Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings

BACKGROUND: The dystrobrevin-binding protein 1 (DTNBP1) gene is a susceptibility gene for schizophrenia. There is growing evidence that DTNPB1 contributes to intelligence and cognition. In this study, we investigated association between single nucleotide polymorphisms (SNPs) in the DTNBP1 gene and intellectual functioning in patients with a first episode of schizophrenia or related psychotic disorder (first-episode psychosis, FEP), their healthy siblings, and unrelated controls. METHODS: From all subjects IQ measurements were obtained (verbal IQ [VIQ], performance IQ [PIQ], and full scale IQ [FSIQ]). Seven SNPs in the DTNBP1 gene were genotyped using single base primer extension and analyzed by matrix-assisted laser deionization mass spectrometry (MALDI-TOF). RESULTS: Mean VIQ, PIQ, and FSIQ scores differed significantly (p < 0.001) between patients, siblings, and controls. Using a family-based and a case-control design, several single SNPs were significantly associated with IQ scores in patients, siblings, and controls. CONCLUSION: Although preliminary, our results provide evidence for association between the DTNBP1 gene and intelligence in patients with FEP and their unaffected siblings. Genetic variation in the DTNBP1 gene may increase schizophrenia susceptibility by affecting intellectual functioning

AMPT-induced monoamine depletion in humans: evaluation of two alternative [123I]IBZM SPECT procedures

Purpose Acute monoamine depletion paradigms using alpha-methyl-para-tyrosine (AMPT) combined with single photon emission computed tomography (SPECT) have been used successfully to evaluate disturbances in central dopaminergic neurotransmission. However, severe side effects due to relatively high doses (4,500 to 8,000 mg) of AMPT have been reasons for study withdrawal. Thus, we assessed the effectiveness and tolerability of two alternative procedures, using lower doses of AMPT. Methods Six healthy subjects underwent three measurements of striatal dopamine D2 receptor (D2R)-binding potential (BPND) with SPECT and the selective radiolabeled D2R antagonist [123I]IBZM. All subjects were scanned in the absence of pharmacological intervention (baseline) and after two different depletion procedures. In the first depletion session, over 6 h, subjects were administered 1,500 mg of AMPT before scanning. In the second depletion session, over 25 h, subjects were administered 40 mg AMPT/kg body weight. We also administered the Subjective Well-being Under Neuroleptic Treatment Scale, a self-report instrument designed to measure the subjective experience of patients on neuroleptic medication. Results We found no change of mean D2R BPND after the first and short AMPT challenge compared to the baseline. However, we found a significant increase in striatal D2R BPND binding after the AMPT challenge adjusted for bodyweight compared to both other regimen. Although subjective well-being worsened after the prolonged AMPT challenge, no severe side effects were reported. Conclusions Our results imply a low-dosage, suitable alternative to the common AMPT procedure. The probability of side effects and study withdrawal can be reduced by this procedure

A normative chart for cognitive development in a genetically selected population

Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS

Psychiatric and neurological manifestations in adults with Smith-Magenis syndrome:A scoping review

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder caused by a 17p11.2 deletion or a pathogenic variant of the RAI1 gene, which lies within the 17p11.2 region. Various psychiatric and neurological disorders have been reported in SMS, with most literature focusing on children and adolescents. To provide an overview of the current knowledge on this topic in adults with SMS, we performed a comprehensive scoping review of the relevant literature. Our findings suggest that many manifestations that are common in childhood persist into adulthood. Neuropsychiatric manifestations in adults with SMS include intellectual disability, autism spectrum- and attention deficit hyperactivity disorder-related features, self-injurious and physical aggressive behaviors, sleep-wake disorders, and seizures. Findings of this review may facilitate optimization of management strategies in adults with SMS, and may guide future studies exploring late-onset psychiatric and neurological comorbidities in SMS

Genetic risk of mental illness:What do we know and how do we communicate this?

Background Insights from psychiatric genetics research and large international psychiatric genetics consortia are promising but still remain outside the realm of clinical practice. Aim To provide an overview of developments in the field of psychiatric genetics; and to offer guidance for health professionals how to assess and manage clinical implications of these developments. Method In this review, we address: recent developments in psychiatric genetics, with a focus on polygenic risk scores (PRS); ethical dilemmas associated with clinical application of PRS; and basic principles of genetic counseling for psychiatric disorders. Results PRS are not yet ready for implementation in clinical practice because of limited predictive value and poor generalizability. In addition, it is still unclear how genetic risk and PRS can be communicated clearly to patients and families. Conclusion Advances in psychiatric genetics and increased availability of genetic risk scores may lead to questions from patients and families coping with psychiatric illness. These questions may be best addressed using psychiatric genetic counseling techniques. We recommend that psychiatrists have some basic knowledge of psychiatric genetics and know how to refer their patients to a clinical geneticist. Implementing a psychiatric genetics theme in training and education may be helpful

Guidelines on genetic testing in psychiatry:an overview

Background In recent years, technological advances have led to the identification of numerous genetic variations that are associated with psychiatric symptoms. Establishing a genetic cause may provide patients and family members with an explanation for the problems and in specific cases allows targeted treatment of psychiatric and somatic (co)morbidity. At present, patients with psychiatric disorders are rarely referred for genetic testing. Aim To provide an overview of literature and (inter)national guidelines in the field of genetic testing for patients with psychiatric disorder, and to present guidance on indications for genetic testing in clinical practice. Method A systematic search was conducted in PubMed and Embase focusing on articles with recommendations on genetic testing in psychiatric disorders. In addition, national and international guidelines on genetic testing in psychiatry were studied. The main findings were summarized in an infographic. Results Based on the current literature and (inter)national guidelines, patients with (comorbid) intellectual disability should always be referred to a clinical geneticist. Psychiatrists should consider genetic testing in patients with other psychiatric disorders if there are 'red flags' such as a positive family history, congenital abnormalities, developmental delay, dysmorphic features, movement disorders or cognitive decline. Psychiatrists may request genetic testing themselves or refer patients to clinical geneticists. Conclusion Psychiatric disorders may be underpinned by a genetic anomaly, particularly in patients presenting with psychiatric as well as somatic symptomatology. Psychiatrists should recognize symptoms and warning signs indicative of an underlying genetic abnormality, and know when to refer their patients for genetic testing