Susceptibility to subsequent episodes of spontaneous recurrence of methamphetamine psychosis1

Drug and Alcohol Dependence 64 (2001) 133– 142 www.elsevier.com/locate/drugalcdep

Susceptibility to subsequent episodes of spontaneous recurrence of methamphetamine psychosis Kunio Yui a,b,*,1, Kimihiko Goto c, Shigenori Ikemoto c,d, Koichi Nishijima a, Tatsuki Yoshino a, Takeo Ishiguro a b

a Department of Psychiatry, Jichi Medical School, Tochigi 329 -0498, Japan Medical Care Section, Urawa Ju6enile Classification Home, Ministry of Justice, Urawa 336 -0011, Japan c Nippon Veterinary and Animal Science Uni6ersity, Tokyo 180 -8602, Japan d Department of Legal Medicine and Human Genetics, Jichi Medical School, Tochigi 329 -0498, Japan

Received 6 June 2000; received in revised form 15 December 2000; accepted 15 December 2000

Abstract We examine susceptibility to subsequent spontaneous recurrences of methamphetamine psychosis (i.e. flashbacks) in 11 flashbackers with a single episode and in nine flashbackers with subsequent episodes. All had undergone frightening stressful experiences during previous MAP use. Mild psychosocial stressors then triggered flashbacks. During flashbacks, the nine flashbackers with subsequent episodes had more markedly increased norepinephrine levels, with slightly increased 3-methoxytyramine levels. The duration of imprisonment in this subgroup approached significantly long levels than in the 11 flashbackers with a single episode. Robust noradrenergic hyperactivity with slightly increased dopamine release may therefore predict subsequent flashbacks. Longer exposure to distressing situations may also contribute to robust noradrenergic hyperactivity. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Methamphetamine psychosis; Susceptibility; Subsequent flashbacks; Noradrenergic hyperactivity; 3-Methoxytyramine; Distressing situations

1. Introduction A severe consequence of amphetamine (AMP) or methamphetamine (MAP) abuse in non-schizophrenic subjects is paranoid-hallucinatory episodes, with vivid auditory as well as visual hallucinations and paranoid delusions (Segal and Janowsky, 1978). AMP or MAP psychosis can recur on exposure to stress in individuals with a history of MAP psychosis (i.e., flashbacks) (Sato, 1992; Yui et al., 1996). We have reported that stressful experiences during * Corresponding author. Tel.: + 81-48-8627520; fax: +81-488361372. E-mail address: [email protected] (K. Yui). 1 Institute at which the work was carried out: Department of Legal Medicine and Human Genetics, Jichi Medical School, Minamikawachi, Tochigi 329-0498, Japan, and Medical Care Section, Tochigi Prison, Ministry of Justice, Sozya 2484, Tochigi 328-0002, Japan.

MAP use may increase sensitivity to stress associated with noradrenergic hyperactivity (Yui et al., 1996, 1997), involving dopaminergic changes (Yui et al., 2000a,b), and that this increased sensitivity to stress may be important for the development of flashbacks. About 50% of subjects with flashbacks in our sample had subsequent flashbacks with shortening of remission. The first episode of affective disorder is more likely to be associated with major psychosocial stressors than subsequent episodes, so that the later episodes may imply an increasing susceptibility to recurrence in affective disorders (Ellicott et al., 1990; Post, 1992). While, some subjects experience major stress but do not show an increase in symptoms in bipolar disorder (Ellicott et al., 1990). Moreover, a previous study that used a prospective design to assess stress and symptom levels found a close similarity in the frequency or type of stress experienced by patients who relapsed and those who remained well in bipolar disorder (Hall et al.,

0376-8716/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 6 - 8 7 1 6 ( 0 0 ) 0 0 2 4 0 - 4

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1977). It is therefore possible that stress reactivity associated with noradrenergic hyperactivity and dopaminergic changes in an initial episode and in any subsequent episodes, where those occur, may differ in the first episode of flashbacks due to previous MAP psychosis. Based on this possibility, we have determined the nature of stress reactivity associated with noradrenergic hyperactivity and dopaminergic changes during the first flashback episode, in subjects with a single flashback episode and in those with subsequent flashback episodes, to determine susceptibility to subsequent flashbacks. Since increased sensitivity to stress is important for the development of flashbacks (Yui et al., 2000a,b), we study which stress factors contribute to the difference in stress reactivity between these two flashbacker subgroups.

2. Subjects and methods

2.1. Subject selection Table 1 shows a profile of the subject subgroups. The subjects were 80 physically healthy females recruited from inmates at a women’s prison. These were made up of 39 who had previously experienced MAP psychosis, eight with persistent MAP psychosis, and 33 normal controls (22 MAP users and 11 non-users, none of whom had experienced MAP psychosis or flashbacks). The subject subgroups were age-matched (between flashbacker subgroups, Z or Zc =0.05 – 1.83, P =0.07– 0.94). All subjects were deemed physically healthy, based on physical and neurological examinations and biochemical screening. Violators of the Stimulant Drug Control Law in Japan, including our subjects, are usually sentenced in a public court to up to 2 years in

prison. None had abused other substances or experienced any psychiatric disorder in the absence of MAP use. Subjects had been tested for other substances by the police and all results were negative. Of the 39 subjects with a history of MAP psychosis, 20 experienced flashbacks during their 15–20 months of incarceration (flashbackers), and the other 19 did not (non-flashbackers). The 20 flashbackers were selected on the basis that their plasma monoamine metabolite levels were assayed during the first flashback episode, and again within 30 days of its passing. Of these, 11 experienced a single flashback episode, while the other nine experienced subsequent episodes (two flashbacks per subject). The eight subjects with persistent MAP psychosis, persisting for at least 6 months (mean= 17.6910.5 S.D. months) before blood collection, were included for comparison with the 20 flashbackers (spontaneous versus persistent recurrence) to study the relation between prior exposure to stressful experiences and plasma monoamine metabolite levels. Because MAP psychosis in the 20 flashbackers had disappeared within 730 days prior to blood collection (215.49208.2 S.D. days), the 19 non-flashbackers were selected by adjustment of the time of disappearance of MAP psychosis (276.29 221.8 S.D. days). They gave informed consent before participation in the study, which was approved by the Medical Care and Classification Division of the Ministry of Justice. Our previous studies have involved 5– 6 or 8 (Yui et al., 1996, 1997, 2000a,b, respectively) of the 20 flashbackers, 10 of the 19 nonflashbackers, 15 of the 22 user controls, five of the 11 non-user controls (Yui et al., 1996, 1997), and four or seven of the eight subjects with persistent MAP psychosis (Yui et al., 1997, 2000a,b, respectively). Clinical diagnosis was confirmed using the DSM-IV criteria for AMP-induced psychotic disorder, based on a structured interview and inmate record review. Subjects were fur-

Table 1 Profile of subject subgroupsa Subject subgroup

N

MAP use

MAP psychosis

Flashbacks

Flashbackers Flashbackers with a single episodeb Flashbackers with subsequent episodes Medicated flashbackersd Later-medicated flashbackersc Non-flashbackers Subjects with persistent MAP psychosis Normal controls MAP users MAP non-users

20 11 9 7 13 19 8

+ + + + + + +

+ + + + + + +

+ + + + + − −

22 11

+ −

− −

− −

a

+, subjects who experienced methamphetamine (MAP) psychosis or related flashbacks; −, subjects who did not experience MAP psychosis or related flashbacks. b Of the 20 flashbackers, 11 experienced a single flashback episode, while the other nine experienced subsequent flashbacks. c The flashbackers who received neuroleptic treatment before and during the study. d The flashbackers who received neuroleptic treatment after blood collection during flashbacks and during remission.

K. Yui et al. / Drug and Alcohol Dependence 64 (2001) 133–142

ther screened using the Structured Clinical Interview for DSM-IV checklist to exclude those with schizophrenia, brief psychotic disorders, delusional disorder, anxiety disorders and Posttraumatic stress disorder (PTSD). To avoid biased recollections of experiences during previous MAP use, all subjects were excluded who had distinct deviations in recall and processing of their environmental stimuli, based on neurological examination. Flashbacks due to previous MAP psychosis are defined with reference to a general definition of psychedelic drug flashbacks (Matefy et al., 1978) and DSM-IV criteria for hallucinogen persisting perceptions disorder (flashbacks) as a spontaneous recurrence of MAP-induced paranoid-hallucinatory states after a period of normalcy during which the pharmacological effects of MAP had worn off. Of the 20 flashbackers, seven complained of paranoid-hallucinatory flashback states before blood collection and were accordingly treated with haloperidol (1– 2 mg/day), chlorpromazine (25– 75 mg/day) or thioridazine (25–75 mg/day) for at least 4 weeks before and during the study (medicated flashbackers). The other 13 flashbackers were unmedicated for at least 3 months prior to blood collection. However, they received the neuroleptic treatment specified above after blood collection during flashbacks, because of flashback aggravation (later-medicated flashbackers). The defining characteristics did not differ between the two subgroups. The eight subjects with persistent MAP psychosis were maintained on haloperidol (1– 9 mg/ day) or chlorpromazine (25– 125 mg/day) for at least 1 month (2.79 2.0 months) before blood collection. The 19 non-flashbackers were unmedicated for at least 3 months before and during the study, because they had no psychiatric symptoms. All subjects were free of other medications.

2.2. Stress factors Details of the pattern of MAP use, stressful experiences, and symptoms of MAP psychosis during previous MAP use were obtained from structured interviews and inmate record reviews. The interviews were conducted by two psychiatrists unaware of the subjects’ subgroups prior to the occurrence of flashbacks on admission to the prison. Questions addressed specific topics such as whether the subjects had underwent stressful experiences, what stressful experiences had occurred during previous MAP use, and what behavior the subjects had displayed. Stress is usually defined as a physical or psychological factor that poses a threat to the well-being of the subjects, producing a defensive response (Landau, 1986). Accordingly, the criteria for stressful events during previous MAP use were based on whether the subjects had been overwhelmingly distressed; whether the events met the DSM-III-R criteria

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for a severe to catastrophic type of psychosocial stressor (axis IV scores of 4–6); and whether the subjects had escaped from the stressful situations (defensive response). The criteria for MAP-induced fear-related paranoid-hallucinatory states (perception of threat) were based on whether the subjects had been overwhelmingly threatened and whether they had taken refuge near or in their houses out of fear (defensive response). Details of the factors that triggered the flashbacks were obtained from structured interviews consisting of questions about situations distressing to the subjects, including their personal relationships with inmates, and from reports made by prison staff. All subjects responded cooperatively to our interview questions. All data were verified through follow-up interviews in which the same questions were asked. Since stressful events and triggering factors were psychosocial stressors, they were assessed using the Severity of Psychosocial Stressor Scale (axis IV) from the DSM-III-R. When more than one stressor was present, the rating chosen was that of the most severe stressor. Imprisonment involves confinement in the restricted area, daily penal servitude, no visitor nor receiving sealed correspondence, restriction of free action and of diet (lowmonoamine, alcohol-free and caffeine-restricted diet), and disciplinary punishment. This usually distresses prisoners, including our subjects. To determine the effect of the duration of confinement in the prison before the beginning of blood collection on stress reactivity in the flashbacker subgroups, this duration was compared between the two flashbacker subgroups. To assess anxiety levels related to stress at the time the flashbacks occurred, the State-Trait Anxiety Inventory (STAI) was used (Spielberger, 1983). The scale consisted of two separate 20-question scales intended to measure both levels of transitory anxiety at the time of testing (state anxiety) and longer-lasting anxiety (trait anxiety). The state form of the STAI is utilized to assess subjective, consciously perceived feelings of tension or heightened autonomic nervous system activity (Mathew et al., 1981). STAI data were available for random subsamples of 12 of the 20 flashbackers at two times (when the flashbacks occurred and at remission), and at one time for random subsamples of 10 of the 19 non-flashbackers, nine of the 22 user controls, and seven of the 11 non-user controls (on admission to the prison). Blood pressure and heart rate were measured at the time of blood sampling.

2.3. Monitoring secret MAP use In Japan all prisoners in detention houses and prisons are rigorously prevented from taking MAP or other substances. Incarceration involves repeated searches. The prison staff thoroughly searched the prisoners’ belongings and clothes, and under the mats in their

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living quarters. MAP and other substances have never been used in detention houses or prisons (Ohashi, 1996). Our subjects expected to be searched by methods authorized under the Prison Law, so that they were not frightened by the searches. Venous plasma was tested for MAP in a random subsample of seven of the 20 flashbackers at the time the flashbacks occurred, using gas chromatography/mass spectrometry (Yui et al., 1996). All analyses were negative.

treatment as the between subject factor, and presence or absence of flashbacks as the within subject repeated factor (Havilcek and Crain, 1988). Comparison between the subject subgroups were performed using the Kruskal–Wallis test followed by the Mann–Whitney U-test and the  2-test.

2.4. Plasma monoamine metabolite le6els

4.1. Stress factors

All subjects were given a low-monoamine, alcoholfree and caffeine-restricted diet for at least 3 months before and during the study while confined in detention houses and the prison. Blood was obtained from the 11 flashbackers with a single episode and the nine flashbackers with subsequent episodes during the prominent paranoid-hallucinatory state of the first flashback episode, which occurred within 14 days of the occurrence of the first flashback episode, and again within 30 days after cessation of the flashbacks. The other subjects had a single blood sample assayed on admission to the prison. Blood was collected at random using venipuncture from 10:30 to 12:00 h. Subjects remained supine for 20 min before and during blood sampling. Excessive motor activity (e.g., walking around) was not allowed in the prison. Plasma was stored at −80°C until it was assayed for norepinephrine (NE) and its metabolite normetanephrine (NM); epinephrine (E); and dopamine (DA) and its metabolites 3-methoxytyramine (3-MT) and dihydroxyphenylacetic acid (DOPAC), using high-performance liquid chromatography with an electrochemical detector (Yui et al., 1996). The sensitivity was 0.01 pmol/ml except for NM, at 0.05 pmol/ml. The intra-assay and inter-assay coefficients of variation averaged 10.0 and 21.1%, respectively.

The flashbackers exhibited reactivated MAP psychosis without reexperiencing stressful events or the symptoms of PTSD or acute stress disorder as listed in the DSM-IV criteria. The number of medicated subjects did not differ significantly between the 11 flashbackers with a single episode (3/11) and the nine flashbackers with subsequent episodes (4/9) (P=0.58). The mean duration of confinement before the beginning of blood collection in the nine flashbackers with subsequent episodes (69.59 79.1 days) approached significantly longer levels compared to that in the 11 flashbackers with a single episode (160.89 116.1 days) (Z=1.86, P= 0.06). As shown in Table 2, the numbers of stressful events and MAP-induced fear-related paranoid-hallucinatory states, and the axis IV scores in each of the 11 flashbackers with a single episode (stressful events,  2 = 5.64, fear-related symptoms  2 = 6.55, axis IV score Z= 3.54) and in the nine flashbackers with subsequent episodes (stressful events  2 = 4.70, fear-related symptoms  2 = 6.56, axis IV score Z= 2.93) were significantly higher than for the 19 non-flashbackers. No scores were significantly different between the two flashbacker subgroups (P= 0.07–0.97). These stressful events corresponded to severe (axis IV scores of 4) or extreme types of psychosocial stressor (axis IV scores of 5), and overwhelmingly threatened the subjects. The six flashbackers who had not been exposed to stressful events had experienced MAP-induced fear-related paranoid-hallucinatory states. All eight subjects with persistent MAP psychosis had experienced significantly higher numbers of threatening, stressful events ( 2 = 4.11) and fear-related psychotic symptoms,  2 =5.93, and significantly higher axis IV scores (Zc = 2.64) than the 19 non-flashbackers. As shown in Table 3, the triggering factors met the DSM-III-R criteria for a mild type of psychosocial stressor (axis IV scores of 2), involving mainly mild fear of other people. Although these factors occurred sporadically, they represent nonspecific, omnipresent psychosocial stressors arising from general conflicts in the prison. Indeed, most of the other subjects reported mild fear of other people when asked the same question. There was no significant difference in the numbers having mild fear of other

3. Data analysis Distributions of plasma monoamine metabolite levels were often extremely skewed. The number of observations in this study was small. We therefore applied a square-root transformation to reduce the skewness and make the data suitable for parametric t-testing (Millns et al., 1995). The transformed data were scrutinized by one-way analysis of variance (ANOVA) followed by post hoc tests (Fisher’s protected least significant difference), which is a multiple t-test. To confirm any significant differences in monoamine metabolite levels between flashbacks and remission, and absence of significant effects of our neuroleptic treatment on monoaminergic values in the flashbackers, the transformed data were analyzed using repeated measures ANOVA with the presence or absence of neuroleptic

4. Results

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Table 2 Stressful experiences during previous methamphetamine (MAP) use Flashbackers n = 20 (%)

Flashbacker subgroups A single episode n =11 (%)

Stressful events Physical abuse Sexual abuse Divorce Rejecting parents Unwanted pregnancy DSM-III-R axis IV scores Fear-related symptomsa

14 8 1 2 2

(70.0)c (40.0) (5.0) (10.0) (10.0)

8 4 0 2 1

(72.7)b (36.4) ( 0.0) (18.2) (9.1)

Subjects with persistent MP psychosis n =8 (%)

Non-flashbackers n =19 (%)

Subsequent episodes n =9 (%) 6 4 1 0 1

(66.7)b (44.4) (11.1) (0.0) (11.1)

5 4 0 0 1

(62.5)b (50.0) (0.0) (0.0) (12.5)

2 2 0 0 0

(10.5) (10.5) (0.0) (0.0) (0.0)

1 (5.0)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

3.659 1.73c

3.73 9 1.62c

3.56 91.94c

3.38 9 2.00c

1.42 9 1.26

13 (65.0)c

7 (63.6)c

6 (66.7)c

5 (62.5)b

1 (5.3)

a

Percentages do not total 100 because some subjects had more than one symptom. PB0.05 compared to the non-flashbackers ( 2-tests). c PB0.01 compared to the non-flashbackers ( 2-tests). b

people between the 11 flashbackers with a single episode (12/11) and the nine flashbackers with subsequent episodes (9/9) (P = 0.89). The STAI-state scores did not differ significantly among the subject subgroups: the flashbackers during flashbacks, 58.39 9.9; the flashbackers at remission, 54.89 11.9; the non-flashbackers, 53.29 7.6; the user controls, 50.795.6; the non-user controls, 50.49 7.5. The STAI-trait scores during flashbacks (60.799.2) were significantly higher than in the 10 non-flashbackers (51.497.1) (Z= 2.32, P B0.05), in the nine user controls (45.298.1) (Z = 3.06, P B 0.01) and in the seven non-user controls (45.4911.6) (Z= 2.83, PB 0.01). The STAI-trait scores at remission (59.19 13.0) were significantly higher than in the nine user controls (Z = 2.49, PB 0.05). Heart rate and heart rate did not increase during flashbacks.

4.2. Plasma monoamine metabolite le6els As shown in Table 4, repeated measures ANOVA indicated significant differences in plasma levels of NE (F(1, 20)=4.98) and 3-MT (F(1, 18)= 4.51) between flashbacks and remission. There was no evidence of interaction between testing time (during flashbacks and remission) and neuroleptic treatment, or its effect, for plasma levels of any monoamine metabolite. The 11 flashbackers with a single episode had significantly higher NE levels during flashbacks than the 22 user controls, but their NE levels during flashbacks did not differ significantly from levels during remission. However, the nine flashbackers with subsequent episodes had significantly higher NE levels during flashbacks than during remission, and significantly higher NE

levels than the 19 non-flashbackers and the 20 user and 11 non-user controls. In all of the 20 flashbackers, plasma NE levels during flashbacks were significantly higher than during remission, and were significantly higher than in the 19 non-flashbackers, and the 22 user and 11 non-user controls. Plasma 3-MT levels during flashbacks in the two flashbacker subgroups were significantly higher than in the 22 user controls. In all 20 flashbackers, plasma 3-MT levels during flashbacks were significantly higher than during remission, and were significantly higher than in the 22 user controls. Plasma E levels did not differ significantly among the subject subgroups (P= 0.21–0.93). The eight subjects with persistent MAP psychosis had significantly higher NE levels than the 22 user and 11 non-user controls. The seven medicated and the 13 later-medicated flashbackers had significantly higher NE levels than the 22 user and 11 nonuser controls. The 13 later-medicated flashbackers had significantly higher 3-MT levels during flashbacks than the seven medicated flashbackers, the 19 non-flashbackers and the 22 user controls (Table 3).

5. Discussion MAP psychosis reported here differs from schizophrenia, in that schizophrenic thought disorder is characterized by a concreteness of abstract thought and an impairment in goal-directed thought (Segal and Janowsky, 1978). All subjects in the two flashbacker subgroups had experienced paranoid-hallucinatory states after taking MAP, but not after exposure to any severe stressor. They exhibited transient paranoid-hallu-

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cinatory states closely resembling their previous MAP psychosis when exposed to mild psychosocial stressors. There was no possibility of secret use of MAP or any other substance. The flashbacks reported here therefore most likely occurred as a spontaneous psychosis due to previous MAP psychosis. The 11 flashbackers with a single episode and the nine flashbackers with subsequent episodes had been exposed to threatening stressful events, or MAP-induced fear-related psychotic states, or both during previous MAP use. They then exhibited flashbacks due to previous MAP psychosis in situations of mild psychosocial stressors, involving mainly mild fear of other people. During flashbacks the nine flashbackers with subsequent episodes showed a much greater increase in NE levels, while the 11 flashbackers with a single episode had a smaller increase. Both flashbacker subgroups had slightly increased 3-MT levels during flashbacks. In animal studies, initial exposure to stressful stimuli results in sensitization of the brain and peripheral noradrenergic system to subsequent stress that is mild enough to have no measurable effect on non-exposed animals so that re-exposure to similar but less severe stress can readily evoke excessive NE release (Irwin et al., 1986; Petty et al., 1994; Anisman and Zacharko, 1995). AMP induces enduring sensitization to stress via dopaminergic changes (Robinson et al., 1987). Frightening stressful experiences, together with MAP use, may therefore induce noradrenergic hyperreactivity to subsequent less severe situations than previous similar situations. Thus, although mild psychosocial stressors were sufficient mild not to induce changes in plasma E levels, heart rate or blood pressure, they readily induce an increase of plasma NE levels. The high trait anxiety of the flashbackers may reflect such peripheral noradrenergic hyperreactivity, as in the case of normal volunteers with high trait anxiety (Pe´ ronnet et al., 1986). The eight subjects with persis-

tent MAP psychosis had been exposed to frightening, stressful experiences similar to the flashbackers during previous MAP use. Their plasma NE levels were increased. Thus, noradrenergic hyperactivity may be related mainly to persistent recurrences of MAP psychosis in situations of omnipresent, mild stressors. It is well documented that 3-MT levels in the rat brain are a more sensitive index of DA release than homovanillic acid (HVA) or DOPAC (Wood and Altar, 1988; Heal et al., 1990). The administration of benzedrine, a peripheral decarboxylase inhibitor, results in simultaneous synthesis of 3-MT in plasma, cerebrospinal fluid and brain in the rats (Kent et al., 1990). A peripheral origin of 3-MT has been proposed (Dalmaz and Peyrin, 1978). It follows that small increases in 3-MT levels during flashbacks may reflect some degree of increased DA release. Repeated stressful stimuli can sensitize brain 3-MT release under subsequent stress (Charpusta et al., 1997). Collectively, frightening stressful experiences, together with MAP use, may induce sensitization of DA release in addition to noradrenergic hyperactivity in response to mild psychosocial stressors, predisposing to the initial flashback episode and further flashbacks. Therefore, the higher levels of NE, as well as 3-MT, may be causally related to the occurrence of flashbacks, rather than being the result of flashbacks. Drawing these strands together, for the development of flashbacks, both noradrenergic hyperactivity and increased DA release in response to mild stressors may be responsible. Consequently, some degree of increased NE levels together with slightly increased DA release in the flashbacker with a single episode might suffice to trigger flashbacks in response to mild stressors. These findings strengthen our previous studies indicating that noradrenergic hyperactivity, including increased DA release, is critical for the development of flashbacks (Yui et al., 2000a,b).

Table 3 Factors that triggered the flashbacksa Single episode n =11

Mild fear of other people Conflicts with inmates Fear of disciplinary punishment Fear of emitting body odor Fear of prison setting, including fear of the prison staff Being afraid of other inmates’ words and actions Other factorsb a

12 5 0 1 3 3 2

Subsequent episodes First n =9

Second n=9

9 3 0 1 5 1 3

8 2 0 1 4 1 0

All flashbacks n = 29

29 10 0 3 12 5 5

Percentages do not total 100 because some subjects had more than one factor. Worrying about family (n= 1), obligation to perform prison labor (n =1), sleep disturbance due to tension (n =1), back pain (n =1) and general fatigue (n =1) in all 29 flashbacks. b

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Table 4 Plasma levels of noreplnephrlne (NE), epinephrine (E), 3-methoxytyramine (3-MT), dihydroxyphenylacetic acid (DOPAC), and dopamir (DA)a Subject subgroups

Age (years)

NE

E

3-MT

DOPAC

DA

All flashbackers during flashbacks Flashbackers with a single episode Flashbackers with subsequent episodes Medicated flashbackers Later-medicated flashbackers

27.995.8 28.496.8 27.294.6 26.192.0 28.897.0

0.65 90.66b,c,d,g,i 0.45 9 0.64f 0.89 90.64c,e,g,i 0.66 9 0.87g,h 0.64 9 0.57f,i

0.45 9 0.57 0.40 9 0.56 0.51 9 0.62 0.29 9 0.50 0.57 9 0.62

1.35 9 2.22b,c,f 1.28 92.17f l.44 9 2.42f 0.26 9 0.70 1.93 92.55d,i,m

0.15 9 0.46 0.22 9 0.62 0.07 9 0.12 0.06 9 0.13 0.12 9 0.57

0.05 9 0.0 0.04 9 0.0 0.06 9 0.1 0.06 9 0.0 0.04 90.0

All flashbackers during remission Flashbackers with a single episode Flashbackers with subsequent episodes Medicated flashbackers Later-medicated flashbackers

28.0 9 6.0 28.697.1 27.294.6 26.192.0 29.0 9 7.2

0.34 90.41 0.22 9 0.26 0.50 9 0.51 0.42 90.52 0.30 9 0.35

0.37 9 0.56 0.21 9 0.42 0.56 9 0.68 0.40 9 0.53 0.35 90.60

0.31 9 0.75 0.06 90.19 0.62 9 1.05 0.11 9 0.28 0.42 90.91

0.28 90.61 0.23 9 0.61 0.35 9 0.64 0.12 9 0.19 0.37 9 0.73

0.11 9 0.1f 0.11 90.1 0.12 90.2i 0.03 9 0.05 0.15 9 0.21

Subjects with persistent MAP psychosis Non-flashbackers User controls Non-user controls

25.09 2.5 30.89 9.3 31.79 8.1 31.696.6

0.56 90.45f,h 0.38 90.34 0.15 90.25 0.15 9 0.16

0.49 9 0.86 0.77 9 1.34 0.85 91.70 0.32 90.45

0.45 90.93 0.98 9 2.10 0.10 90.40 1.06 91.76

0.03 9 0.09 0.32 9 0.64 0.09 9 0.18 0.42 9 1.12

0.13 90.22 0.14 9 0.21 0.07 90.14 0.29 9 0.26

Data represent mean 9 S.D. pmol/ml. All monoaminergic values were square-root transformed to reduce skewness. PB0.05 compared to the flashbackers during remission (repeated measures ANOVA). c PB0.05 compared to the flashbackers during remission. d PB0.05 compared to the non-flashbackers. e PB0.01 compared to the non-flashbackers. f PB0.05 compared to the user controls. g PB0.01 compared to the user controls. h PB0.05 compared to the non-user controls. i PB0.01 compared to the non-user controls. m PB0.05 compared to the medicated flashbackers (post hoc test). a

b

Our subjects did not meet DSM-IV criteria for AMPinduced mood disorder and related flashbacks due to previous MAP-induced mood disorder. There have been few informations on spontaneous recurrences of MAP- or AMP-induced mood disorder. AMP induces euphoria and activation, and increases synaptic DA (Kuczenski and Segal, 1994). Acute intravenous administration of AMP (0.3 mg/kg) has been reported to induce the transient greater behavioral response resembling mania in bipolar disorder patients possibly due to enhanced postsynaptic DA responsivity (Anand et al., 2000). Accordingly, possible role of DA in bipolar disorder (especially mania) has been proposed (Kelsoe et al., 1996). Drugs which reduce DA neurotransmission are effective in reducing manic symptoms (Silverstone, 1985). Moreover, a relative deficiency in dopamine and serotonin neurotransmission occurs following prolonged MAP abuse, and this deficiency may be associated with depression (McCane et al., 1999). While, no consistently altered sensitivity to monoaminergic stimulation by AMP in bipolar disorder patients was reported (Nurnberger et al., 1982). Further studies might consider the possibility that AMP-induced mood disorder can recur on exposure to stress in relation to monoaminergic changes.

Sensitization to stress, acting through noradrenergic systems, can induce recall of traumatic events in PTSD (Bremner et al., 1995). By reproducing noradrenergic hyperactivity, memories of frightening and traumatic experiences can be elicited following exposure to stress related to the original trauma in PTSD (Southwick et al., 1993). AMP-induced sensitization to stress in central dopaminergic systems is plausibly related to the enduring hypersensitivity to psychotogenic effects of stress found in spontaneous recurrences of AMP psychosis (Robinson et al., 1987). Thus, noradrenergic hyperactivity with slightly increased DA release in the two flashbacker subgroups could elicit memories of MAP psychosis closely related to frightening, stressful experiences during previous MAP use after exposure to mild psychosocial stressors, thereby triggering flashbacks. Central noradrenergic hyperactivity is associated with psychotic relapse in schizophrenia (van Kammen et al., 1994). Central and peripheral noradrenergic hyperreactivity to mild stress appears to be a precipitating factor in stress-related psychiatric disorders (Irwin et al., 1986; Anisman and Zacharko, 1995). Overall, noradrenergic hyperreactivity to mild stress may induce susceptibility to psychotic decompensation. Thus, ro-

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bust noradrenergic hyperactivity with slightly increased DA release in response to mild psychosocial stressors, in flashbackers with subsequent episodes, may trigger the initial episode and further predispose them to subsequent episodes. By contrast, less robust noradrenergic hyperactivity with slightly increased DA release in response to mild psychosocial stressors, occurring in flashbackers with a single episode, may be insufficient to predispose to subsequent flashbacks. Collectively, robust noradrenergic hyperactivity with slightly increased DA release could predict further episodes. This extends our earlier findings (Yui et al., 1997, 2000a,b) and has practical implications in recurrent invasive psychotic symptoms. There was no significant difference in the number of stressful events and MAP-induced fear-related states, and in the axis IV scores between these two flashbacker subgroups. The proportion of mild fear of other people to the number of the first flashback episode did not differ significantly between the two flashbacker subgroups. The impact of stressful experiences may not therefore be related to robust noradrenergic hyperactivity in the flashbackers with subsequent episodes. The number of medicated subjects did not differ significantly between the two flashbacker subgroups, suggesting that robust noradrenergic hyperactivity is not attributable to the neuroleptics. While, the mean duration of confinement before the start of blood sampling, during the first flashback episode in flashbackers with subsequent episodes, approached significantly longer levels compared to that in the flashbackers with a single episode. According to recent studies, cumulative stress effects (Yehuda et al., 1993) or ruminations associated with aversive events (Anisman and Zacharko, 1995) may have a more substantial impact on the reservoir of adaptive energy that affects biological adaptation (Yehuda et al., 1993), or induce further NE changes (Anisman and Zacharko, 1995). Therefore, long-term exposure to distressing situations (imprisonment) in flashbackers with subsequent episodes might reflect their robust noradrenergic hyperactivity. Although plasma monoamine metabolite levels do not accurately reflect central monoamine neurotransmitter activity, plasma NE levels (Roy et al., 1988) and levels of brain 3-MT (Kent et al., 1990) can respectively reflect gross changes in whole brain noradrenergic and dopaminergic metabolism. The present findings raise the possibility that the elevated NE (Pe´ ronnet et al., 1986) and 3-MT levels (Charpusta et al., 1997) may reflect heightened sympathetic activity. Plasma E levels, which reflect fluctuations in emotional stress (Dimsdale and Moss, 1980), STAI-state scores, blood pressure and heart rate did not increase during the flashbacks. According to preclinical study, a stimulus of sufficient intensity, indicated by heart rate, can activate peripheral noradrenergic systems (Abercrombie and Jacobs,

1987). Thus, the raised NE and 3-MT levels may not be secondary to sympathetic arousal. Plasma NE levels are increased by exercise in normal volunteers through increased blood flow in working muscles (Maeda et al., 1997). However, motor activity of our subjects was highly restricted in the prison. Thus, this is not the cause. It is possible that the neuroleptics used here affect plasma NE and 3-MT levels. Haloperidol (5– 10 or 10–20 mg/day) has been shown to decrease plasma NE levels in schizophrenics over a 6 week course of treatment (Green et al., 1993). Infusion of chlorpromazine (25 mg) has been reported to reduce plasma NE levels in patients with arteriosclerosis (Risbo et al., 1983). Neither treatment with haloperidol (4 mg/day) for 5 weeks in chronic schizophrenics (Breier et al., 1994), nor administration of haloperidol (4–8 mg/day) or thioridazine (150–400 mg/day) for at least 10 days in patients with acute psychoses (Tuck, 1973), has any significant effect on peripheral noradrenergic activity. Recent clinical studies have shown that treatment with haloperidol (3–20 mg/day) for at least 1 year (Nagaoka et al., 1997), or with haloperidol (5–15 mg/day) for 3 weeks (Brown et al., 1987), does not alter plasma NE levels in schizophrenics. On the other hand, treatment with chlorpromazine (200– 800 mg/day) for 2 weeks has been reported to increase plasma NE levels in chronic schizophrenics (Rice et al., 1984). Few comparative clinical studies exist of the effects of neuroleptics on plasma 3-MT levels. A preclinical study has reported that injection of haloperidol (0.5 mg/kg) or chlorpromazine (20 mg/kg) has no significant effect on brain 3-MT levels (Westerink and Spaan, 1982). However, brain 3-MT levels have been reported as increasing after injections of haloperidol (0.5–1.0 mg/kg), chlorpromazine (2.3 or 14.0 mg/kg) or thioridazine (5 or 30 mg/kg) (Wood and Altar, 1988). Chronic haloperidol treatment has been found to reduce 3-MT levels in the rat brain (VonVoigtlander et al., 1990). Neuroleptic effects on plasma NE and brain 3-MT levels therefore change with subject selection criteria or design of study. In this study, repeated measures ANOVA revealed no significant effect of neuroleptic treatment on plasma NE or 3-MT levels. Both medicated and later-medicated flashbackers had significantly higher NE levels during flashbacks than the user and non-user controls. The later-medicated flashbackers had higher 3-MT levels during flashbacks, at which time they had not yet received the neuroleptics, than the medicated flashbackers, the non-flashbackers or the user controls. Overall, the present neuroleptic treatment is not necessarily significant in raising NE and 3-MT levels. Since our analysis of the differences between the subject subgroups included subjects with and without neuroleptics, influence of neuroleptics on plasma NE and 3-MT levels cannot be definitively ruled out. Further studies are needed to settle this question.

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In summary, the 11 flashbackers with a single episode, the nine flashbackers with subsequent episodes, and the eight subjects with persistent MAP psychosis had all undergone frightening stressful experiences during previous MAP use. Mild psychosocial stressors then triggered flashbacks. During flashbacks all 20 flashbackers had markedly increased NE levels and increased 3-MT levels; the nine flashbackers with subsequent episodes had more markedly increased NE levels and slightly increased 3-MT levels. The eight subjects with persistent MAP psychosis had increased levels of NE alone. Thus, for the development of flashbacks, noradrenergic hyperactivity with increased DA release in response to mild stressors may be responsible. Noradrenergic hyperactivity may be related to persistent recurrences of MAP psychosis. Robust noradrenergic hyperactivity with slightly increased DA release in response to mild stress should predict subsequent flashbacks. A longer duration of confinement could contribute to this robust noradrenergic hyperreactivity to mild stressors.

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