BIOL PSYCHIATRY 19oi :~,;;:413-410
413
Panic Attacks in Healthy Vc !unteers Treated w,;t h a Catechohunine Synthesis Inhibitor Una D. McCann, David M. Peneta~', and Gregory Belenky
Introduction "lhough the etiology of panic attacks is not known, evidence for altered adrenergic function m some patients with panic disorder, coupled with tile ability for adrenergic agonists ,~ induce p~mic in a subgroup of normal individuals (Chamey and Hen~nger 1986), has led several researchers to postulate that abnormal regtflation of noradrenergic neuronal function may underlie panicogenesis (Charney et al 1987; Cameron et al 1990). We now report that atpha-me,hyl-paratyrosine (AMFT), a drug tt~at :~c'ro~.ses brain concentratio~, of catecholamines by competitively inhibiting tyrosine hydroxylase {Nagatsu et al 19(r~)~ the rate-lim;.ting step in ,:azc~i~oP amine synthesis (L,wit* et al 1965), may cat~,c panic in normal individuals. This was an i~ci dental finding during the co,arse of a study investigating the role ~f catecholamines in alertness, sleep, and cognitive performance. Methods Forty medically healthy male volunteers, aged 21-36 years, were recruited via newspaper ad-
Hun~an voluntet:r ~,pamlicipated in this stwJy after giving ~heir free a~d infinn~edc~n'J~,~l,hwestigator'~i~i~r,ed to AR 70~25atxl USAMRDC Reg 70-25 on the use of volunleel's ill research, The o1:in./ons~r assertions ~;onlai~'~cdherein ar~:the pr~va+¢views of,'he au',h~rxaim a~e not to I~:construed asoft~ciat or'is vellectwgtile viewsoDhe Departmerit ol the Army or the Department of Dc|i.'n~,e. From ~i~e Depa~imcm oi Bet~avior'al Bfiflogy, Wallet !,:eed Army Institute of Resei~ch. Washinglon DC (UDM, DMP, GB) atRl Deparlment of Psychiatry Unif~tmed Services University of tt~e Health Science~;, Bethesda, MD 20889 (UDM) Address reprint requests to Dr. Usa D. M¢Cann, The ~ p , ~ r ~ e n l of Behavioral Biology, Walter R¢.'ed AmW h3slitute of Re,search, Washington. IX." 20307-5100. Rrceived August 22, lt~); rcvi~d April 2, 1991.
:!~ 1991 Society of Biological Psychiatry
vertiscments. S~bjects and their first-degr¢ :~,relatives were free of significant psychiatric illness. All subjects gave informt;d consent prior to study participation. Subjects were randomized to one of fbur conditions: (1) sleep depi-':,a|ion (no sleep tbr 40.5 hr) plus treatment with AMlrl ', N = 11; (2) sleep deprivation p~u,~; treatment with lacto~ placebo, n = 10; (3) nightly rest (7~ hr per night) plus treatment with AMPT, n = !0; or (4) nightly rest plu~; treatment with lactose placetx3, n = O. After ~' ~?ights of steep io ii~c lalx~rakJiy0 ~reatme~a~ ~'1,~.i~AMF[' was initiated. A M F f (or t~ZlClCli:'~ ~ +'+'+:'~S ~t ,+ ministered orally at a dosage of 7§0 t~%~, approximately ever), 6 hr over a 2-day Weriod fi)r a total of seven doses (total do~: = 5.25 g). °Ibis dosage has Ix.~en found to ~.ad to a 70%-80% decrease in tyrosine hydroxyla~ activity (Engelman ct al 1968b) with an associated 50%-59% dec::case in catechotanfine metabolites in cerebro:;pinal fluid, and 68%-77% decrease in uri~ary catechoiammc mctadx31ites (Bunney et al 1t971, 1977: Wyatt et al 1971). The drug was administered in a double-blind fashion. Sleep conditions were not blinded. Over the 5-day stugy, repeated measures :ff cognitive peribrmal;i;~3, ~ocd, a~d alertl;~%s wc~e taken using a computerized b~ite~y fF~ , ' ~ e ~, al 1985), sleep latency tests (Carskadon and Dc~ ment 1982), ambulatory electroencephalogram (EEG), and a visual analogue ~ale (Monk 1989). Laboratory assistants monitored subjects at all times to ensure that they remained awake during the experiment. ~)6-3223/91/$03.50
414
BlOt,PSYCHIATRY 199~;3~J:,~3-416
Brief Reports
scribed, !?~'~re~3.fiveco~tfibution of thcir underlying di?,=, ~,.~ ;:~3~tilat of AMPT were not clear. Of the 21 subjects who received AMPT, 3 deCur finding, of an association betw,,~n AIVLlrI"and veloped symptoms that fulfilled criteria for DSM~ panic in :;e~iithy individuals suggests that reIII-R panic attacks (Spitzer and Wiiliarn~, 198"~)~ d u c ~ CN5 catecholamines were involved. No subjects who received placebo developed I-he development of panic symptoms in the panic. Timing of panic attacks relative to drug setting of decreased CNS catecholamine concenadministration and sleep deprivation are illustratio,~s might seem contrary to the concept of intrated in Table 1. Both sleep-deprived (n = 2) creased noradrenergic activity in panicogenesis. and rested (n = l) individuals developed panic However, there are several potential mechaattacks, suggesting that AMPT alone may be nisms by which acute depletions of CNS catesufficient to induce panic. cholamines could lead to increased noradrenerFor all 3 subjects, self-rated measures of anxgic activity. For example, acute AMPT-induced iety waxed and waned alter their firs~ panic atdepletion of CNS norepinephri'ne concentrations tack, and were unrelated to time of day, extent could lead to decreased feedback inhibition via of sleep deprivation, or time since the last dose presynaptic alpha-2 autoreceptors. This in turn of AMPT. While taking AMPT, all 3 subjects might augment the release of remaining preexhad repeated episodes of panic. Following cesisting presynaptic norepinephrine (possibly actsatior~ of medication (and resumption of normal ing at supersensitive postsynaptic receptors). sleep-wake scheduling for the sleep-deprived Further, as AMPT only depletes tht cytoplasmic subjects), mild anxiety persisted for approxipool of catecholamines (Selden and Dykstra mately 18 hr in all 3 subjects. Follow-up by an 1977), following depletion of cytoplasmic norinvestigator 9 months after the stud)' revealed epinephrine by AMPT, the unaffected granular that no subject had further attac;~s of panic or pool may be mobilized, intermittently increasing periods of unusual anxiety. available cytoplasmic norepinephrine for release. It scould be no~-d that tbzagh AMPT depletes Comment cytoplasmic stores of norepinephrine, it also deThe present results suggest that AMPT, a central pletes brain dopamine stores. As manipulations nervous system (CNS) catecholamine depleting cf one neurotransm~tter system often lead to secagent (~'ech et al 1966), may cause panic in ondary alterations in other systems, it is i~,,~3rhe ~|~ty individuals. Though this is the first such tant to consider that alterations in one or several report, AMPT-associated anxiety has been re- neurotransmitter systems (e.g., dopamine, norported in ~..~!nical trial of AMPT in patients with epinephrine, serotoni~) might also have contriba variety of medical conditions (Engelman et al uted to the genesis of panic attacks in these sub~ 1968b), including essential hypertension, Ray- jects. naud's phenomenon, and pheochromocytoma. This report should be considered preliminary. Given the nature of the p .tient population~ de- for several reasons. Because sleep deprivation
Results
Table !. Characteristics of Subjects Who Developed Panic Subject n~,mber
Age
2t ~ 228 244
28 30 25
Race
Hr awakeat time of first panic attack
Number of doses (750 rag) at time of first panic attack
Caucasian Asian Caucasian
24.5 nr (sleep-deprived) 30 hr (sleep-deprived) 15 hr (rested)
4 doses (cumulati~'edose. = 3 g) 4 doses (cumulativedose = 3 g) 6 doses (cumulativedose = 4.5 g)
Hr since last dose of AMPT
Brief Reports
alone can provoke panic attacks in patients with panic disorder (Roy-Byme et ~1 1986), it is possible that sleep deprJvati'~n or the vigorous testing procedures of the experiment contributed to panic symptoms in these healthy individuals. However, to date, over 150 subjects have been sleep deprived for a 64-hr period (as compared with 40.5 hr in this study) in ti~e same experimental facility using similar experimental procedures with other test drugs, and none have developed panic. Nevertheless, given the small number of individuals described, this hypothesis merits a prospective test with a larger population. It is also possible that the 3 subjects described had previously undiagnosed panic disorder. However, given the absence of such a history" as well as the absence of additional panic attacks for,owing completion of the study, this seems unlikely. Indeed, AM!rr's panic-inducing effects persisted only for the period that AMPT has been found to remain in the serum (Engelman et al 1968a), and before catecholamine levels return to baseline (Engelman et al 1968b). The temporal relationship between AMPT administration and subsequent panic attacks provides further support for the concept that AMVr played a role in panic symptom production. In summary, the finding that AMPT may induce panic attacks in healthy individuals is consistent with the view that brain noradrenergic neurons are involved in panic disorder. Furthermore, the fact that both decreases and increases in CNS catecholamines may be sufficient to induce panic could be taken to indicate that acute dysregulation of noradrenergic neurotransmission, rather than increases in baseline noradrenergic functioning per se, may form the basis of panicogenesis.
B1OL PSYCHIATRY 1991;30:4!3-4t6
415
L-dopa, and L-tryptophan in depression and mania. Am J P~ychiat~y 127(7):872-881.
Bunney WE, Kopanda RT, Murphy DL (1977): Sleep and behavioral changes possibly reflecting central receptor hypersensitivity following catecholamine synthesis inhibition in man. Acta P~chiatr Scand 56:189-203. Cameron OG, Smith CD, Lee MA, Hollingsworth PJ, Hill EM, Curtis GC (1990): Adrenergic status in anxiety disorders: Platelet alpha 2-adrenergic receptor binding, blood pressure, pulse, and plasma catecholamines in panic znd generalized anxiety disorder patients and in normal subjects. Biol Psychiatry 28:3-20. Carskadon MA, Dement WC (1982): The multiple sleep latency test: What does it measure? Sleep 5:s67-72. Charney DS, Heninger GR (1986): Abnormal regulation of noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 43:1042-1054. Charney DS, Woods SW, Goodman WK, Heninger GR (1987): Neurobiological mechanisms of panic aaxiety: Biochemical and behavioral correlates of yobimbine-induced panic attacks. Am J Psychiatry 144:1030-1036. Engelman K, Jequier E, Udenfriend S, Sjoerdsma A (1968a): Metabolism of alpha-methyltyrosine in man: Relationship to its potency as an inhibito,~ ofcatecholamine biosynthesis.J Clin Invest 47:568576. Engelman K, Horwitz D, Jequier E, Sjoerdsma A (1968b): Biochemical and pharmacologic effects of alpha-methyl-para-tyrosine in man. J Clin Invest 47:577-593. Levitt M, Spector S, Sjoerdsma A, Udenfriend S (1965): Elucidation of the rate-limiting ~tep in norepinepbxine biosynthesis in the perfused pig heart. J Pharmacol Exp Thor 148:1-8. Monk TH (1989) A visual analogue scale technique to measure global vigor and affect. Psychiatry Res 27:89-99. Nagatsu T, Levitt M, Udenfriend S (t964): Tyrosine hydmxylase--the initial step in norepinephrine biosynthesis. J Biol Chem 239:2910-2917. The authors gratefully acknowledge the invaluable help provided by the staff of the Department of Behavioral Rech RH, Borys HK, Moore KE (1966): Alterations Biologyin conductingthese studies. in behavior and brain cateeholamine levels in rats ~,.ted with alpha-methyltyrosine. J Pharmacol Exp Ther t53(3):412-419. Roy-Byrne PP, Uhde TW, Post RM (1986): Effects References of one night's sleep deprivation on mood and behavior in panic disorder. Arch Gen Psychiatry. Bunney WE, Brodie HKH, Murphy DL, Goodwin 43:895-899. FK (1971): Studies of alpha-methyl-para-tyrosine,
416
BIOLPSYCHIATRY
Brief Reports
1991;30:413-416
Seiden LS, Dykstra LA (1977): Dopamine, norepinephrine and behavior. In Seiden LS, Dykstra LA (eds), Psychopharmacology: A Biochemical and Behavioral Approach. New York: Van Nostrand Reinhold Co, pp 151-152. Spitzer RL, Williams JBW (eds) (1987) Dicgnostic and Statistical Manual of Mental Disorders D~MIII-R. (ed 3-revised). Washington, DC: American
Psychiatric Association.
Thome D, Genser S, Sing H, Hegge F (1985): The Walter Reed performance assessment battery. Neurobehav Toxicol Teratol 7:415--418. Wyatt RJ, Chase TN, Kupfer DJ, Scott J, Snyder F (1971): Brain cat:.~cholamines and human sleep. Nature 233:63-05.
413
Panic Attacks in Healthy Vc !unteers Treated w,;t h a Catechohunine Synthesis Inhibitor Una D. McCann, David M. Peneta~', and Gregory Belenky
Introduction "lhough the etiology of panic attacks is not known, evidence for altered adrenergic function m some patients with panic disorder, coupled with tile ability for adrenergic agonists ,~ induce p~mic in a subgroup of normal individuals (Chamey and Hen~nger 1986), has led several researchers to postulate that abnormal regtflation of noradrenergic neuronal function may underlie panicogenesis (Charney et al 1987; Cameron et al 1990). We now report that atpha-me,hyl-paratyrosine (AMFT), a drug tt~at :~c'ro~.ses brain concentratio~, of catecholamines by competitively inhibiting tyrosine hydroxylase {Nagatsu et al 19(r~)~ the rate-lim;.ting step in ,:azc~i~oP amine synthesis (L,wit* et al 1965), may cat~,c panic in normal individuals. This was an i~ci dental finding during the co,arse of a study investigating the role ~f catecholamines in alertness, sleep, and cognitive performance. Methods Forty medically healthy male volunteers, aged 21-36 years, were recruited via newspaper ad-
Hun~an voluntet:r ~,pamlicipated in this stwJy after giving ~heir free a~d infinn~edc~n'J~,~l,hwestigator'~i~i~r,ed to AR 70~25atxl USAMRDC Reg 70-25 on the use of volunleel's ill research, The o1:in./ons~r assertions ~;onlai~'~cdherein ar~:the pr~va+¢views of,'he au',h~rxaim a~e not to I~:construed asoft~ciat or'is vellectwgtile viewsoDhe Departmerit ol the Army or the Department of Dc|i.'n~,e. From ~i~e Depa~imcm oi Bet~avior'al Bfiflogy, Wallet !,:eed Army Institute of Resei~ch. Washinglon DC (UDM, DMP, GB) atRl Deparlment of Psychiatry Unif~tmed Services University of tt~e Health Science~;, Bethesda, MD 20889 (UDM) Address reprint requests to Dr. Usa D. M¢Cann, The ~ p , ~ r ~ e n l of Behavioral Biology, Walter R¢.'ed AmW h3slitute of Re,search, Washington. IX." 20307-5100. Rrceived August 22, lt~); rcvi~d April 2, 1991.
:!~ 1991 Society of Biological Psychiatry
vertiscments. S~bjects and their first-degr¢ :~,relatives were free of significant psychiatric illness. All subjects gave informt;d consent prior to study participation. Subjects were randomized to one of fbur conditions: (1) sleep depi-':,a|ion (no sleep tbr 40.5 hr) plus treatment with AMlrl ', N = 11; (2) sleep deprivation p~u,~; treatment with lacto~ placebo, n = 10; (3) nightly rest (7~ hr per night) plus treatment with AMPT, n = !0; or (4) nightly rest plu~; treatment with lactose placetx3, n = O. After ~' ~?ights of steep io ii~c lalx~rakJiy0 ~reatme~a~ ~'1,~.i~AMF[' was initiated. A M F f (or t~ZlClCli:'~ ~ +'+'+:'~S ~t ,+ ministered orally at a dosage of 7§0 t~%~, approximately ever), 6 hr over a 2-day Weriod fi)r a total of seven doses (total do~: = 5.25 g). °Ibis dosage has Ix.~en found to ~.ad to a 70%-80% decrease in tyrosine hydroxyla~ activity (Engelman ct al 1968b) with an associated 50%-59% dec::case in catechotanfine metabolites in cerebro:;pinal fluid, and 68%-77% decrease in uri~ary catechoiammc mctadx31ites (Bunney et al 1t971, 1977: Wyatt et al 1971). The drug was administered in a double-blind fashion. Sleep conditions were not blinded. Over the 5-day stugy, repeated measures :ff cognitive peribrmal;i;~3, ~ocd, a~d alertl;~%s wc~e taken using a computerized b~ite~y fF~ , ' ~ e ~, al 1985), sleep latency tests (Carskadon and Dc~ ment 1982), ambulatory electroencephalogram (EEG), and a visual analogue ~ale (Monk 1989). Laboratory assistants monitored subjects at all times to ensure that they remained awake during the experiment. ~)6-3223/91/$03.50
414
BlOt,PSYCHIATRY 199~;3~J:,~3-416
Brief Reports
scribed, !?~'~re~3.fiveco~tfibution of thcir underlying di?,=, ~,.~ ;:~3~tilat of AMPT were not clear. Of the 21 subjects who received AMPT, 3 deCur finding, of an association betw,,~n AIVLlrI"and veloped symptoms that fulfilled criteria for DSM~ panic in :;e~iithy individuals suggests that reIII-R panic attacks (Spitzer and Wiiliarn~, 198"~)~ d u c ~ CN5 catecholamines were involved. No subjects who received placebo developed I-he development of panic symptoms in the panic. Timing of panic attacks relative to drug setting of decreased CNS catecholamine concenadministration and sleep deprivation are illustratio,~s might seem contrary to the concept of intrated in Table 1. Both sleep-deprived (n = 2) creased noradrenergic activity in panicogenesis. and rested (n = l) individuals developed panic However, there are several potential mechaattacks, suggesting that AMPT alone may be nisms by which acute depletions of CNS catesufficient to induce panic. cholamines could lead to increased noradrenerFor all 3 subjects, self-rated measures of anxgic activity. For example, acute AMPT-induced iety waxed and waned alter their firs~ panic atdepletion of CNS norepinephri'ne concentrations tack, and were unrelated to time of day, extent could lead to decreased feedback inhibition via of sleep deprivation, or time since the last dose presynaptic alpha-2 autoreceptors. This in turn of AMPT. While taking AMPT, all 3 subjects might augment the release of remaining preexhad repeated episodes of panic. Following cesisting presynaptic norepinephrine (possibly actsatior~ of medication (and resumption of normal ing at supersensitive postsynaptic receptors). sleep-wake scheduling for the sleep-deprived Further, as AMPT only depletes tht cytoplasmic subjects), mild anxiety persisted for approxipool of catecholamines (Selden and Dykstra mately 18 hr in all 3 subjects. Follow-up by an 1977), following depletion of cytoplasmic norinvestigator 9 months after the stud)' revealed epinephrine by AMPT, the unaffected granular that no subject had further attac;~s of panic or pool may be mobilized, intermittently increasing periods of unusual anxiety. available cytoplasmic norepinephrine for release. It scould be no~-d that tbzagh AMPT depletes Comment cytoplasmic stores of norepinephrine, it also deThe present results suggest that AMPT, a central pletes brain dopamine stores. As manipulations nervous system (CNS) catecholamine depleting cf one neurotransm~tter system often lead to secagent (~'ech et al 1966), may cause panic in ondary alterations in other systems, it is i~,,~3rhe ~|~ty individuals. Though this is the first such tant to consider that alterations in one or several report, AMPT-associated anxiety has been re- neurotransmitter systems (e.g., dopamine, norported in ~..~!nical trial of AMPT in patients with epinephrine, serotoni~) might also have contriba variety of medical conditions (Engelman et al uted to the genesis of panic attacks in these sub~ 1968b), including essential hypertension, Ray- jects. naud's phenomenon, and pheochromocytoma. This report should be considered preliminary. Given the nature of the p .tient population~ de- for several reasons. Because sleep deprivation
Results
Table !. Characteristics of Subjects Who Developed Panic Subject n~,mber
Age
2t ~ 228 244
28 30 25
Race
Hr awakeat time of first panic attack
Number of doses (750 rag) at time of first panic attack
Caucasian Asian Caucasian
24.5 nr (sleep-deprived) 30 hr (sleep-deprived) 15 hr (rested)
4 doses (cumulati~'edose. = 3 g) 4 doses (cumulativedose = 3 g) 6 doses (cumulativedose = 4.5 g)
Hr since last dose of AMPT
Brief Reports
alone can provoke panic attacks in patients with panic disorder (Roy-Byme et ~1 1986), it is possible that sleep deprJvati'~n or the vigorous testing procedures of the experiment contributed to panic symptoms in these healthy individuals. However, to date, over 150 subjects have been sleep deprived for a 64-hr period (as compared with 40.5 hr in this study) in ti~e same experimental facility using similar experimental procedures with other test drugs, and none have developed panic. Nevertheless, given the small number of individuals described, this hypothesis merits a prospective test with a larger population. It is also possible that the 3 subjects described had previously undiagnosed panic disorder. However, given the absence of such a history" as well as the absence of additional panic attacks for,owing completion of the study, this seems unlikely. Indeed, AM!rr's panic-inducing effects persisted only for the period that AMPT has been found to remain in the serum (Engelman et al 1968a), and before catecholamine levels return to baseline (Engelman et al 1968b). The temporal relationship between AMPT administration and subsequent panic attacks provides further support for the concept that AMVr played a role in panic symptom production. In summary, the finding that AMPT may induce panic attacks in healthy individuals is consistent with the view that brain noradrenergic neurons are involved in panic disorder. Furthermore, the fact that both decreases and increases in CNS catecholamines may be sufficient to induce panic could be taken to indicate that acute dysregulation of noradrenergic neurotransmission, rather than increases in baseline noradrenergic functioning per se, may form the basis of panicogenesis.
B1OL PSYCHIATRY 1991;30:4!3-4t6
415
L-dopa, and L-tryptophan in depression and mania. Am J P~ychiat~y 127(7):872-881.
Bunney WE, Kopanda RT, Murphy DL (1977): Sleep and behavioral changes possibly reflecting central receptor hypersensitivity following catecholamine synthesis inhibition in man. Acta P~chiatr Scand 56:189-203. Cameron OG, Smith CD, Lee MA, Hollingsworth PJ, Hill EM, Curtis GC (1990): Adrenergic status in anxiety disorders: Platelet alpha 2-adrenergic receptor binding, blood pressure, pulse, and plasma catecholamines in panic znd generalized anxiety disorder patients and in normal subjects. Biol Psychiatry 28:3-20. Carskadon MA, Dement WC (1982): The multiple sleep latency test: What does it measure? Sleep 5:s67-72. Charney DS, Heninger GR (1986): Abnormal regulation of noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 43:1042-1054. Charney DS, Woods SW, Goodman WK, Heninger GR (1987): Neurobiological mechanisms of panic aaxiety: Biochemical and behavioral correlates of yobimbine-induced panic attacks. Am J Psychiatry 144:1030-1036. Engelman K, Jequier E, Udenfriend S, Sjoerdsma A (1968a): Metabolism of alpha-methyltyrosine in man: Relationship to its potency as an inhibito,~ ofcatecholamine biosynthesis.J Clin Invest 47:568576. Engelman K, Horwitz D, Jequier E, Sjoerdsma A (1968b): Biochemical and pharmacologic effects of alpha-methyl-para-tyrosine in man. J Clin Invest 47:577-593. Levitt M, Spector S, Sjoerdsma A, Udenfriend S (1965): Elucidation of the rate-limiting ~tep in norepinepbxine biosynthesis in the perfused pig heart. J Pharmacol Exp Thor 148:1-8. Monk TH (1989) A visual analogue scale technique to measure global vigor and affect. Psychiatry Res 27:89-99. Nagatsu T, Levitt M, Udenfriend S (t964): Tyrosine hydmxylase--the initial step in norepinephrine biosynthesis. J Biol Chem 239:2910-2917. The authors gratefully acknowledge the invaluable help provided by the staff of the Department of Behavioral Rech RH, Borys HK, Moore KE (1966): Alterations Biologyin conductingthese studies. in behavior and brain cateeholamine levels in rats ~,.ted with alpha-methyltyrosine. J Pharmacol Exp Ther t53(3):412-419. Roy-Byrne PP, Uhde TW, Post RM (1986): Effects References of one night's sleep deprivation on mood and behavior in panic disorder. Arch Gen Psychiatry. Bunney WE, Brodie HKH, Murphy DL, Goodwin 43:895-899. FK (1971): Studies of alpha-methyl-para-tyrosine,
416
BIOLPSYCHIATRY
Brief Reports
1991;30:413-416
Seiden LS, Dykstra LA (1977): Dopamine, norepinephrine and behavior. In Seiden LS, Dykstra LA (eds), Psychopharmacology: A Biochemical and Behavioral Approach. New York: Van Nostrand Reinhold Co, pp 151-152. Spitzer RL, Williams JBW (eds) (1987) Dicgnostic and Statistical Manual of Mental Disorders D~MIII-R. (ed 3-revised). Washington, DC: American
Psychiatric Association.
Thome D, Genser S, Sing H, Hegge F (1985): The Walter Reed performance assessment battery. Neurobehav Toxicol Teratol 7:415--418. Wyatt RJ, Chase TN, Kupfer DJ, Scott J, Snyder F (1971): Brain cat:.~cholamines and human sleep. Nature 233:63-05.
