Abstract
The work of Patricia Goldman-Rakic and Amy Arnsten has been central in understanding the role of the prefrontal cortex (PFC) in working memory [1, 2]. Goldman-Rakic described the circuitry of the primate prefrontal cortex, and the regulation of behaviour by representational memory [1]. The circuitry included connections of the principal sulcus (dorsolateral prefrontal cortex) with parietal association and limbic cortex and projections to the caudate nucleus, superior colliculus and other premotor centers. These connections emerged between 2 and 4 months in primates and around 8–12 months in humans, during the period of synaptic exuberance from 8 months to 2 years of age, a time period in which linguistic ability was also developing.
Arnsten was able to show that while moderate levels of dopamine (DA) activity are necessary for PFC working memory [2], and D1 receptors are important in this regard [3, 4], there was evidence that excessive levels of DA receptor stimulation in the PFC impaired working memory formation [5–7]. In addition, Arnsten discussed the role of noradrenaline (NA) in working memory [2, 3]. She described evidence that low levels of NA enhance working memory and attention functions of the PFC through actions at post-synaptic α-1 adrenoreceptors. Arnsten, based on animal and human work, described an ‘amygdala switch’ that may play a critical role in shifting control of behaviour from the PFC to posterior cortical and subcortical structures during times of stress. This shuts down complex PFC reflective actions and allows more automatic or habitual responses. This switch is accompanied by increasing extrasynaptic catecholamine (DA and NA) levels through hypothalamic projections. These facilitate the release of steroids, which in turn block extraneuronal catecholamine transporters, thus enhancing associative and long-term memory, but impairing working memory. Increased catecholamine release also alters attentional regulation, allowing attention to be ‘captured’ by prominent salient stimuli in the environment by increasing β or α-1 adrenergic receptor enhancement. While this may be helpful in conditions of danger, it may be problematic in everyday settings such as the classroom. Thus optimal catecholamine levels are central for working memory. According to Madras et al., variations in DA/NA relationships are important in prefrontal functions [8].
Weinberger (and colleagues) investigated the role of dopamine and the PFC in schizophrenia [9]. Egan et al. described a potential susceptibility mechanism involving regulation of prefrontal dopamine by the catechol-O-methyltransferase (COMT) gene, where the more efficient Val allele showed significantly increased transmission to schizophrenic offspring in a family-based association analysis in contrast with the Met allele [11]. The data suggested that the COMT Val allele impaired prefrontal cognition by increasing DA metabolism. Myer-Lindenberg et al. suggested that when baseline DA signalling is suboptimal, there is an improvement in the efficiency of PFC information processing in Val/Val individuals after amphetamine, presumably because of a shift of DA signalling from the lower end of the normal range to a higher level on the putative inverted-U curve [11]. In contrast, there is a decrement in the efficiency of PFC information processing in Met/Met individuals on amphetamine at high load.
The present case describes the development and treatment of a psychosis in a pubertal girl, diagnosed at a young age with autistic disorder. The possible relationship of her condition and treatments to catecholamine function in the PFC is explored.
Psychiatric history
C (age 13 years) was first seen following a 6 month period of elective mutism at age 3 years, despite initially normal speech development. At age 5 she was seen at a developmental clinic after her class teacher reported communication problems involving difficulty following directions, picking up cues and answering questions. She was found to have a significant delay in both language and speech and had difficulty in forming peer relationships. At age 6 she repeated the year to assist with social skills development and received speech therapy. Psychological assessments in 1997/98 indicated a mild global delay in general ability, verbal skills and verbal comprehension.
C was intermittently prescribed dexamphetamine from 2001 to April 2003, when this was ceased following concerns regarding slow growth and depressed mood. At the beginning of 2003 (age 11), C was noticed to have become anxious, unreactive and flat in affect and unmotivated. Prior to this she had participated in singing and dancing at school. In May 2003, she was increasingly socially withdrawn, with depressed mood and affect, minimal verbal responses, repetitive behaviours and obsessive slowness, and was diagnosed as having a depressive disorder. In November 2003 she was noticed to be smiling and giggling to herself and complaining of voices in her head. In February 2004 she was minimally communicative with yes/no answers and episodes of shouting ‘Be quiet I'm trying to think’. She was oppositional, pulling at her lower lip, and inappropriately touching her genitals in the classroom.
In March 2004 C was admitted to an inpatient mental health service in a general children's hospital, manifesting perplexity, a bowed bizarre gait with arms swinging forward and blunted affect. Between February and July 2004 she was trialled on risperidone, amisulpride, and olanzapine, but her mental state continued to deteriorate with auditory and visual hallucinations, persecutory delusions, thought disorder and disorganized aggressive behaviour, minimal interactions with peers, monosyllabic speech delay, lack of creative thinking and obsessive fixations. She was diagnosed as having a dual diagnosis of acute psychosis and autistic disorder (initially autistic spectrum disorder was suggested).
In July 2004 C was transferred to a locked inpatient adolescent hospital because her aggressive and unpredictable behaviour was unable to be managed in an open ward. She had been briefly started on clozapine, but all medications were initially ceased to allow exhaustive testing for an organic disorder, which was excluded, and a review of her diagnosis. Her behaviour and mental state deteriorated and she displayed auditory hallucinations, paranoid thinking, formal thought disorder, mood instability and impulsivity, bizarre manneristic behaviour, and ambitendency with further regression. The clozapine treatment was resumed, and there was a significant improvement in her positive symptoms, but she remained thought disordered at times, with echolalia, echopraxia and selective mutism, but few further aggressive incidents. She was allowed home on weekend leave without major problems, and was discharged in December 2004 to outpatient care, by the present child and adolescent psychiatrist.
Investigations determined no abnormalities on full blood count, serum cortisol, oestradiol and luteinizing hormone, liver function tests, cholesterol, or thyroid function tests. Cerebrospinal fluid measles antibodies, microscopy protein and glucose were normal. No abnormalities were detected on electroencephalogram or magnetic resonance imaging (MRI).
Neurological examination detected no abnormality. Brain MRI showed a solitary focus of low signal intensity in the posterior aspect of the left frontal lobe, possibly representing a small cavernous haemangioma. There were signs of early puberty.
Outpatient treatment
C was enrolled in a special school programme suited to her intellectual needs, and to continue her clozapine treatment. This initially proved a problem because she refused to comply with venepunctures for clozapine levels and white cell counts. The venepuncture problem was finally successfully overcome with the help of two play therapist nurses who carried out a successful desensitization programme. However, it became clear to the treating psychiatrist that her progress was severely impeded by her extreme distractibility, when she was unable to sit in her chair and constantly touched furniture and objects on the psychiatrist's desk or in the office in the manner of a younger attention deficit–hyperactivity disorder child. A course of a small dose of methylphenidate (2.5 mg) in addition to the clozapine was briefly tried. This resulted in her again becoming very quiet and possibly hallucinating.
At this stage, it was decided to add the relatively newly available noradrenergic re-uptake inhibitor atomoxetine (Strattera, Eli Lilley) to her treatment regimen. There was an immediate improvement: she was visibly less distractible, more cooperative in class and her appetite, which had been voracious on the clozapine, stabilized. She no longer greeted the psychiatrist with ‘Can I have a lolly’, and her weight remained stable. She slowly became more verbally responsive, although with limitations. She completed the year 2005 at school, with improved peer relations and was more communicative. Current medication is clozapine 150 mg b.i.d. and atomoxetine 40 mg daily. Genetic testing was normal for the C22 deletion. The COMT gene was heterozygous.
Discussion
The present case raises a number of interesting issues. In view of recent concerns about psychosis-inducing side-effects of stimulant medications, the question should be asked whether the intermittent treatment with dexamphetamine had a role in precipitating her psychosis. While this is possible, her dose level was not excessively high (2.5 mg b.i.d.) and she was not taking dexamphetamine at the onset of her illness. In contrast, the onset of puberty and hormonal changes may well have had a role, given that this is a vulnerable developmental stage and possibly more so in developmentally at-risk children.
Even more interesting is her treatment course. First the response to clozapine is complex and broad spectrum, but dopaminergic and serotonergic systems are likely involved. Clozapine is a prototype broad-spectrum antagonist. Its binding profile is quite different from other antipsychotics both within and outside the dopaminergic system. It has relatively low affinity for D2 receptors in the striatum, while its in vitro affinity for the D4 receptors is approximately 10-fold greater than that for D2 receptors and it has also been shown to bind to the D1, D3 and D5 receptors. Because D4 density is highest in the frontal cortex and amygdala but relatively low in the basal ganglia, that may be the explanation for the efficacy of clozapine in alleviating the symptoms of schizophrenia without causing extra pyramidal side-effects [13].
In the current case, the presence of early autistic symptoms could suggest predominantly subcortical influences on dopamine metabolism [14]. Courchesne et al. described evidence of brain maldevelopment in the first years of life in autism [15]. They described abnormally accelerated growth in head circumference in the first 2 years, thought to indicate brain size. Subsequent studies from 5 years onwards have shown no difference in size from normal brain volumes. Evidence from 5-year-old to adult autistic brain suggests that neurons are small and mini-columns narrow and underdeveloped. Courchesne and Pierce have hypothesized underdevelopment of large integrative and projecting pyramidal neurons, most especially those in the frontal cortex, resulting in reduced long distance anterior to posterior cortico-cortical connectivity and increased local and short-distance cortical connectivity [16],17]. Underdevelopment of large frontal pyramidal neurons was thought to be a critical event in the developmental derailment of socioemotional and other higher-order functions in autism.
The heterozygous findings for the COMT were not predictive of stimulant response in C's case, but given the hypotheses of Meyer-Lindenberg et al. and Mattay et al. regarding an inverted-U response to stimulant medications, based on initial prefrontal synaptic levels of dopamine [12, 14], COMT remains an interesting psychogenomic candidate. However, this may not be predictive in atypical prefrontal development such as autism. C's possible relapse on a small dose of Ritalin (Moyartis) also implicates dopaminergic systems, but the response of her extreme distractibility to atomoxetine (a noradrenergic re-uptake inhibitor) raises the more general question of the role of noradrenergic neurotransmission in working memory as discussed by Arnsten. It also suggests the question of whether noradrenergic agonists might have a role in the treatment of psychosis, when working memory and distractibility are problematic, particularly in dual diagnosis cases.
Footnotes
Acknowledgements
The Child and Adolescent teams at Sydney Children's Hospital, Child and Family East, Prince of Wales Hospital and Gna Ka Lun Adolescent Inpatient Unit, Campbelltown Hospital, are acknowledged as dedicated contributors to C's care. The helpful contribution of C's family is acknowledged.