 5-
.! ... . • HT!receptors may be necessary for their therapeu-tiC activity.
:yhe mechanism of the anxiolytic effects of these corripounds is unclear. Although buspirone affects bot'cl dopaminergic (Taylor et al. 1982) and norad~~nergic activity (Gower & Tricklebank 1988), thdr~ is evidence to suggest that the anxiolytic actiy\t~ of 5-HTIA partial agonists is related to their eff~dt on 5-HT neurotransmission (Eison et al.
12
1986). However, the precise nature of the effect on 5-HT neurotransmission has not been fully elucidated. While there is evidence to suggest that 5-HT1A partial agonists inhibit 5-HT neurotransmission (VanderMaelen & Wilderman I 984a,b), most likely via 5-HT lA autoreceptor stimulation (Dourish et al. 1986), there is also evidence that these agents have postsynaptic 5-HT1A agonistic activity as well (Martin & Mason 1987; Rowan & Anwyl 1987). The overall balance between inhibitory and facilitatory effects on 5-HT neurotransmission may vary in different areas of the brain.
To further complicate matters, there is evidence to suggest that 5-HT has both anxiolytic and anxiogenic properties. Studies using animal models of anxiety generally suggest that 5-HT promotes anxiety (Geller & Blum 1970; Johnston & File 1986; Tye et al. 1977). In contrast, other evidencesuggests that a 5-HT -deficient state might promote anxiety (Brody 1970; Mendels & Fraser 1974). Soubrie (1986) has suggested that animal conflict paradigms may actually be investigating impulsivity rather than anxiety. 5-HT lA partial agonists similarly demonstrate both anxiolytic and anxiogenic properties in animal models of anxiety (Craft et al. 1988; Engel et al. 1984; Geller & Hartman 1982; Higgins et al. 1988; Sanger et al. 1985; Shimizu et al. 1987).
It is clear that no simple theory about 5-HT and anxiety can account for the findings reviewed above. The apparent contradictions may relate to complexities in the regulation of 5-HT neurotransmlsslOn.
1.2 Panic Disorder
In 2 collaborative published controlled trials of buspirone in the treatment of panic disorder (Pohl et al. 1989; Robinson et al. 1989a; Sheehan et al. 1990), the results were inconclusive. In the pooled data analysis, neither buspirone nor imipramine (a standard treatment with pr<;>ven efficacy) was significantly better than placeb,o. However, there was a nonsignificant trend towards increased efficacy with buspirone. The failur~ to demonstrate a significant difference inefficacYI may have been in
Drugs 41 (1) 1991
part related to a robust placebo response in these studies.
Despite the lack of demonstrated efficacy, there is evidence to suggest that enhancement of the 5-HT system may reduce panic attacks. The locus coeruleus hypothesis of panic disorder suggests that activity in the brain noradrenergic neurons is increased during panic attacks (Charney & Redmond 1983). The dorsal raphe nuclei send 5-HT projections to the locus ceruleus (Morgane & Jacobs 1979) which are inhibitory (Segal 1979)., Although buspirone increases the firing of neurons in the locus ceruleus acutely, its long term effect is unknown (Sanghera et al. 1983). Interestingly, Chignon and Lepine (1989) report a case of panic attacks precipitated by the addition of a single dose of buspirone to an existing tricyclic antidepressant reglmen.
5-HT -selective reuptake inhibitors (e.g. fluvoxamine) are effective in treating panic attacks (Den Boer & Westenberg 1988; Den Boer et al. 1987). The 5-HT precursors, tryptophan ~nd 5-hydroxytryptophan (5-HTP, oxitriptan) also have weak anti panic activity (Hoes et al. 1981; Kahn & Westenberg 1985; Kahn et al. 1987). Furthermore, the anti panic effects of fluvoxamine may be unrelated to its 5-HT2 antagonism since 5-HT2 antagonists are ineffective as antipanic agents (Westenberg & Den Boer 1989). In addition, the therapeutic effect of fluvoxamine appears biphasic. After an initial exacerb~tion, the panic symptoms subsequently improve (Den Boer et al. 1987). This suggests that chronic modulation of 5-HT 1 receptors may be necessary for its antipanic properties. Since the precise nature of the acute and chronic effects of 5-HT IA partial agonists on 5-HT neurotransmission has not yet been definitively established, additional clinical trials are needed to determine whether these agents are beneficial in the treatment of panic disorder.
1.3 Obsessive Compulsive Disorder
There is strong evidence to suggest serotonergic involve,ment in the pathogenesis of OCD. Clomipramine (chlorimipramine), an antidepressant with
12
1986). However, the precise nature of the effect on 5-HT neurotransmission has not been fully elucidated. While there is evidence to suggest that 5-HT1A partial agonists inhibit 5-HT neurotransmission (VanderMaelen & Wilderman I 984a,b), most likely via 5-HT lA autoreceptor stimulation (Dourish et al. 1986), there is also evidence that these agents have postsynaptic 5-HT1A agonistic activity as well (Martin & Mason 1987; Rowan & Anwyl 1987). The overall balance between inhibitory and facilitatory effects on 5-HT neurotransmission may vary in different areas of the brain.
To further complicate matters, there is evidence to suggest that 5-HT has both anxiolytic and anxiogenic properties. Studies using animal models of anxiety generally suggest that 5-HT promotes anxiety (Geller & Blum 1970; Johnston & File 1986; Tye et al. 1977). In contrast, other evidencesuggests that a 5-HT -deficient state might promote anxiety (Brody 1970; Mendels & Fraser 1974). Soubrie (1986) has suggested that animal conflict paradigms may actually be investigating impulsivity rather than anxiety. 5-HT lA partial agonists similarly demonstrate both anxiolytic and anxiogenic properties in animal models of anxiety (Craft et al. 1988; Engel et al. 1984; Geller & Hartman 1982; Higgins et al. 1988; Sanger et al. 1985; Shimizu et al. 1987).
It is clear that no simple theory about 5-HT and anxiety can account for the findings reviewed above. The apparent contradictions may relate to complexities in the regulation of 5-HT neurotransmlsslOn.
1.2 Panic Disorder
In 2 collaborative published controlled trials of buspirone in the treatment of panic disorder (Pohl et al. 1989; Robinson et al. 1989a; Sheehan et al. 1990), the results were inconclusive. In the pooled data analysis, neither buspirone nor imipramine (a standard treatment with pr<;>ven efficacy) was significantly better than placeb,o. However, there was a nonsignificant trend towards increased efficacy with buspirone. The failur~ to demonstrate a significant difference inefficacYI may have been in
Drugs 41 (1) 1991
part related to a robust placebo response in these studies.
Despite the lack of demonstrated efficacy, there is evidence to suggest that enhancement of the 5-HT system may reduce panic attacks. The locus coeruleus hypothesis of panic disorder suggests that activity in the brain noradrenergic neurons is increased during panic attacks (Charney & Redmond 1983). The dorsal raphe nuclei send 5-HT projections to the locus ceruleus (Morgane & Jacobs 1979) which are inhibitory (Segal 1979)., Although buspirone increases the firing of neurons in the locus ceruleus acutely, its long term effect is unknown (Sanghera et al. 1983). Interestingly, Chignon and Lepine (1989) report a case of panic attacks precipitated by the addition of a single dose of buspirone to an existing tricyclic antidepressant reglmen.
5-HT -selective reuptake inhibitors (e.g. fluvoxamine) are effective in treating panic attacks (Den Boer & Westenberg 1988; Den Boer et al. 1987). The 5-HT precursors, tryptophan ~nd 5-hydroxytryptophan (5-HTP, oxitriptan) also have weak anti panic activity (Hoes et al. 1981; Kahn & Westenberg 1985; Kahn et al. 1987). Furthermore, the anti panic effects of fluvoxamine may be unrelated to its 5-HT2 antagonism since 5-HT2 antagonists are ineffective as antipanic agents (Westenberg & Den Boer 1989). In addition, the therapeutic effect of fluvoxamine appears biphasic. After an initial exacerb~tion, the panic symptoms subsequently improve (Den Boer et al. 1987). This suggests that chronic modulation of 5-HT 1 receptors may be necessary for its antipanic properties. Since the precise nature of the acute and chronic effects of 5-HT IA partial agonists on 5-HT neurotransmission has not yet been definitively established, additional clinical trials are needed to determine whether these agents are beneficial in the treatment of panic disorder.
1.3 Obsessive Compulsive Disorder
There is strong evidence to suggest serotonergic involve,ment in the pathogenesis of OCD. Clomipramine (chlorimipramine), an antidepressant with
Future of 5-HT lA Partial Agonists
a preferential effect on serotonin reuptake inhibition, is more effective in the treatment of OCD than other . antidepressants that have greater noradrenergic effects (Ananth et al. 1981 ; Insel et al. 1983; McTavish & Benfield 1990; Thoren et al. 1980; Volavka et al. 1985). Clinical efficacy in OCD has also been demonstrated for other 5-HT -selective reuptake inhibitors (Fontaine & Chouinard 1986; Goodman et al. 1989): metergoline, a nonspecific 5-HT antagonist, increases anxiety and OCD symptoms in patients undergoing successful treatment with clomipramine (Benkelfat et al. 1989). In one study, a combination of 5-HT potentiating agents, L-tryptophan, nicotinic acid (niacin) and pyridoxine (vitamin B6), also improved OCD symptoms (Yaryura-Tobias & Bhagavan 1977).
One preliminary report in abstract form of the only controlled study of buspirone in OCD to date found it to be as effective as clomipramine in reducing OCD symptoms (Pato et al. 1989). In contrast, an open trial of buspirone in OCD found no improvement (Jenike & Baer 1988). Another open trial found buspirone to be effective in augmenting the response to fluoxetine in OCD (Markovitz et al. 1990).
Whether 5-HTIA partial agonists may prove beneficial for the treatment of OCD by facilitating 5-HT neurotransmission or through some other mechanism needs to be further investigated.
2. Depression
There is also evidence to support the involvement of 5-HT in depression. In general, most clinically effective antidepressants facilitate 5-HT neurotransmission. 5-HT -Selective reuptake inhibitors are as effective as nonselective coml?ounds for depression (Nystrom & Hallstrom 198'7;. Shatzberg et al. 198'7). Furthermore, p-chlOI:ophenylalanine (PCPA), which inhibits 5-HT syntj1es~s, antagonises the antidepressant effect of tricycltcs and monoamine oxidase inhibitors (Aprison & liingten 1972).
There is evidence to suggest that an alter~dbalance between 5-HT I and 5-HT 2 may contribute to
13
the pathophysiology of depression (Deakin 1988; Pericit & Manev 1988). Animals treated long term with antidepressants have decreased numbers of 5-HTIA (Palfreyman et al. 1986) and 5-HT2 (Stolz et al. 1983; Willner 1985) binding sites. In a similar fashion to antidepressants, gepirone also appears to downregulate 5-HT2 receptor density (Deakin 1988; Eison & Y occa 1985), and decreases the sensitivity and/or number of 5-HT cell body autoreceptors (Blier & de Montigny 1987; Weiner et al. 1989). Furthermore, the adaptive effect of 5-HTIA partial agonists on animal models of depression appears to be associated with a desensitisation of 5-HT IA autoreceptors (Curzon 1989).
Both preclinical and clinical studies with 5-HT IA partial agonists have revealed some evidence of antidepressant activity (Amsterdam et al. 1987; Cervo & Samanin 1987; Feighner et al. 1982; Giral et al. 1988; Glaser 1988; Kennett et al. I 987a,b; Schweizer et al. 1986), including some recent controlled studies that reveal that bus pirone and gepirone are superior to placebo in the treatment of depression (Jenkins et al. 1990; Robinson et al. 1989).
The findings reviewed above suggest that 5-HTIA partial agonists may be useful in the treatment of depression, possibly by downregulation of either 5-HTIA or 5-HT2 receptors or both. Again, further controlled studies are needed to confirm these preliminary findings.
3. Impulse Control Disorders 3.1 Aggression and Impulsivity
Several studies have reported antiaggressive effects of 5-HTIA partial agonists in animal models (Glaser 1988; McMillen et al. 1987). Low levels of 5-HT's metabolite, 5-hydroxyindoleacetic acid (5-HIAA), have been reported in the CSF of aggressive and impulsive individuals (Brown & Goodwin 1986; Lidberg et al. 1985; Linnoila et al. 1983; Moss 1987; Virkkunen et al. 1987) and the 5-HT precursors, tryptophan and 5-HTP, have been reported to have beneficial effects on aggressive behaviour (Morand et al. 1983; Soulairac et al. 1976; Young & Teff 1989). This suggests that enhance-
Future of 5-HT lA Partial Agonists
a preferential effect on serotonin reuptake inhibition, is more effective in the treatment of OCD than other . antidepressants that have greater noradrenergic effects (Ananth et al. 1981 ; Insel et al. 1983; McTavish & Benfield 1990; Thoren et al. 1980; Volavka et al. 1985). Clinical efficacy in OCD has also been demonstrated for other 5-HT -selective reuptake inhibitors (Fontaine & Chouinard 1986; Goodman et al. 1989): metergoline, a nonspecific 5-HT antagonist, increases anxiety and OCD symptoms in patients undergoing successful treatment with clomipramine (Benkelfat et al. 1989). In one study, a combination of 5-HT potentiating agents, L-tryptophan, nicotinic acid (niacin) and pyridoxine (vitamin B6), also improved OCD symptoms (Yaryura-Tobias & Bhagavan 1977).
One preliminary report in abstract form of the only controlled study of buspirone in OCD to date found it to be as effective as clomipramine in reducing OCD symptoms (Pato et al. 1989). In contrast, an open trial of buspirone in OCD found no improvement (Jenike & Baer 1988). Another open trial found buspirone to be effective in augmenting the response to fluoxetine in OCD (Markovitz et al. 1990).
Whether 5-HTIA partial agonists may prove beneficial for the treatment of OCD by facilitating 5-HT neurotransmission or through some other mechanism needs to be further investigated.
2. Depression
There is also evidence to support the involvement of 5-HT in depression. In general, most clinically effective antidepressants facilitate 5-HT neurotransmission. 5-HT -Selective reuptake inhibitors are as effective as nonselective coml?ounds for depression (Nystrom & Hallstrom 198'7;. Shatzberg et al. 198'7). Furthermore, p-chlOI:ophenylalanine (PCPA), which inhibits 5-HT syntj1es~s, antagonises the antidepressant effect of tricycltcs and monoamine oxidase inhibitors (Aprison & liingten 1972).
There is evidence to suggest that an alter~dbalance between 5-HT I and 5-HT 2 may contribute to
13
the pathophysiology of depression (Deakin 1988; Pericit & Manev 1988). Animals treated long term with antidepressants have decreased numbers of 5-HTIA (Palfreyman et al. 1986) and 5-HT2 (Stolz et al. 1983; Willner 1985) binding sites. In a similar fashion to antidepressants, gepirone also appears to downregulate 5-HT2 receptor density (Deakin 1988; Eison & Y occa 1985), and decreases the sensitivity and/or number of 5-HT cell body autoreceptors (Blier & de Montigny 1987; Weiner et al. 1989). Furthermore, the adaptive effect of 5-HTIA partial agonists on animal models of depression appears to be associated with a desensitisation of 5-HT IA autoreceptors (Curzon 1989).
Both preclinical and clinical studies with 5-HT IA partial agonists have revealed some evidence of antidepressant activity (Amsterdam et al. 1987; Cervo & Samanin 1987; Feighner et al. 1982; Giral et al. 1988; Glaser 1988; Kennett et al. I 987a,b; Schweizer et al. 1986), including some recent controlled studies that reveal that bus pirone and gepirone are superior to placebo in the treatment of depression (Jenkins et al. 1990; Robinson et al. 1989).
The findings reviewed above suggest that 5-HTIA partial agonists may be useful in the treatment of depression, possibly by downregulation of either 5-HTIA or 5-HT2 receptors or both. Again, further controlled studies are needed to confirm these preliminary findings.
3. Impulse Control Disorders 3.1 Aggression and Impulsivity
Several studies have reported antiaggressive effects of 5-HTIA partial agonists in animal models (Glaser 1988; McMillen et al. 1987). Low levels of 5-HT's metabolite, 5-hydroxyindoleacetic acid (5-HIAA), have been reported in the CSF of aggressive and impulsive individuals (Brown & Goodwin 1986; Lidberg et al. 1985; Linnoila et al. 1983; Moss 1987; Virkkunen et al. 1987) and the 5-HT precursors, tryptophan and 5-HTP, have been reported to have beneficial effects on aggressive behaviour (Morand et al. 1983; Soulairac et al. 1976; Young & Teff 1989). This suggests that enhance-
14
ment of 5-HT neurotransmission may be beneficial. In support of these findings, 5-HT lesions or depletion induce predatory and aggressive behaviour in rats (Eriksson & Humble 1990), while 5-HT decreases such behaviour (Eichel man 1987; Naumenko et al. 1989).
There is some suggestion of antiaggressive effects of buspirone in humans (Feighner et al. 1982; Goldberg & Finnerty 1982; Rickels et al. 1982). A recent case report revealed a dramatic improvement in distractibility, impulsiveness, anger and irritability in a patient with adult attention deficit hyperactivity disorder (ADHD) in response to buspirone (Balon 1990). Since buspirone has some dopaminergic properties similar to stimulants commonly used to treat ADHD, it is unclear whether this potential therapeutic effect is mediated via dopaminergic or serotonergic mechanisms. Another series of case reports suggests that buspirone may be effective in decreasing aggressive and self-injurious behaviour in patients with developmental disabilities (Ratey et al. 1989). Further control1ed studies with this and other more selective 5-HTIA partial agonists appear to be indicated.
3.2 Suicide
One of the most consistent findings involving 5-HT and psychopathology is that suicidal subjects with or without depression often have low cerebrospinal fluid 5-hydroxy indole-acetic acid (5-HIAA) levels (Arora & Meltzer 1989; Asberget al. 1976, 1986; Coccaro et a1. 1989). This suggests a possible beneficial effect for agents like 5-HT I A partial agonists which may enhance 5-HT neurotransmission.
3.3 Alcohol Abuse
Animal studies suggest that direct 5-HT activation decreases alcohol intake and depletion enhances consumption (Tollefson 1989). 5-HT -Selective reuptake inhibitors have also been reported to decrease alcohol consumption (Gorelik 1986; Naranjo et al: 1987). One study revealed that buspirone altered the drinkirig preference of animals
Drugs 41 (lJ 1991
from alcohol to water (Collins & Myers 1987; Privette et a1. 1988). In a recent double-blind placebocontrolled study, buspirone reduced the alcohol craving and consumption in alcohol abuse patients (Bruno 1989). In an open trial in alcoholics, treatment with buspirone was associated with a decreased craving for alcohol only in patients with high levels of anxiety (Kranzler & Meyer 1989). Although confirmation of these · findings is needed, 5-HTIA partial agonists may be useful in the management of recovering alcohol abusers.
4. Discussion
For the treatment of generalised anxiety, 5-HT I A partial agonists offer the advantage over benzodiazepines of causing fewer side effects, most notably sedation (Hjorth & Carlsson 1982). Other side effects not present with 5-HT I A partial agonists, but sometimes of concern with benzodiazepines, include cognitive and motor impairment, memory impairment and interactions with other CNS depressants (Lader 1982; Moshowitz & Smiley 1982; Rickels 1981). In addition, there appears to be little or no abuse potential or potentially life-threatening withdrawal reactions with these agents (Balster 1990; Cole et a1. 1982; Murphy et al. 1989; Rakel 1990; Riblet et al. 1982). One . disadvantage, however, is a possible delayed onset of therapeutic activity.
Further studies are needed to determine the potential role for 5-HTIA agonists in OCD and impulse control disorders. A case report suggests buspirone may also be effective · for the treatment of tardive dyskinesia (Neppe 1989).
Although the use of 5-HTIA partial agonists for depression is still investigational, there is increasing evidence that they may be effective. In addition, they may offer the benefit of improved impulse control in suicidal patients. Again, these agents appear to have potential1y fewer side effects and may provide an additional option for those patients who are refractory to treatment with conventional antidepressants. Similar to tricyclic antidepressants, there have been several case reports of the possible induction of mania by buspirone in
14
ment of 5-HT neurotransmission may be beneficial. In support of these findings, 5-HT lesions or depletion induce predatory and aggressive behaviour in rats (Eriksson & Humble 1990), while 5-HT decreases such behaviour (Eichel man 1987; Naumenko et al. 1989).
There is some suggestion of antiaggressive effects of buspirone in humans (Feighner et al. 1982; Goldberg & Finnerty 1982; Rickels et al. 1982). A recent case report revealed a dramatic improvement in distractibility, impulsiveness, anger and irritability in a patient with adult attention deficit hyperactivity disorder (ADHD) in response to buspirone (Balon 1990). Since buspirone has some dopaminergic properties similar to stimulants commonly used to treat ADHD, it is unclear whether this potential therapeutic effect is mediated via dopaminergic or serotonergic mechanisms. Another series of case reports suggests that buspirone may be effective in decreasing aggressive and self-injurious behaviour in patients with developmental disabilities (Ratey et al. 1989). Further control1ed studies with this and other more selective 5-HTIA partial agonists appear to be indicated.
3.2 Suicide
One of the most consistent findings involving 5-HT and psychopathology is that suicidal subjects with or without depression often have low cerebrospinal fluid 5-hydroxy indole-acetic acid (5-HIAA) levels (Arora & Meltzer 1989; Asberget al. 1976, 1986; Coccaro et a1. 1989). This suggests a possible beneficial effect for agents like 5-HT I A partial agonists which may enhance 5-HT neurotransmission.
3.3 Alcohol Abuse
Animal studies suggest that direct 5-HT activation decreases alcohol intake and depletion enhances consumption (Tollefson 1989). 5-HT -Selective reuptake inhibitors have also been reported to decrease alcohol consumption (Gorelik 1986; Naranjo et al: 1987). One study revealed that buspirone altered the drinkirig preference of animals
Drugs 41 (lJ 1991
from alcohol to water (Collins & Myers 1987; Privette et a1. 1988). In a recent double-blind placebocontrolled study, buspirone reduced the alcohol craving and consumption in alcohol abuse patients (Bruno 1989). In an open trial in alcoholics, treatment with buspirone was associated with a decreased craving for alcohol only in patients with high levels of anxiety (Kranzler & Meyer 1989). Although confirmation of these · findings is needed, 5-HTIA partial agonists may be useful in the management of recovering alcohol abusers.
4. Discussion
For the treatment of generalised anxiety, 5-HT I A partial agonists offer the advantage over benzodiazepines of causing fewer side effects, most notably sedation (Hjorth & Carlsson 1982). Other side effects not present with 5-HT I A partial agonists, but sometimes of concern with benzodiazepines, include cognitive and motor impairment, memory impairment and interactions with other CNS depressants (Lader 1982; Moshowitz & Smiley 1982; Rickels 1981). In addition, there appears to be little or no abuse potential or potentially life-threatening withdrawal reactions with these agents (Balster 1990; Cole et a1. 1982; Murphy et al. 1989; Rakel 1990; Riblet et al. 1982). One . disadvantage, however, is a possible delayed onset of therapeutic activity.
Further studies are needed to determine the potential role for 5-HTIA agonists in OCD and impulse control disorders. A case report suggests buspirone may also be effective · for the treatment of tardive dyskinesia (Neppe 1989).
Although the use of 5-HTIA partial agonists for depression is still investigational, there is increasing evidence that they may be effective. In addition, they may offer the benefit of improved impulse control in suicidal patients. Again, these agents appear to have potential1y fewer side effects and may provide an additional option for those patients who are refractory to treatment with conventional antidepressants. Similar to tricyclic antidepressants, there have been several case reports of the possible induction of mania by buspirone in
Future of 5-HTIA Partial Agonists
patients with bipolar disorder (Liegghio & Yeragani 1988; McDaniel et al. 1990; Pierce & Bielefeld 1989). This suggests that such patients should be carefully monitored for the emergence of hypomanic symptoms while undergoing trials with buspirone.
Since many patients present with combinations of various symptoms, medications which act broadly across multiple diagnostic categories may be particularly useful. In this regard, 5-HT IA partial agonists may be particularly useful for anxious and/or depressed patients who also abuse alcohol. While potentially decreasing alcohol consumption, unlike benzodiazepines, they do not carry the additional risk of abuse.
Since the effect of 5-HTIA partial agonists on 5-HT neurotransmission has not been fully established and may include changes in 5-HT2 receptor function as well as 5-HTIA-mediated actions, questions regarding diagnostic specificity for 5-HT receptor subtypes cannot be answered. Studies with more selective and specific agents or in combination with selective antagonists are needed to furtherdelineate the role of the individual 5-HT receptor subtypes in psychopathology.
References
Amsterdam JD, Berwish N, Potter L, Rickels K. Open trial of gepirone in the treatment of major depressive disorder. Current Theory and Research 41 (Suppl. 2): 185-193, 1987
Ananth J, Peckhold JC, vandenSteen N, Englesmann F. Doubleblind comparative study of clomipramine and amitriptyline in obsessive neurosis. Progress in Neuropsychopharmacology and Biological Psychiatry 5: 257-262, 1981
Aprison MH, Hingten IN. Serotonin and behavior: a brief summary. Federation Proceedings 31: 121-129, 1972
Arora RC, Meltzer HY. Serotonergic measures in the brains of suicide victims: 5-HT2 binding sites in the frontal cortex of suicide victims and control subjects. American Journal of Psychiatry 146 (6): 730-736, 1989
Asberg M, Nordstrom P, Traskman-Bendz L. Cerebrospinal fluid in suicide: an overview. Annals of the New York Academy of Sciences 487: 243-255, 1986
Asberg M, Traskman L, Thoren P. 5-HIAA in the cerebrospinal fluid: a biochemical suicide predictor? Archives of General Psychiatry 33: 1193, 1976
Balon R. Buspirone for attention deficit hyperactivity disorders. Journal of Clinical Psychopharmacology 10 (I): 77,1990
Balster RL. Abuse potential of bus pirone and related drugs. Journal of Clinical Psychopharmacology 10 (Suppl.): 3IS-37S, 1990
Benkelfat C, Murphy DL, Zohar J, Hill JL, Grover G, et al. Clomipramine in obsessive-compulsive disorder: further evidence for a serotonergic mechanism of action. Archives of General Psychiatry 46: 23-28, 1989
15
Blier P, de Montigny C. Modification of 5-HT neuron properties by sustained administration of the 5-HTI A agonist gepirone: electrophysiological studies in the rat brain. Synapse I: 470-480, 1987
Bohm C, Placchi M, Stallone F, Gammans RE, Alms DR, et al. A double-blind comparison of buspirone, clobazam, and placebo in patients with anxiety treated in a general practice setting. Journal of Clinical Psychopharmacology 10 (Suppl.): 38S-42S, 1990
Brody JF. Behavioral effects of serotonin depletion and of p-chlorophenylalanine (a serotonin depletor) in rats. Psychopharmacologia 17: 14-33, 1970
Brown GL, Goodwin FK. Cerebrospinal fluid correlates of suicide attempts and aggression. Annals of the New York Academy of Sciences 487: 175-188, 1986
Bruno F. Buspirone in the treatment of alcoholic patients. Psychopathology 22 (Suppl. I): 49-59, 1989
Cervo L, Samanin R. Potential antidepressant properties of 8-hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin IA receptor agonist. European Journal of Pharmacology 144: 223-229, 1987
Charney DS, Redmond Jr DE. Neurobiological mechanisms in human anxiety: evidence supporting central noradrenergic hyperactivity. Neuropharmacology 22: 1531-1536, 1983
Chignon JM, Lepine JP. Panic and hypertension associated with single dose of buspirone. Lancet 2 (8653): 46-47, 1989
Coccaro EF, Siever LJ, Klar HM, Maurer G, Cochrane K, et al. Serotonergic studies in patients with affective and personality disorders: correlates with suicidal and impUlsive aggressive behavior. Archives of General Psychiatry 46(7): 587-599, 1989
Cole JO, Orzack MH, Beake B. Assessment of the abuse liability of buspirone in recreational sedative users. Journal of Clinical Psychiatry ,43: 69-74, 1982
Collins DM, Myers RD. Buspirone attenuates volitional alcohol intake in the chronically drinking monkey. Alcohol 4: 49-56, 1987
Cott JM, Kurtz NM, Robinson DS, Lancaster SP, Copp JE. A 5-HTi A ligand with both antidepressant and anxiolytic properties. Psychopharmacology Bulletin 24 (I): 164-167, 1988
Craft RM, Howard JL, Pollard GT. Conditioned defensive burying as a model for identifying anxiolytics. Pharmacology, Biochemistry and Behavior 30 (3): 775-780, 1988
Csanalosi I, Schweizer E, Case WG, Rickels K. Gepirone in anxiety: a pilot study. Journal of Clinical Psychopharmacology 7 (I): 31-33, 1987
Curzon G. 5-Hydroxytryptamine and corticosterone in an animal model of depression. Progress in Neuropsychopharmacology and Biological Psychiatry 13: 3-4, 1989
Deakin JFW. 5HT2 receptors, depression and anxiety. Pharmacology, Biochemistry and Behavior 29: 819-820, 1988
Den Boer JA, Westenberg HGM. Effect of a serotonin and noradrenaline uptake inhibitor in panic disorder: a double-blind comparative study with fluvoxamine and maprotiline. International Clinical Psychopharmacology 3: 59-74, 1988
Den Boer JA, Westenberg HGM, Kamerbeek WDJ, Ferhoeven WM. Effect of serotonin uptake inhibitors in anxiety disorders: a double-blind comparison of clomipramine and fluvoxamine. International Clinical Psychopharmacology 2: 21-32, 1987
Dourish CT, Mutson PH, Curzon G. Putative anxiolytics 8-0HDPAT, buspirone and TVX Q 7821 are agonists at 5-HT IA autoreceptors in the raphe nuclei. Trends in Pharmacological Sciences 7: 212-214, 1986
Eichelman B. Neurochemical basis of aggressive behavior. Psychiatry Annals 17: 371-374, 1987
Eison AS, Eison MS, Stanley M, Riblet LA. Serotonergic mechanisms in the behavioral effects of buspirone and gepirone. Pharmacology, Biochemistry and Behavior 24: 701-707, 1986
Eison AS, Yocca FD. Reduction in cortical 5HT2 receptor sen-
Future of 5-HTIA Partial Agonists
patients with bipolar disorder (Liegghio & Yeragani 1988; McDaniel et al. 1990; Pierce & Bielefeld 1989). This suggests that such patients should be carefully monitored for the emergence of hypomanic symptoms while undergoing trials with buspirone.
Since many patients present with combinations of various symptoms, medications which act broadly across multiple diagnostic categories may be particularly useful. In this regard, 5-HT IA partial agonists may be particularly useful for anxious and/or depressed patients who also abuse alcohol. While potentially decreasing alcohol consumption, unlike benzodiazepines, they do not carry the additional risk of abuse.
Since the effect of 5-HTIA partial agonists on 5-HT neurotransmission has not been fully established and may include changes in 5-HT2 receptor function as well as 5-HTIA-mediated actions, questions regarding diagnostic specificity for 5-HT receptor subtypes cannot be answered. Studies with more selective and specific agents or in combination with selective antagonists are needed to furtherdelineate the role of the individual 5-HT receptor subtypes in psychopathology.
References
Amsterdam JD, Berwish N, Potter L, Rickels K. Open trial of gepirone in the treatment of major depressive disorder. Current Theory and Research 41 (Suppl. 2): 185-193, 1987
Ananth J, Peckhold JC, vandenSteen N, Englesmann F. Doubleblind comparative study of clomipramine and amitriptyline in obsessive neurosis. Progress in Neuropsychopharmacology and Biological Psychiatry 5: 257-262, 1981
Aprison MH, Hingten IN. Serotonin and behavior: a brief summary. Federation Proceedings 31: 121-129, 1972
Arora RC, Meltzer HY. Serotonergic measures in the brains of suicide victims: 5-HT2 binding sites in the frontal cortex of suicide victims and control subjects. American Journal of Psychiatry 146 (6): 730-736, 1989
Asberg M, Nordstrom P, Traskman-Bendz L. Cerebrospinal fluid in suicide: an overview. Annals of the New York Academy of Sciences 487: 243-255, 1986
Asberg M, Traskman L, Thoren P. 5-HIAA in the cerebrospinal fluid: a biochemical suicide predictor? Archives of General Psychiatry 33: 1193, 1976
Balon R. Buspirone for attention deficit hyperactivity disorders. Journal of Clinical Psychopharmacology 10 (I): 77,1990
Balster RL. Abuse potential of bus pirone and related drugs. Journal of Clinical Psychopharmacology 10 (Suppl.): 3IS-37S, 1990
Benkelfat C, Murphy DL, Zohar J, Hill JL, Grover G, et al. Clomipramine in obsessive-compulsive disorder: further evidence for a serotonergic mechanism of action. Archives of General Psychiatry 46: 23-28, 1989
15
Blier P, de Montigny C. Modification of 5-HT neuron properties by sustained administration of the 5-HTI A agonist gepirone: electrophysiological studies in the rat brain. Synapse I: 470-480, 1987
Bohm C, Placchi M, Stallone F, Gammans RE, Alms DR, et al. A double-blind comparison of buspirone, clobazam, and placebo in patients with anxiety treated in a general practice setting. Journal of Clinical Psychopharmacology 10 (Suppl.): 38S-42S, 1990
Brody JF. Behavioral effects of serotonin depletion and of p-chlorophenylalanine (a serotonin depletor) in rats. Psychopharmacologia 17: 14-33, 1970
Brown GL, Goodwin FK. Cerebrospinal fluid correlates of suicide attempts and aggression. Annals of the New York Academy of Sciences 487: 175-188, 1986
Bruno F. Buspirone in the treatment of alcoholic patients. Psychopathology 22 (Suppl. I): 49-59, 1989
Cervo L, Samanin R. Potential antidepressant properties of 8-hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin IA receptor agonist. European Journal of Pharmacology 144: 223-229, 1987
Charney DS, Redmond Jr DE. Neurobiological mechanisms in human anxiety: evidence supporting central noradrenergic hyperactivity. Neuropharmacology 22: 1531-1536, 1983
Chignon JM, Lepine JP. Panic and hypertension associated with single dose of buspirone. Lancet 2 (8653): 46-47, 1989
Coccaro EF, Siever LJ, Klar HM, Maurer G, Cochrane K, et al. Serotonergic studies in patients with affective and personality disorders: correlates with suicidal and impUlsive aggressive behavior. Archives of General Psychiatry 46(7): 587-599, 1989
Cole JO, Orzack MH, Beake B. Assessment of the abuse liability of buspirone in recreational sedative users. Journal of Clinical Psychiatry ,43: 69-74, 1982
Collins DM, Myers RD. Buspirone attenuates volitional alcohol intake in the chronically drinking monkey. Alcohol 4: 49-56, 1987
Cott JM, Kurtz NM, Robinson DS, Lancaster SP, Copp JE. A 5-HTi A ligand with both antidepressant and anxiolytic properties. Psychopharmacology Bulletin 24 (I): 164-167, 1988
Craft RM, Howard JL, Pollard GT. Conditioned defensive burying as a model for identifying anxiolytics. Pharmacology, Biochemistry and Behavior 30 (3): 775-780, 1988
Csanalosi I, Schweizer E, Case WG, Rickels K. Gepirone in anxiety: a pilot study. Journal of Clinical Psychopharmacology 7 (I): 31-33, 1987
Curzon G. 5-Hydroxytryptamine and corticosterone in an animal model of depression. Progress in Neuropsychopharmacology and Biological Psychiatry 13: 3-4, 1989
Deakin JFW. 5HT2 receptors, depression and anxiety. Pharmacology, Biochemistry and Behavior 29: 819-820, 1988
Den Boer JA, Westenberg HGM. Effect of a serotonin and noradrenaline uptake inhibitor in panic disorder: a double-blind comparative study with fluvoxamine and maprotiline. International Clinical Psychopharmacology 3: 59-74, 1988
Den Boer JA, Westenberg HGM, Kamerbeek WDJ, Ferhoeven WM. Effect of serotonin uptake inhibitors in anxiety disorders: a double-blind comparison of clomipramine and fluvoxamine. International Clinical Psychopharmacology 2: 21-32, 1987
Dourish CT, Mutson PH, Curzon G. Putative anxiolytics 8-0HDPAT, buspirone and TVX Q 7821 are agonists at 5-HT IA autoreceptors in the raphe nuclei. Trends in Pharmacological Sciences 7: 212-214, 1986
Eichelman B. Neurochemical basis of aggressive behavior. Psychiatry Annals 17: 371-374, 1987
Eison AS, Eison MS, Stanley M, Riblet LA. Serotonergic mechanisms in the behavioral effects of buspirone and gepirone. Pharmacology, Biochemistry and Behavior 24: 701-707, 1986
Eison AS, Yocca FD. Reduction in cortical 5HT2 receptor sen-
16
sitivity after continuous gepirone treatment. European Journal of Pharmacology III : 389-392, 1985 I
Engel JA, Hjorth S, Svensson K, Carlsson A, Lijequist S. Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-0H-DPAT). European Journal of Pharmacology 105: 365-368, 1984
Eriksson E, Humble M. Serotonin in psychiatric pathophysiology: a review of data from experimental and dinical research. In Pohl R & Gershon S (Eds) Progress in basic and clinical pharmacology: biological basis of psychiatric treatment, pp. 66-119, Karger AG, Basel, 1990
Feighner JP, Cohn JB. Analysis of individual symptoms in generalized anxiety: a pooled, multistudy, double-blind evaluation of buspirone. Neuropsychobiology 21: 124-130, 1989
Feighner JP, Merideth CH, Hendrickson GA. A double-blind comparison of buspirone and diazepam in outpatients with generalized anxiety disorder. Journal of Clinical Psychiatry 43 (12): 103-107, 1982
Fontaine R, Chouinard G. An open clinical trial of fluoxetine in the treatment of obsessive compulsive .disorder. Journal of Clinical Psychopharmacology 6: 98-10 I, 1986
Geller I, Blum K. The effects of 5-HTP on para-chlorophenylalanine (p-CPA) attentuation of 'conflict' behavior. European Journal of Pharmacology 9: 319-324, 1970
Geller I, Hartman RJ. Effects of buspirone on operant behavior of laboratory rats andcynomologus monkeys. Journal ofClinid Psychiatry 43 (12): 25, 1982
Giral P, Martin P, Soubrie P, Simon P. Reversal of helpless behavior in rats by putative 5-HTIA agonists. Biological Psychiatry 23: 237-242, 1988
Glaser T. Ipsapirone, a potent and selective 5-HT I A-receptor ligand with anxiolytic and antidepressant properties. Drugs of the Future 13: 429-439, 1988
Goa KL, Ward A. Buspirone: a preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs n: 114-129, 1986
Goldberg HL, Finnerty R. The comparative efficacy of buspirone and diazepam in the treatment of anxiety. American Journal of Psychiatry 136 (9): 1184-1187; 1979
Goldberg HL, Finnerty R. Comparison of bus pirone in two separate studies. Journal of Clinical Psychiatry 32 (12): 87-91,1982
Goodman WK, Price LH, Rasmussen SA, Delgado PL, Heninger GR, et al. Efficacy of fluvoxamine ,in obsessive-compulsive disorder: a double-blind 'comparison with placebo. Archives of General Psychiatry 46: 36-44, 1989
Gorelik DA. Effect of fluoxetine on alcohol consumption. Alcoholism (NY) 10: ID, 1986
Gower AJ, Tricklebank MD. Alpha-2-adrenoceptor antagonist activity may account for the effects of buspirone in an anticonflict test in the rat. European Journal of Pharmacology 155: 129-137,1988
Harto NE, Branconnier RJ, Spera KF, Dessain EC. Clinical profile ofgepirone, a nonbenzodiaiepineanxiolytic. Psychopharmacology Bulletin 24 (I): 154-160, 1988
Higgins GA, Bradbury AJ, Jones BJ, Oakley NR. Behavioural and biochemical consequences. following activation of 5HTIlike and GABA receptors in the dorsal raphe nucleus of the rat. Neuropharmacology.27 (10):, 993-.1001, 1988
Hjorth S, Carlsson A. Buspironeeffects on central monoaminergic transmission: possibleTele~ance to animal experimental and clinical findings. European Journal of Pharmacology 83: 299-303, 1982
Hoes MJAJM, Colla P, Folgering H. Hyperventilation syndrome, treatment with L-tryptophan and pyridoxine; predictive values ofxanthurenic acid excretion. Journal of Orthomolecular Psychiatry 10: 7-15, 1981
Insel TR, Murphy DL, Cohen RM, Alterman I, Kilts C, et al. Obsessive-compulsive disorder: a double-blind trial of clomi-
Drugs 41 (1) 1991
pramine and clorgyline. Archives of General Psychiatry 40: 605-612, 1983
Jen ike MA, Baer L. An open trial of buspirone in obsessive-compulsive disorder. American Journal of Psychiatry 145 (10): 1285-1286, 1988
Jenkins SW, Robinson DS, Fabre LF, Andary JJ, Messina ME, et al. Gepirone in the treatment of major depression. Journal of Clinical Psychopharmacology 10 (Suppl.): 77S-85S, 1990
Johnston AL, File SE. 5-HT and anxiety: promises and pitfalls. Pharmacology, Biochemistry and Behavior 24: 1467-1470, 1986
Kahn RS, Westenberg HGM. L-5-hydroxytryptophan in the treatment of anxiety disorders . .Journal of Affective Disorders 8: 197-200, 1985
Kahn RS, Westenberg HGM, Verhoeven WMA, Gispen-de Wied CC, Kamerbeck WD. Effect of a serotonin precursor and uptake inhibitor in anxiety disorders: a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. International Clinical Psychopharmacology 2: 21-32, 1987
Kennett GA, Dourish CT, Curzon G. Antidepressant-like action of 5-HTlA agonists and conventional antidepressants in an animal model of depression. European Journal of Pharmacology 134: 265-272, 1987a
Kennett GA, Marcou M, Dourish CT, Curzo'n G. Single administration of 5-HTlA agonists decreases 5-;HTlA presynaptic, but not postsynaptic receptor-medicated responses: relationship to antidepressant-like action. European Journal of Pharmacology 138: 53-60, 1987b
Kranzler HR, Meyer RE. An open trial of bus pirone in alcoholics. Journal of Clinical Psychopharmacology ~ (5): 379-380, 1989
Lader M. Psychological effects of buspirone. iJournal of Clinical Psychiatry 43: 62-67, 1982
Legghio NE, Yeragani VK. Buspirone-induced hypomania: a case report. Journal of Clinical Psychopharmacdlogy 8 (3): 226-227, 1988
Lidberg L, Tuck JR, Asberg M, Scalia-Tomba GP, Bertilsson L. Homicide, suicide .and CSF 5-HIAA. Acta Psychiatrica Scandinavica 71: 230-236, 1985
Linnoila M, Virkkunen M, Scheinin M, Nuubla A, Rimon R, et al. Low cerebrospinal fluid 5-hydroxyindol~acetic acid concentration differentiates impulsive from nonirtJpulsive violent behavior. Life Sciences 33: 2609-2614, 1983 '
Markovitz PJ, Stagno SJ, Calabrese JR. Buspirone augmentation of fluoxetine in obsessive-compulsive disorder. American Journal of Psychiatry 147 (6): 798'800, 1 ~90
Martin KF, Mason R. Ipsapirone is a partial agonist at 5-hydroxytryptamine IA (5-HT IA) receptors i~ the rat hippocampus: electrophysiological evidence. EUropean Journal of Pharmacology 141 : 479-483, 1987 .
McDaniel JS, Ninan PT, Magnuson JV. Possible induction of mania by buspirone. American Journal of Psychiatry 147 (I): 125-126, 1990
McMillen BA, Scott SM, Williams HL, Sangnera MK. Effects of gepirone, an aryl-piperazine anxiolytic dnig, on aggressive behavior and brain monoaminergic neufotI'ansmission. Archiv der Pharmazie 335: 454-464, 1987 .
McTavish D, Benfield P. Clomipramine: an overview of its pharmacological properties and a review of its therapeutic use in obsessive compulsive disorder and panic disorder. Drugs 39: 136-153, 1990
Mendels J, Frazer A. Brain biogenic amine d¢pletion and mood. Archives of General Psychiatry 30: 447-4~1, 1974
Morand C, Young SN, Ervin FR . . C1.inical response of aggressive schizophrenics to oral tryptophan. Biological Psychiatry 18: 575-578, 1983
Morgane PJ, Jacobs MS. Raphe projections to the locus coeruleus in the rat. Brain Research Bulletin 4: 519,534, 1979
Moshowitz H, Smiley A. Effects of chronically administen:d buspirone and diazepam on driving-related !skills performance. Journal of Clinical Psychiatry 43: 45-55, \982
16
sitivity after continuous gepirone treatment. European Journal of Pharmacology III : 389-392, 1985 I
Engel JA, Hjorth S, Svensson K, Carlsson A, Lijequist S. Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-0H-DPAT). European Journal of Pharmacology 105: 365-368, 1984
Eriksson E, Humble M. Serotonin in psychiatric pathophysiology: a review of data from experimental and dinical research. In Pohl R & Gershon S (Eds) Progress in basic and clinical pharmacology: biological basis of psychiatric treatment, pp. 66-119, Karger AG, Basel, 1990
Feighner JP, Cohn JB. Analysis of individual symptoms in generalized anxiety: a pooled, multistudy, double-blind evaluation of buspirone. Neuropsychobiology 21: 124-130, 1989
Feighner JP, Merideth CH, Hendrickson GA. A double-blind comparison of buspirone and diazepam in outpatients with generalized anxiety disorder. Journal of Clinical Psychiatry 43 (12): 103-107, 1982
Fontaine R, Chouinard G. An open clinical trial of fluoxetine in the treatment of obsessive compulsive .disorder. Journal of Clinical Psychopharmacology 6: 98-10 I, 1986
Geller I, Blum K. The effects of 5-HTP on para-chlorophenylalanine (p-CPA) attentuation of 'conflict' behavior. European Journal of Pharmacology 9: 319-324, 1970
Geller I, Hartman RJ. Effects of buspirone on operant behavior of laboratory rats andcynomologus monkeys. Journal ofClinid Psychiatry 43 (12): 25, 1982
Giral P, Martin P, Soubrie P, Simon P. Reversal of helpless behavior in rats by putative 5-HTIA agonists. Biological Psychiatry 23: 237-242, 1988
Glaser T. Ipsapirone, a potent and selective 5-HT I A-receptor ligand with anxiolytic and antidepressant properties. Drugs of the Future 13: 429-439, 1988
Goa KL, Ward A. Buspirone: a preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs n: 114-129, 1986
Goldberg HL, Finnerty R. The comparative efficacy of buspirone and diazepam in the treatment of anxiety. American Journal of Psychiatry 136 (9): 1184-1187; 1979
Goldberg HL, Finnerty R. Comparison of bus pirone in two separate studies. Journal of Clinical Psychiatry 32 (12): 87-91,1982
Goodman WK, Price LH, Rasmussen SA, Delgado PL, Heninger GR, et al. Efficacy of fluvoxamine ,in obsessive-compulsive disorder: a double-blind 'comparison with placebo. Archives of General Psychiatry 46: 36-44, 1989
Gorelik DA. Effect of fluoxetine on alcohol consumption. Alcoholism (NY) 10: ID, 1986
Gower AJ, Tricklebank MD. Alpha-2-adrenoceptor antagonist activity may account for the effects of buspirone in an anticonflict test in the rat. European Journal of Pharmacology 155: 129-137,1988
Harto NE, Branconnier RJ, Spera KF, Dessain EC. Clinical profile ofgepirone, a nonbenzodiaiepineanxiolytic. Psychopharmacology Bulletin 24 (I): 154-160, 1988
Higgins GA, Bradbury AJ, Jones BJ, Oakley NR. Behavioural and biochemical consequences. following activation of 5HTIlike and GABA receptors in the dorsal raphe nucleus of the rat. Neuropharmacology.27 (10):, 993-.1001, 1988
Hjorth S, Carlsson A. Buspironeeffects on central monoaminergic transmission: possibleTele~ance to animal experimental and clinical findings. European Journal of Pharmacology 83: 299-303, 1982
Hoes MJAJM, Colla P, Folgering H. Hyperventilation syndrome, treatment with L-tryptophan and pyridoxine; predictive values ofxanthurenic acid excretion. Journal of Orthomolecular Psychiatry 10: 7-15, 1981
Insel TR, Murphy DL, Cohen RM, Alterman I, Kilts C, et al. Obsessive-compulsive disorder: a double-blind trial of clomi-
Drugs 41 (1) 1991
pramine and clorgyline. Archives of General Psychiatry 40: 605-612, 1983
Jen ike MA, Baer L. An open trial of buspirone in obsessive-compulsive disorder. American Journal of Psychiatry 145 (10): 1285-1286, 1988
Jenkins SW, Robinson DS, Fabre LF, Andary JJ, Messina ME, et al. Gepirone in the treatment of major depression. Journal of Clinical Psychopharmacology 10 (Suppl.): 77S-85S, 1990
Johnston AL, File SE. 5-HT and anxiety: promises and pitfalls. Pharmacology, Biochemistry and Behavior 24: 1467-1470, 1986
Kahn RS, Westenberg HGM. L-5-hydroxytryptophan in the treatment of anxiety disorders . .Journal of Affective Disorders 8: 197-200, 1985
Kahn RS, Westenberg HGM, Verhoeven WMA, Gispen-de Wied CC, Kamerbeck WD. Effect of a serotonin precursor and uptake inhibitor in anxiety disorders: a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. International Clinical Psychopharmacology 2: 21-32, 1987
Kennett GA, Dourish CT, Curzon G. Antidepressant-like action of 5-HTlA agonists and conventional antidepressants in an animal model of depression. European Journal of Pharmacology 134: 265-272, 1987a
Kennett GA, Marcou M, Dourish CT, Curzo'n G. Single administration of 5-HTlA agonists decreases 5-;HTlA presynaptic, but not postsynaptic receptor-medicated responses: relationship to antidepressant-like action. European Journal of Pharmacology 138: 53-60, 1987b
Kranzler HR, Meyer RE. An open trial of bus pirone in alcoholics. Journal of Clinical Psychopharmacology ~ (5): 379-380, 1989
Lader M. Psychological effects of buspirone. iJournal of Clinical Psychiatry 43: 62-67, 1982
Legghio NE, Yeragani VK. Buspirone-induced hypomania: a case report. Journal of Clinical Psychopharmacdlogy 8 (3): 226-227, 1988
Lidberg L, Tuck JR, Asberg M, Scalia-Tomba GP, Bertilsson L. Homicide, suicide .and CSF 5-HIAA. Acta Psychiatrica Scandinavica 71: 230-236, 1985
Linnoila M, Virkkunen M, Scheinin M, Nuubla A, Rimon R, et al. Low cerebrospinal fluid 5-hydroxyindol~acetic acid concentration differentiates impulsive from nonirtJpulsive violent behavior. Life Sciences 33: 2609-2614, 1983 '
Markovitz PJ, Stagno SJ, Calabrese JR. Buspirone augmentation of fluoxetine in obsessive-compulsive disorder. American Journal of Psychiatry 147 (6): 798'800, 1 ~90
Martin KF, Mason R. Ipsapirone is a partial agonist at 5-hydroxytryptamine IA (5-HT IA) receptors i~ the rat hippocampus: electrophysiological evidence. EUropean Journal of Pharmacology 141 : 479-483, 1987 .
McDaniel JS, Ninan PT, Magnuson JV. Possible induction of mania by buspirone. American Journal of Psychiatry 147 (I): 125-126, 1990
McMillen BA, Scott SM, Williams HL, Sangnera MK. Effects of gepirone, an aryl-piperazine anxiolytic dnig, on aggressive behavior and brain monoaminergic neufotI'ansmission. Archiv der Pharmazie 335: 454-464, 1987 .
McTavish D, Benfield P. Clomipramine: an overview of its pharmacological properties and a review of its therapeutic use in obsessive compulsive disorder and panic disorder. Drugs 39: 136-153, 1990
Mendels J, Frazer A. Brain biogenic amine d¢pletion and mood. Archives of General Psychiatry 30: 447-4~1, 1974
Morand C, Young SN, Ervin FR . . C1.inical response of aggressive schizophrenics to oral tryptophan. Biological Psychiatry 18: 575-578, 1983
Morgane PJ, Jacobs MS. Raphe projections to the locus coeruleus in the rat. Brain Research Bulletin 4: 519,534, 1979
Moshowitz H, Smiley A. Effects of chronically administen:d buspirone and diazepam on driving-related !skills performance. Journal of Clinical Psychiatry 43: 45-55, \982
Future of 5-HTIA Partial Agonists
Moss HB. Serotonergic activity and disinhibitory psychopathy in alcoholism. Medical Hypotheses 23: 353-361 , 1987
Murphy SM, Owen R, Tyrer P. Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone. British Journal of Psychiatry 154: 529-534, 1989
Naranjo CA, Sellers EM, Sullivan JT, Woodley DV, Kadlec K, et al. The serotonin uptake inhibitor catalopram attenuates ethanol intake. Clinical Pharmacological Therapy 41 : 266-274, 1987
Naumenko EV, Popova NK, Nikulina EM,Oygalo NN, Shiskina GT, et al. Behavior, adrenocortical activity, and brain monoamines in Norway rats selected for reduced aggressiveness towards man. Pharmacology, Biochemistry and Behavior 33 (I): 85-91, 1989
Neppe VM. High-dose buspirone in case of tardive dyskinesia. Lancet 2 (8677): 1458, 1989
Nystrom C, Hallstrom T. Comparison between a serotonin and a noradrenaline reuptake blocker in the treatment of depressed outpatients: a cross-over study. Acta Psychiatrica Scandinavica 75: 377-382, 1987
Palfreyman MG, Mir AK, Kubina M, Middlemiss DN, Richards M, et al. Monoamine receptor sensitivity changes following chronic administration of MDL 72394, a site-directed inhibitor of monoamine oxidase. European Journal of Pharmacology 106: 539-546, 1986
Pato MT, Pigott TA, Hill JL, Grover G, Bernstein SE, et al. Clomipramine vs buspirone in OCD: a controlled trial. New Research Program and Abstracts of the Annual Meeting of the American Psychiatric Association, p. 34, San Francisco, May 6-11 , 1989
Pecknold JC, Matas M, Howarth BG, Ross C, Swinson R, et al. Evaluation of buspirone as an antianxiety agent: buspirone and diazepam versus placebo. Canadian Journal of Psychiatry 34: 766-771, 1989
PeriCii: D, Manev H. Behavioural evidence for simultaneous dual changes of 5-HT receptor subtypes: mode of antidepressant action? Life Sciences 42: 2593-2601 , 1988
Peroutka SJ, Sleight AJ , McCarthy BG, Pierce PA, Schmidt A W, et al. The clinical utility of pharmacological agents that act as serotonin receptors. Journal of Neuropsychiatry I (3): 253-262, 1989
Peroutka SJ, Snyder SH. Multiple serotonin receptors: differential binding of (3H) serotonin, (3H) lysergic acid diethylamide, and (3H) spiroperidol. Molecular Pharmacology 16: 687-699,1979
Pierce W A, Bielefeld M. Buspirone-induced mania. Journal of Clinical Psychopharmacology 9: 150-151 , 1989
Pohl R, Balon R, Yeragani VK, Gershon S. Serotonergic anxioIytics in the treatment of panic disorder: a controlled study with buspirone. Psychopathology 22 (Suppl. I): 60-67, 1989
Privette TH, Hornsby RI, Myers RD. Buspirone alters alcohol drinking induced in rats by tetrahydropapaveroline injected into brain monoaminergic pathways. Alcohol 5: 147-152, 1988
Rakel RE. Long term buspirone therapy for chronic anxiety: a multicenter international study to determine safety. Southern Medical Journal 83 (2): 194-198, 1990
Ratey 11, Sovner R, Mikkelsen E, Chmielinski HE. Buspirone therapy for m~ladaptive behavior and anxiety in developmentally disabl¢d persons. Journal of Clinical Psychiatry 50 (10): 382-384, 1'989
Riblet LA, Taylor DP, Eison MS, Stanton He. Pharmacology and neurochemistry of buspirone. Journal of Clinical Psychiatry 43: 11-16, 1982
Rickels K. Recent advances in anxiolytic therapy. Journal of Clinical Psychiatry 42: 40-44, 1981
Rickels K, WeisJtian K, Norstad N, Singer M, Stoltz D, et al. Buspirone and diazepam in anxiety: a controlled study. Journal of Clinical Psychiatry 43 (12): 18-86, 1982
Robinson DS, Alms DR, Shrotriya RC, Messina M, Wickramar-
17
atne P. Serotonergic anxiolytics and treatment of depression. Psychopathology 22 (Suppl. I): 27.36, 1989
Robinson DS, Shrotriya RC, Alms DR, Messina M, Andary J. Treatment of panic disorder: nonbenzodiazepine anxiolytics, including buspirone. Psychopharmacology Bulletin 25 (I): 21-26, 1989a
R.owan MJ, Anwyl R. Neurophysiological effects .of bus pirone and ipsapirone in the hippocampus: comparison with 5-hydroxytryptamine. Eur.opean Journal of Pharmac.ology 141 : 479~483, 1987
Sanger DJ, Joly D, Zivkovic B. Behavioral effects of n.onbenzodiazepine anxiolytic drugs: it comparison of COS 9896 and z.opiclone with chlordiazepoxide. Journal .of Pharmacological and Experimental Therapeutics 232: 831-837, 1985
Sanghera MK, McMillen BA, German De. Buspirone, a non-benzodiazepine anxiolytic, increases locus coeruleus noradrenergic neuronal activity. European Journal .of Pharmac.ology 86: 107-110, 1983
Schatzberg AF, Dessain E, O'Neil P, Katz DL, Cole J. Recent studies .on selective serotonergic antidepressants: trazodone, flu.oxetine, and fluvoxamine. Journal of Clinical Psych.opharmacology 7 (Suppl.): 44S-49S, 1987
Schweizer EE, Amsterdam J, Rickels K, Kaplan M, Dr.oba M. Open trial .of buspirone in the treatment of maj.or depressive disorder. Psychopharmacology Bulletin 22 (I): 183-185, 1986
Segal M. Serotonergic innervation ofthe locus coeruleus from the d.orsal raphe and its acti.on on responses to n.oxi.ous stimuli. Journal of Physiology 286: 401-415, 1979
Sheehan DV, Raj AB, Sheehan KH, Sot.o S. Is buspirone effective for panic disorder? Journal of Clinical Psychopharmacology 10 (I): 3-11, 1990
Shimizu H, Hirose A, Tatsuno T, Nakamura M, Katsube J. Pharmacological properties of SM-3997: a new anxi.oselective anxiolytic candidate. Japanese Journal of Pharmacology 45: 493-500, 1987
Soubrie P. Reconciling the role of central serotonin neurons in human and animal behavi.or. Behavioral and Brain Sciences 9: 319-354, 1986
Soulairac A, Lambinet H, Aymard N. Action du precurseur de la ser.ot.onine, Ie 5-hydroxy-tryptophane sur la symptomatologie agressive. Annales Medico-Psychologiques 2: 459-463, 1976
Stolz JF, Marsden CA, Middlemiss DN. Effect of chronic antidepressant treatment and subsequent withdrawal on (3H)-5-hydroxytryptamine and (3H)-spiperone binding in rat frontal cortex and serotonin receptor mediated behaviour. Psychopharmacology (Berlin) 80: 150-155, 1983
Taylor DP, Riblet LA, Stanton He. Dopamine and antianxiety activity. Pharmacology, Biochemistry and Behaviour 17 (Suppl. I): 25-35, 1982
Th.oren P, Asberg M, Cronholm B, Jornestedt L, Traskman L. Cl.omipramine treatment .of .obsessive-compulsive disorder: I. A controlled clinical trial. Archives of General Psychiatry 37: 1281"1285, 1980
T.ollefson.Gq. ~er.otonin and alcohol: interrelationships. Psychopathology 22 (Suppl. I): 37-48, 1989
Tomp~in:~ Eq, Clemtmto AJ , Taylor DP, Perhach JL. Inhibition of aggres~iye behaviour in rhesus monkeys by buspir.one. ResearchiCdnununications in Psychology and Psychiatric Behavior ~: ; ~37-;352, 1980
Tye N€, 'iEvefiU BJ, Iversen SD. 5-Hydroxytryptamine and punc ishm~nt. ~ature 268: 741-743, 1977
Vande~Maelen CP, Wilderman Re. Buspirone, a non-benzodiazepin¢ a~xiolytic idrug, causes inhibition of serotonergic dorsal raphe neurons lin the rat brain slice. Abstract. Social Neuroscience 10: 259, 11984a
Vanded\1!1elen CP, Vrilderman Re. Iontophoretic and systemic admir\istr~tion of the non-benzodiazepine anxiolytic drug bu-
Future of 5-HTIA Partial Agonists
Moss HB. Serotonergic activity and disinhibitory psychopathy in alcoholism. Medical Hypotheses 23: 353-361 , 1987
Murphy SM, Owen R, Tyrer P. Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone. British Journal of Psychiatry 154: 529-534, 1989
Naranjo CA, Sellers EM, Sullivan JT, Woodley DV, Kadlec K, et al. The serotonin uptake inhibitor catalopram attenuates ethanol intake. Clinical Pharmacological Therapy 41 : 266-274, 1987
Naumenko EV, Popova NK, Nikulina EM,Oygalo NN, Shiskina GT, et al. Behavior, adrenocortical activity, and brain monoamines in Norway rats selected for reduced aggressiveness towards man. Pharmacology, Biochemistry and Behavior 33 (I): 85-91, 1989
Neppe VM. High-dose buspirone in case of tardive dyskinesia. Lancet 2 (8677): 1458, 1989
Nystrom C, Hallstrom T. Comparison between a serotonin and a noradrenaline reuptake blocker in the treatment of depressed outpatients: a cross-over study. Acta Psychiatrica Scandinavica 75: 377-382, 1987
Palfreyman MG, Mir AK, Kubina M, Middlemiss DN, Richards M, et al. Monoamine receptor sensitivity changes following chronic administration of MDL 72394, a site-directed inhibitor of monoamine oxidase. European Journal of Pharmacology 106: 539-546, 1986
Pato MT, Pigott TA, Hill JL, Grover G, Bernstein SE, et al. Clomipramine vs buspirone in OCD: a controlled trial. New Research Program and Abstracts of the Annual Meeting of the American Psychiatric Association, p. 34, San Francisco, May 6-11 , 1989
Pecknold JC, Matas M, Howarth BG, Ross C, Swinson R, et al. Evaluation of buspirone as an antianxiety agent: buspirone and diazepam versus placebo. Canadian Journal of Psychiatry 34: 766-771, 1989
PeriCii: D, Manev H. Behavioural evidence for simultaneous dual changes of 5-HT receptor subtypes: mode of antidepressant action? Life Sciences 42: 2593-2601 , 1988
Peroutka SJ, Sleight AJ , McCarthy BG, Pierce PA, Schmidt A W, et al. The clinical utility of pharmacological agents that act as serotonin receptors. Journal of Neuropsychiatry I (3): 253-262, 1989
Peroutka SJ, Snyder SH. Multiple serotonin receptors: differential binding of (3H) serotonin, (3H) lysergic acid diethylamide, and (3H) spiroperidol. Molecular Pharmacology 16: 687-699,1979
Pierce W A, Bielefeld M. Buspirone-induced mania. Journal of Clinical Psychopharmacology 9: 150-151 , 1989
Pohl R, Balon R, Yeragani VK, Gershon S. Serotonergic anxioIytics in the treatment of panic disorder: a controlled study with buspirone. Psychopathology 22 (Suppl. I): 60-67, 1989
Privette TH, Hornsby RI, Myers RD. Buspirone alters alcohol drinking induced in rats by tetrahydropapaveroline injected into brain monoaminergic pathways. Alcohol 5: 147-152, 1988
Rakel RE. Long term buspirone therapy for chronic anxiety: a multicenter international study to determine safety. Southern Medical Journal 83 (2): 194-198, 1990
Ratey 11, Sovner R, Mikkelsen E, Chmielinski HE. Buspirone therapy for m~ladaptive behavior and anxiety in developmentally disabl¢d persons. Journal of Clinical Psychiatry 50 (10): 382-384, 1'989
Riblet LA, Taylor DP, Eison MS, Stanton He. Pharmacology and neurochemistry of buspirone. Journal of Clinical Psychiatry 43: 11-16, 1982
Rickels K. Recent advances in anxiolytic therapy. Journal of Clinical Psychiatry 42: 40-44, 1981
Rickels K, WeisJtian K, Norstad N, Singer M, Stoltz D, et al. Buspirone and diazepam in anxiety: a controlled study. Journal of Clinical Psychiatry 43 (12): 18-86, 1982
Robinson DS, Alms DR, Shrotriya RC, Messina M, Wickramar-
17
atne P. Serotonergic anxiolytics and treatment of depression. Psychopathology 22 (Suppl. I): 27.36, 1989
Robinson DS, Shrotriya RC, Alms DR, Messina M, Andary J. Treatment of panic disorder: nonbenzodiazepine anxiolytics, including buspirone. Psychopharmacology Bulletin 25 (I): 21-26, 1989a
R.owan MJ, Anwyl R. Neurophysiological effects .of bus pirone and ipsapirone in the hippocampus: comparison with 5-hydroxytryptamine. Eur.opean Journal of Pharmac.ology 141 : 479~483, 1987
Sanger DJ, Joly D, Zivkovic B. Behavioral effects of n.onbenzodiazepine anxiolytic drugs: it comparison of COS 9896 and z.opiclone with chlordiazepoxide. Journal .of Pharmacological and Experimental Therapeutics 232: 831-837, 1985
Sanghera MK, McMillen BA, German De. Buspirone, a non-benzodiazepine anxiolytic, increases locus coeruleus noradrenergic neuronal activity. European Journal .of Pharmac.ology 86: 107-110, 1983
Schatzberg AF, Dessain E, O'Neil P, Katz DL, Cole J. Recent studies .on selective serotonergic antidepressants: trazodone, flu.oxetine, and fluvoxamine. Journal of Clinical Psych.opharmacology 7 (Suppl.): 44S-49S, 1987
Schweizer EE, Amsterdam J, Rickels K, Kaplan M, Dr.oba M. Open trial .of buspirone in the treatment of maj.or depressive disorder. Psychopharmacology Bulletin 22 (I): 183-185, 1986
Segal M. Serotonergic innervation ofthe locus coeruleus from the d.orsal raphe and its acti.on on responses to n.oxi.ous stimuli. Journal of Physiology 286: 401-415, 1979
Sheehan DV, Raj AB, Sheehan KH, Sot.o S. Is buspirone effective for panic disorder? Journal of Clinical Psychopharmacology 10 (I): 3-11, 1990
Shimizu H, Hirose A, Tatsuno T, Nakamura M, Katsube J. Pharmacological properties of SM-3997: a new anxi.oselective anxiolytic candidate. Japanese Journal of Pharmacology 45: 493-500, 1987
Soubrie P. Reconciling the role of central serotonin neurons in human and animal behavi.or. Behavioral and Brain Sciences 9: 319-354, 1986
Soulairac A, Lambinet H, Aymard N. Action du precurseur de la ser.ot.onine, Ie 5-hydroxy-tryptophane sur la symptomatologie agressive. Annales Medico-Psychologiques 2: 459-463, 1976
Stolz JF, Marsden CA, Middlemiss DN. Effect of chronic antidepressant treatment and subsequent withdrawal on (3H)-5-hydroxytryptamine and (3H)-spiperone binding in rat frontal cortex and serotonin receptor mediated behaviour. Psychopharmacology (Berlin) 80: 150-155, 1983
Taylor DP, Riblet LA, Stanton He. Dopamine and antianxiety activity. Pharmacology, Biochemistry and Behaviour 17 (Suppl. I): 25-35, 1982
Th.oren P, Asberg M, Cronholm B, Jornestedt L, Traskman L. Cl.omipramine treatment .of .obsessive-compulsive disorder: I. A controlled clinical trial. Archives of General Psychiatry 37: 1281"1285, 1980
T.ollefson.Gq. ~er.otonin and alcohol: interrelationships. Psychopathology 22 (Suppl. I): 37-48, 1989
Tomp~in:~ Eq, Clemtmto AJ , Taylor DP, Perhach JL. Inhibition of aggres~iye behaviour in rhesus monkeys by buspir.one. ResearchiCdnununications in Psychology and Psychiatric Behavior ~: ; ~37-;352, 1980
Tye N€, 'iEvefiU BJ, Iversen SD. 5-Hydroxytryptamine and punc ishm~nt. ~ature 268: 741-743, 1977
Vande~Maelen CP, Wilderman Re. Buspirone, a non-benzodiazepin¢ a~xiolytic idrug, causes inhibition of serotonergic dorsal raphe neurons lin the rat brain slice. Abstract. Social Neuroscience 10: 259, 11984a
Vanded\1!1elen CP, Vrilderman Re. Iontophoretic and systemic admir\istr~tion of the non-benzodiazepine anxiolytic drug bu-
18
spirone causes inhibition of serotonergic dorsal raphe neurons in rats. federation Proceedings 43: 947, 1984b
Virkkunen M, Nuutila A, Goodwin fK, Linnoila M. Cerebrospinal fluid monoamine metabolite levels in male arsonists. Archives of General Psychiatry 44: 241-247,1987
Volavka J, Neziroglu F, Yaryura-Tobias JA. Clomipramine and imipramine in obsessive-compulsive disorder. Psychiatry Research 14:83-91, 1985
Weiner SA, De Montigny C, Desroches J, Desjardins P, SuranyiCadotte BE. Autoradiographic quantificiation of serotonin I A receptors in rat brain following antidepressant drug treatment. Synapse 4: 347-352, 1989
Westen berg HG, Den Boer JA. Serotonin-influencing drugs in the treatment of panic disorder. Psychopathology 22 (Suppl. I): 68-77; 1989
Drugs 41 (1) 1991
Wheatley D. Buspirone: multicenter efficacy study. Journal of Clinical Psychiatry 43 (12): 92-94, 1982
Willner P. Antidepressants and serotonergic neurotransmission: an integrative review. Psychopharmacology (Berlin) 85: 387-404, 1985
Yaryura-Tobias JA, Bhagavan HN. L-tryptophan in obsessivecompulsive disorders. American Journal of Psychiatry 134: 1298-1299, 1977
Young SN, Teff KL Tryptophan availability, 5HT synthesis and 5HT function. Progress in Neuro-Psychopharmacology and Biological Psychiatry 13 (3-4): 373-379. 1989
Correspondence and reprints: Dr Debra A. Glitz, Adult Outpatient Department, Lafayette Clinic, 951 East Lafayette, Detroit, MI 48207, USA.
British Geriatrics Society for the health of the aged
Spring Scientific Meeting Date: 4-6 April 1991
Venue: Belfast, Northern Ireland
For further information please contact: Administrative Director
1 St Andrew's Place Regent's Park
London NWI 4LB ENGLAND
18
spirone causes inhibition of serotonergic dorsal raphe neurons in rats. federation Proceedings 43: 947, 1984b
Virkkunen M, Nuutila A, Goodwin fK, Linnoila M. Cerebrospinal fluid monoamine metabolite levels in male arsonists. Archives of General Psychiatry 44: 241-247,1987
Volavka J, Neziroglu F, Yaryura-Tobias JA. Clomipramine and imipramine in obsessive-compulsive disorder. Psychiatry Research 14:83-91, 1985
Weiner SA, De Montigny C, Desroches J, Desjardins P, SuranyiCadotte BE. Autoradiographic quantificiation of serotonin I A receptors in rat brain following antidepressant drug treatment. Synapse 4: 347-352, 1989
Westen berg HG, Den Boer JA. Serotonin-influencing drugs in the treatment of panic disorder. Psychopathology 22 (Suppl. I): 68-77; 1989
Drugs 41 (1) 1991
Wheatley D. Buspirone: multicenter efficacy study. Journal of Clinical Psychiatry 43 (12): 92-94, 1982
Willner P. Antidepressants and serotonergic neurotransmission: an integrative review. Psychopharmacology (Berlin) 85: 387-404, 1985
Yaryura-Tobias JA, Bhagavan HN. L-tryptophan in obsessivecompulsive disorders. American Journal of Psychiatry 134: 1298-1299, 1977
Young SN, Teff KL Tryptophan availability, 5HT synthesis and 5HT function. Progress in Neuro-Psychopharmacology and Biological Psychiatry 13 (3-4): 373-379. 1989
Correspondence and reprints: Dr Debra A. Glitz, Adult Outpatient Department, Lafayette Clinic, 951 East Lafayette, Detroit, MI 48207, USA.
British Geriatrics Society for the health of the aged
Spring Scientific Meeting Date: 4-6 April 1991
Venue: Belfast, Northern Ireland
For further information please contact: Administrative Director
1 St Andrew's Place Regent's Park
London NWI 4LB ENGLAND
