Aripiprazole and Other Third-Generation Antipsychotics as a Risk Factor for Impulse Control Disorders: A Systematic Review and Meta-Analysis.

BACKGROUND: Increasing evidence suggests an association between third-generation antipsychotics (TGAs) and impulse control disorders (ICDs). This is thought to be due to their partial agonism of dopamine receptors. However, neither the relative nor absolute risks of ICDs in those prescribed TGAs are well established. To inform clinical practice, this systematic review and meta-analysis summarizes and quantifies the current evidence for an association. METHODS: An electronic search of Medline, PsychINFO, EMBASE, and the Cochrane Clinical Trials Database was undertaken from database inception to November 2022. Three reviewers screened abstracts and reviewed full texts for inclusion. A random-effects meta-analysis was conducted with eligible studies. RESULTS: A total of 392 abstracts were retrieved, 214 remained after duplicates were removed. Fifteen full texts were reviewed, of which 8 were included. All 8 studies found that TGAs were associated with increased probability of ICDs. Risk of bias was high or critical in 7 of 8 studies. Three studies were included in the pooled analysis for the primary outcome, 2 with data on each of aripiprazole, cariprazine, and brexpiprazole. Exposure to TGAs versus other antipsychotics was associated with an increase in ICDs (pooled odds ratio, 5.54; 2.24-13.68). Cariprazine and brexpiprazole were significantly associated with ICDs when analyzed individually. Aripiprazole trended toward increased risk, but very wide confidence intervals included no effect. CONCLUSIONS: Third-generation antipsychotics were associated with increased risk of ICDs in all studies included and pooled analysis. However, the risk of bias is high, confidence intervals are wide, and the quality of evidence is very low for all TGAs examined.

Dopamine agonist serum concentrations and impulse control disorders in Parkinson's disease.

BACKGROUND AND PURPOSE: Impulse control disorders (ICDs) are common among Parkinson's disease patients using dopamine agonists. We wanted to determine whether ICD patients have higher dopamine agonist serum concentrations than those without any sign of ICD. METHODS: Patients who used either pramipexole or ropinirole depot once daily were screened for ICDs using the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale. Those who scored above the cut-off for one or more of the four defined ICDs (gambling, compulsive sexual behavior, compulsive shopping, and binge-eating) were compared in a case-control study to patients who scored zero points (no evidence of ICD) on the same items. They were examined clinically and evaluated using relevant scales. Three blood samples were taken on the same day: before daily dose, and then 6 and 12 h later. RESULTS: Forty-six patients were included: 19 ICD-positive and 27 controls. Ropinirole serum concentrations 6 h after daily intake (Cmax ) were higher in the case group compared to the control group, as was the daily ropinirole dosage. No differences were observed in serum concentrations, dosage or total drug exposure for pramipexole. Disease duration and length of dopamine agonist treatment was significantly longer among ICD patients for ropinirole, but not for pramipexole. CONCLUSIONS: The use of pramipexole may in itself confer high ICD risk, whereas ICDs among ropinirole users depend more on serum concentration and drug exposure. The pharmacokinetic properties of ropinirole make it challenging to predict its effects on patients, which supports the need for therapeutic drug monitoring to reduce risk of ICD.

Impulse control disorders in patients with dopamine agonist-treated pituitary adenomas: a cross-sectional multicenter study.

BACKGROUND: Impulse control disorders (ICDs) have been described as underrecognized side effects of dopamine agonists (DAs) in neurological disorders but are not sufficiently understood in endocrine conditions. OBJECTIVE: To identify the prevalence of DAs induced ICDs and determine potential risk factors related to these disorders in patients with prolactinoma and non-function pituitary adenomas (NFPAs). METHODS: This is a cross-sectional multicenter study involving 200 patients with prolactinoma and NFPAs, who received follow-ups in tertiary referral centers. DA-induced ICDs were assessed using ICD questionnaires modified from prior studies. RESULT: At least one ICD was reported by 52% of participants, among whom 28.5% mentioned compulsive shopping, 24.5% punding, and 24.5% hypersexuality. Furthermore, 33% of the patients reported the presence of one type of ICD behavior, while 12% specified two and 7% had three types of such behavior. The multivariable logistic regression showed that the significant risk factors of ICD were younger age (adjusted odds ratio [AOR]: 0.92, 95% confidence interval [CI]: 0.88-0.97, p 0.001), being single (AOR: 0.15, 95%CI: 0.03-0.84, p 0.03), and a positive history of psychiatric illness (AOR: 7.67, 95% CI: 1.37-42.97, p 0.021). CONCLUSION: ICDs with a broad range of psychiatric symptoms are common in individuals with DA-treated prolactinoma and NFPAs. Endocrinologists should be aware of this potential side effect, particularly in patients with a personal history of psychiatric disorder.

Effect of Dopaminergic Therapy on Impulse Control Disorders in Patients With a Prolactinoma.

BACKGROUND: Studies have reported an increase in the incidence of impulse control disorders (ICDs) in patient groups treated with dopamine agonists (DAAs), especially in Parkinson disease (PD). However, very few studies have reported on ICDs in individuals with a prolactinoma who were treated with DAAs. OBJECTIVE: To see whether a DAA by itself causes ICDs in individuals with a prolactinoma by controlling the susceptibility to impulsivity by excluding individuals with other risk factors for ICDs. METHOD: We compared the performance of 31 individuals with a prolactinoma receiving DAA therapy (DAA+) on various behavioral scales and the Iowa gambling task (IGT), a neuropsychological instrument that measures risky decision-making, with the performance of 20 individuals with a prolactinoma who were not on DAA therapy (DAA-) and 30 healthy controls (HC). RESULTS: There was no significant difference among the groups concerning performance on the Zuckerman Sensation Seeking Scale-V, Minnesota Impulse Disorders Interview, Barratt Impulsiveness Scale-11, or IGT. No correlation was found between the scores on these scales and the duration or dose of DAA in the DAA+ group. The incidence of ICDs was 25.8% in the DAA+ group, 15% in the DAA- group, and 16.7% in the HC. The differences among the groups did not reach statistical significance. CONCLUSION: Individuals who are under treatment with low-dose, D 2 -selective DAAs for a prolactinoma do not face an increased risk for ICDs, especially when they are carefully screened for any psychiatric comorbidity that may also display impulsivity.

Exploring the underlying mechanisms of drug-induced impulse control disorders: a pharmacovigilance-pharmacodynamic study.

INTRODUCTION: Impulse control disorders (e.g. pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on D3-receptor agonism, and switching to alternatives with different pharmacologic mechanisms represents a common management strategy. Nonetheless, treatment failure is common and gaining pathophysiological insights is needed. AIM: We aimed to identify targets potentially contributing to pathologic impulsivity. METHOD: We performed a pharmacovigilance-pharmacodynamic study on dopamine agonists and antipsychotics using the Food and Drug Administration Adverse Event Reporting System (January 2004-December 2021). We estimated disproportionate reporting using the Bayesian information component. Using online public databases (IUPHAR, ChEMBL, PDSP, DrugBank), we calculated drug occupancies. To identify the targets potentially contributing to impulsivity, we fitted univariate regression models interpolating information components and occupancies within dopamine agonists and antipsychotics. Sensitivity analyses were performed to check for the robustness of the results. RESULTS: Among 19 887 reports of impulsivity, 5898 recorded an antipsychotic, and 3100 a dopamine agonist. The more robust signals concerned aripiprazole (N = 3091; median information component [95% confidence interval] = 4.51[4.45-4.55]) and brexpiprazole (229; 4.00[3.78-4.16]) for antipsychotics, pergolide (105; 5.82[5.50-6.06]) and pramipexole (2009; 5.43[5.36-5.48]) for dopamine agonists. Robust, significant positive associations between drug occupancy and impulsivity reporting were found for D3 within dopamine agonists (beta = 1.52; P-value = 0.047) and 5-HT1a within antipsychotics (1.92, 0.029). CONCLUSION: Our results supported the role of D3-receptor agonism in inducing impulsivity in dopamine receptor agonists and identified a potential role of 5-HT1a receptor agonism in antipsychotics. Investigating these receptors may drive towards a better management of drug-induced impulsivity.

Impulse control disorders in hyperprolactinemic patients on dopamine agonist therapy.

Dopamine agonists (DAs) represent a mainstay of therapy for hyperprolactinemia and prolactinomas. The widespread use of DAs, including bromocriptine, cabergoline and (in some countries) quinagolide, has led to the emergence and recognition of impulse control disorders (ICDs) that may occur in association with DA therapy.Such ICDs include pathological gambling, compulsive shopping, hypersexuality and punding (the performance of repetitive tasks), among others. These manifestations can lead to substantial harms to patients and their families, if left undiagnosed and untreated. Several risk factors that may increase the risk of ICDs have been proposed, including younger age, male gender, smoking and alcohol use and history of depression.The diagnosis of ICDs in hyperprolactinemic patients treated with DAs requires a high index of suspicion and a systematic approach, using available screening questionnaires. However, it should be noted that available test instruments, including questionnaires and computerized tasks, have not been validated specifically in hyperprolactinemic patients. Hyperprolactinemic patients who develop ICDs should be withdrawn from DA therapy or, at a minimum, undergo a DA dose reduction, and considered for psychiatric consultation and cognitive behavioral therapy. However, the role of psychopharmacotherapy in hyperprolactinemic patients with ICDs remains incompletely characterized.Patient counseling regarding the risk of ICDs occurring in association with DA therapy, early detection and prompt intervention may mitigate potential harms associated with ICDs. Additional studies are needed to fully characterize risk factors, underlying mechanisms and identify effective therapies for ICDs in patients with hyperprolactinemia receiving DAs.

The side effects of dopamine receptor agonist drugs in Chinese prolactinoma patients: a cross sectional study.

BACKGROUND: Recently, side effects from Dopamine Receptor Agonist Drugs (DAs) in treating pituitary prolactinoma have raised widespread concern. This study explores the incidence and influencing factors of DAs-related side effects in Chinese prolactinoma patients. METHODS: A cross-sectional study was conducted. 51 prolactinoma patients treated with DAs, 12 prolactinoma or pituitary microadenoma patients without DAs treatment, and 33 healthy controls were included. The Barratt impulsivity scale-11, Patient Health Questionnaire 9, and the ICD screening questionnaire were all used to evaluate the psychological and physical side effects of DAs. Clinical data of all subjects were collected from their electronic medical records. RESULTS: The incidence of ICDs in the treated group, the untreated group, and control group was 9.8% (5/51), 16.7% (2/12), and 9.1% (3/33), respectively. In the treated group in particular, there were 1 patient (2%, 1/51), 2 patients (3.9%, 2/51), and 2 patients (3.9%, 2/51) with positive screening for punding, compulsive shopping, and hypersexuality, respectively. In terms of depression, the incidence of "minimal", "mild" and "moderate" depression in the treated group was 62.8% (32/51), 25.5% (13/51), and 5.9% (3/51), respectively. The incidence of physical symptoms was 51.0% (26/51) in the treated group and gastrointestinal symptoms were the most common symptoms (33.3%, 17/51). In addition, we found that the various parameters of DAs treatment had no association with the occurrence of physical symptoms or ICDs (all P > 0.05). CONCLUSIONS: Chinese prolactinoma patients treated with DAs had a lower incidence of ICDs (9.8%), while gastrointestinal symptoms were common. In this way, more attention should be paid to side effects, especially physical symptoms, in Chinese prolactinoma patients with DAs therapy during follow-up regardless of dose.

New pharmacological and neuromodulation approaches for impulsive-compulsive behaviors in Parkinson's disease.

INTRODUCTION: A significant proportion of patients with Parkinson's disease (PD) display a set of impulsive-compulsive behaviors at some point during the course of illness. These behaviors range from the so-called behavioral addictions to dopamine dysregulation syndrome, punding and hoarding disorders. These behaviors have been consistently linked to the use of dopaminergic medications used to treat PD motor symptoms (dopamine agonists, levodopa, and other agents) and less consistently to neuromodulation techniques such as deep brain stimulation (DBS). Since there are still no approved treatments for these conditions, their pharmacological management is still a big challenge for clinicians. METHODS: We conducted an extensive review of current pharmacological and neuromodulation literature for the management of impulsive-compulsive disorders in PD patients. RESULTS: Pharmacological treatment approaches for impulsive-compulsive behaviors and DDS in PD patients include reduction of levodopa (LD), reduction/cessation of dopamine agonist (DA), and initiation of infusion therapies (apomorphine infusion and duodopa). Also, atomoxetine, a noradrenergic agent approved for the treatment of attention deficit hyperactivity disorder, showed some interesting preliminary results but there is still a lack of controlled longitudinal studies. Finally, while DBS effects on impulsive-compulsive disorders are still controversial, non-invasive techniques (such as transcranial magnetic stimulation and transcranial direct current stimulation) could have a potential positive effect but, again, there is still a lack of controlled trials. CONCLUSION: Managing impulsivity and compulsivity in PD patients is still a non-evidence-based challenge for clinicians. Controlled trials on promising approaches such as atomoxetine and non-invasive neuromodulation techniques are needed.

Behavioural and trait changes in parkinsonian patients with impulse control disorder after switching from dopamine agonist to levodopa therapy: results of REIN-PD trial.

OBJECTIVE: In this multicentre open-label trial, we compared behavioural and neuropsychiatric symptoms in Parkinson's disease (PD) patients with impulse control disorders (ICD) treated with dopamine agonists before and 12 weeks after substituting dopamine agonists with an equivalent dose of levodopa/carbidopa slow-release formulation. METHODS: Baseline characteristics of 50 PD patients with ICD were compared with those of 60 medicated and 40 drug-naive PD control groups. Neuropsychiatric trait changes in the PD-ICD group were investigated 12 weeks after the intervention. ICD behaviours were assessed via modified Minnesota Impulsive Disorders Interview (mMIDI), whereas parkinsonian severity and neuropsychiatric characters were systematically assessed with the Unified PD Rating Scale (UPDRS) and a predefined neuropsychological assessment battery. RESULTS: At baseline, ICD patients showed higher scores in the Neuropsychiatric Inventory and anxiety, anger and obsessive-compulsive traits compared with both PD control groups. In contrast, the three PD groups showed indifference in the impulsivity scales. At 12 weeks post intervention, ICD behaviours significantly improved (p<0.001, Δ modified MIDI score=‒5.27 ± 5.75) along with the UPDRS II daily activity scores (p=0.02, Δ=‒2.07 ± 4.53). Behavioural disinhibition tended to improve (p=0.06), although no significant changes were observed in the Neuropsychiatric Inventory and personality trait scores. Dopamine agonist withdrawal syndrome developed in 5.3% of the PD-ICD group. CONCLUSIONS: This study provides class IV evidence suggesting that switching from dopamine agonists to levodopa/carbidopa slow-release formulations alleviated ICD behaviours in PD patients leading to improvement in daily activities whereas neuropsychiatric traits associated with ICD persisted after the 12-week therapy. TRIAL REGISTRATION NUMBER: NCT01683253.

5-HT2c agonist, lorcaserin, reduces aggressive responding in intermittent explosive disorder: A pilot study.

RATIONALE: Impulsive aggressive behavior is associated with reduced central function of serotonin (5-HT). Although selective serotonin reuptake inhibitors can reduce such behaviors, many with history of impulsive aggression do not respond adequately to selective serotonin reuptake inhibitors and may require treatment with a direct 5-HT agonist. OBJECTIVES: To test the hypothesis that pretreatment with the selective 5-HT2c agonist, lorcaserin, can reduce aggressive responding in impulsively aggressive individuals. METHODS: Ten male and female adults were given lorcaserin (20 mg), or a matching placebo, in random order, on 2 days separated by at least 1 week. The Taylor aggression paradigm was used to assess aggressive responding, which was represented by mean shock setting administered to an opponent and by frequency of setting high and extreme shock levels to the opponent. RESULTS: Compared with placebo, lorcaserin attenuated provoked, but not unprovoked, aggression during the Taylor aggression paradigm. This was manifest by reduction in the frequency of selecting high and extreme levels of shock against the opponent. CONCLUSION: Lorcaserin may possess anti-aggressive properties that could prove useful in the treatment of impulsive aggressive behavior in human subjects. These data, thus, provide a rationale for a follow-up randomized clinical trial of lorcaserin in individuals with prominent histories of impulsive aggressive behavior.

Neuropsychiatric Traits Associated with Refractory Impulse Control Disorder in Parkinson's Disease.

INTRODUCTION: Impulse control disorder (ICD) in Parkinson's disease (PD) is a critical nonmotor symptom with personality or neuropsychiatric traits contributing to ICD. OBJECTIVE: This study aimed to identify predictive traits for persistent or paradoxical aggravation of ICD after dopamine agonist substitution therapy for ICD in PD. METHODS: We conducted a case-control study using a database of a multicenter intervention trial for ICD in PD. The poor-outcome group was defined by showing paradoxical increases in ICD behaviors after the substitution of dopamine agonists with levodopa. We analyzed the pre-intervention personality traits associated with the poor outcome and also evaluated the risk traits for refractory ICD using a receiver-operating characteristic (ROC) curve analysis. RESULTS: The poor-outcome group showed higher levels of anger expression (p =0.007) and obsessive-compulsive traits (p =0.009) compared with the good-outcome group at the pre-intervention state. In the ROC curve analysis, the Obsessive-Compulsive Inventory showed the highest area under the curve with 80.0% sensitivity and 74.3% specificity in discriminating against the poor-outcome group. CONCLUSIONS: Our results suggest that assessment of obsessive compulsiveness may be useful for predicting the refractoriness of ICD behaviors in planning an interventional treatment for ICD in PD.

Pharmacological Treatments for Disordered Gambling: A Meta-analysis.

Disordered gambling is a public health concern associated with detrimental consequences for affected individuals and social costs. Currently, opioid antagonists are considered the first-line treatments to reduce symptoms of uncontrolled gambling. Only recently, glutamatergic agents and combined pharmacological and psychological treatments have been examined appearing promising options for the management of gambling disorder. A multilevel literature search yielded 34 studies including open-label and placebo-controlled trials totaling 1340 participants to provide a comprehensive evaluation of the short- and long-term efficacies of pharmacological and combined treatments. Pharmacological treatments were associated with large and medium pre-post reductions in global severity, frequency, and financial loss (Hedges's g: 1.35, 1.22, 0.80, respectively). The controlled effect sizes for the outcome variables were significantly smaller (Hedges's g: 0.41, 0.11, 0.22), but robust for the reduction of global severity at short-term. In general, medication classes yielded comparable effect sizes independent of predictors of treatment outcome. Of the placebo controlled studies, results showed that opioid antagonists and mood stabilizers, particularly the glutamatergic agent topiramate combined with a cognitive intervention and lithium for gamblers with bipolar disorders demonstrated promising results. However, more rigorously designed, large-scale randomized controlled trials with extended placebo lead-in periods are necessary. Moreover, future studies need to monitor concurrent psychosocial treatments, the type of comorbidity, use equivalent measurement tools, include outcome variables according to the Banff, Alberta Consensus, and provide follow-up data in order to broaden the knowledge about the efficacy of pharmacological treatments for this disabling condition.

Exposure and response prevention therapy augmented with naltrexone in kleptomania: a controlled case study using galvanic skin response for monitoring.

BACKGROUND: Kleptomania is a disease that shares features with obsessive compulsive spectrum disorders (OCD) and with substance abuse disorders (SAD). This is underlined by therapeutic approaches in kleptomania ranging from cognitive behavioural therapy and selective serotonin reuptake inhibitors that are effective in OCD, and opioid antagonists that are currently being used in SAD. However, almost no literature exists about exposure and response prevention (ERP) therapy in kleptomania. Furthermore, there is a clear lack of objective markers that would allow a therapeutic monitoring. AIM: To show the effectiveness of ERP therapy in kleptomania in a single case report. METHOD: An ERP therapy under real-world conditions and later augmentation with the opioid antagonist naltrexone is described. Continuous measurements of galvanic skin response (GSR) before, during and after therapy sessions are reported in association with changes of the Kleptomania Symptom Assessment Scale (KSAS) self-questionnaire. RESULTS: While KSAS scores showed a clear treatment response to ERP sessions, the GSR was significantly lower during ERP treatment in comparison with baseline measures. However, during augmentation with naltrexone, GSR measures increased again and clinical severity did not further improve. CONCLUSIONS: This case shows the possible usefulness of ERP-like approaches and therapy monitoring using electrophysiological markers of arousal for individualized treatment in kleptomania.

Sleep and REM sleep behaviour disorder in Parkinson's disease with impulse control disorder.

INTRODUCTION: Because the association between rapid eye movement sleep behaviour disorder (RBD) and impulse control disorders (ICDs) in Parkinson's disease (PD) has been debated, we assessed the sleep characteristics and the frequency of RBD using video-polysomnography (v-PSG) in patients with PD with versus without ICDs. METHODS: Eighty non-demented patients with PD consecutively identified during routine evaluation at three movement disorders centres were enrolled in a case-control study. Forty patients (22 men; mean age: 62.6±9.7 years, Hoehn & Yahr: 2.1±0.6) with one or more current ICDs were age-matched and sex-matched with 40 patients with no history of ICDs (22 men, mean age: 64.9±7.8 years, Hoehn & Yahr: 2.2±0.6). They underwent a detailed sleep interview followed by a full-night in-lab v-PSG. Sleep was scored blindly to ICDs condition and RBD diagnosis included a clinical complaint of enacted dreams and/or documented behaviour during rapid eye movement (REM) sleep, with the presence of quantified REM sleep without atonia (RSWA). RESULTS: Patients with ICDs had a higher arousal index and higher RSWA than those without ICDs (51.9%±28.2%vs 32.2±27.1%, p=0.004). In addition, RBD was more frequent in the ICD group (85%vs53%, p=0.0001). RBD was still associated with ICDs in a multivariate regression analysis including age of onset, PD duration and severity, treatment duration, levodopa-equivalent and dopamine agonist-equivalent daily doses and antidepressant use (OR: 4.9 (95% CI 1.3 to 18.5), p=0.02). CONCLUSIONS: This large, controlled series of patients with PD with ICDs assessed by v-PSG confirms the association between ICDs and RBD. Increased surveillance of symptoms of ICDs should be recommended in patients with PD with RBD.

Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease.

BACKGROUND: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. METHODS: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. RESULTS: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105). CONCLUSIONS: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society.

New insights into Brunner syndrome and potential for targeted therapy.

We report two families with Brunner syndrome living in one state of Australia. The first family had a predicted protein-truncating variant of monoamine oxidase A (MAOA) (p.S251KfsX2). Affected males had mild intellectual disability (ID), obsessive behaviour, limited friendships and were introverted and placid during clinical interview. The family disclosed episodic explosive aggression after a diagnosis was made. The second family had a missense variant in MAOA (p.R45W). Affected males had borderline-mild ID, attention deficit disorder and limited friendships. One had a history of explosive aggression in childhood and episodic symptoms of flushing, headaches and diarrhoea. Their carrier mother had normal intelligence but similar episodic symptoms. Characteristic biochemical abnormalities included high serum serotonin and urinary metanephrines and low urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA). Symptomatic individuals in the second family had particularly high serotonin levels, and treatment with a serotonin reuptake inhibitor and dietary modification resulted in reversal of biochemical abnormalities, reduction of 'serotonergic' symptoms and behavioural improvement. Brunner syndrome should be considered as a cause of mild ID with paroxysmal behavioural symptoms. It can be screened for with serum/urine metanephrine and serotonin measurement. Cautious treatment with a serotonin reuptake inhibitor, dietary modifications and avoidance of medications contraindicated in patients on monoamine oxidase inhibitors can improve symptoms.