Why the adolescent brain is sensitive to psychosis-inducing effects of cannabis

According to David A. Lewis, MD, who spoke at the American Psychiatric Association Institute on Psychiatric Services on October 31 in San Francisco, California, impairment in working memory is a key finding in schizophrenia, and this impairment is present before onset of psychosis, persists during the illness, and helps predict functional outcome. Furthermore, research in post-mortem brains and animal models shows that layer 3 of the dorsolateral prefrontal cortex is crucial to working memory.

In a lecture titled “Developmental trajectories in cortical circuits: Identifying sensitive periods for the emergence of schizophrenia,” Dr. Lewis, director of the Translational Neuroscience Program and chair of the department of psychiatry at the University of Pittsburgh, described research that has begun to explain why schizophrenia tends to strike people in late adolescence and early adulthood. A circuit consisting of pyramidal cells and inhibitory GABAergic cells, which is recorded electrophysiologically as the “gamma oscillation,” matures during childhood and early adolescence. In this complex process, which involves GABA, NMDA and cannabinoid receptors, some synapses are strengthened and others pruned. During this “sensitive period,” as Lewis called it, exposure to environmental insults can have a profound effect. One manifestation is that people with schizophrenia end up with 20% fewer dendritic spines, which are post-synaptic structures, on the pyramidal cells in cortical layer 3 than unaffected people.

Epidemiologic data consistently show that youth who use marijuana before 16 years of age double or triple their risk for developing schizophrenia. Tetrahydrocannabinol (THC), which binds to cannabinoid receptors on pyramidal and GABAergic neurons in the cortex, affects visual working memory in many people who use it. In an effort to mimic human teenagers’ regular use of marijuana, Dr. Lewis’ lab gave a group of young rhesus monkeys frequent doses of THC. Compared to non-exposed peers, monkeys who had a 6-month exposure to THC developed impairments in spatial working memory similar to enduring deficits exhibited by humans with schizophrenia. The researchers also looked at a second cognitive task that targets object working memory, which depends upon the ventral prefrontal cortex, an area of the brain that matures earlier. This function was unaffected by exposure to THC.

Dr. Lewis emphasized that timing is crucial and may help explain why certain exposures or traumas have major impact at one time in development and minor impact at another. The impact of treatments likewise may vary by developmental stage, and he said that those that aren’t targeted and timely may have unintended consequences.

66th Annual American Psychiatric Association Institute on Psychiatric Services in San Francisco

66th Annual American Psychiatric Association Institute on Psychiatric Services in San Francisco

Randall is pleased to be attending the 66th Annual American Psychiatric Association Institute on Psychiatric Services in San Francisco. He presented findings on 630 patients treated during 1993-2010 on the refractory psychosis ward at Riverview Hospital, British Columbia.

To view his abstract, click here.

Follow the conference on Twitter: #IPS2014

The refractory psychosis ward at Riverview Hospital between 1993 & 2010

Riverview Psychiatric Hospital Coquitlam BC

OBJECTIVES: Patients in British Columbia who have treatment-resistant psychosis may receive care in a publicly funded academic program where each patient undergoes a multidisciplinary diagnostic evaluation. We describe this assessment process and present findings on a series of patients including a large number with treatment-resistant schizoaffective (SZA) disorder.

METHOD: All patients admitted to the refractory psychosis ward at Riverview Hospital between 1993 and 2010 had failed to respond to at least two previous antipsychotic trials. A psychiatrist, social worker, pharmacist, nurse, general physician, and neuropsychologist evaluated each patient. All available summaries of previous psychiatric admissions were reviewed, and medical, pharmacological, social and behavioural histories were recorded. All information was presented at a case conference and a DSM-IV multiaxial diagnosis reflected agreement between at least two psychiatrists and a psychologist. Symptom ratings included the Positive and Negative Syndrome Scale, the Global Assessment of Functioning, and the Clinical Global Impression-Severity scale.

FINDINGS: Of the 642 patients who were admitted, 92 did not complete treatment (died, were transfered or left against advice) or received a diagnosis other than schizophrenia (SZ), SZA or mood disorder (MD). Consensus diagnosis differed from referral diagnosis in 27% of cases. Of 378 patients referred with SZ, the consensus diagnosis was SZ in 78%, SZA in 15%, MD in 2%, and other in 5%. Of the 145 referred with SZA, the consensus diagnosis was SZA in 63%, SZ in 26%, MD in 3%, and other in 2%. Two thirds of the SZA group were bipolar type. People with confirmed MD or SZA tended to be older and had a longer illness duration, and were more likely to be female, noncaucasian, and married. Functioning and symptom severity in the preceding year and at admission were worse in SZ than SZA patients. PANSS positive scores were greater for SZ and SZA than MD, and PANSS negative scores were more severe in SZ than SZA or MD. Prior depressive episodes were very common in MD (98%) and SZA (89%), but 35% of SZ patients also had a previous depressive episode. Lifetime substance use disorder was found in 63% and recent substance abuse in 35% of patients, and these proportions did not differ across diagnoses. At admission, SZA patients were more likely than SZ patients to have been on a mood stabilizer, but the mean number of antipsychotics and total amount (defined daily dose) did not differ.

CONCLUSION: In a series of patients with treatment-resistant psychosis, the most common diagnosis was SZ, but 29% had SZA. SZA patients were frequently misdiagnosed in the community, and compared to SZ patients, tended to have better baseline functioning, lower symptom severity, were older, and had been ill longer.

Brazil: The Use of Nitrous Prusside for Schizophrenia

nitrous prusside, schizophrenia, mental health

In 2013, Drs. Jaime Hallak, Joao Paulo Maia-de-Oliveira and associates in Ribeirao Preto, Brazil, published results from a randomized controlled trial of intravenous nitroprusside in schizophrenia. Two Canadian researchers from the University of Alberta collaborated on the trial. This study was the first to find that sodium nitroprusside, a treatment for hypertensive crises, has a rapid and prolonged effect on both positive and negative symptoms in patients with acute psychosis. The presumed mechanism is enhancement of nitric oxide in the central nervous system, which may modulate the NMDA receptor-cGMP pathway. In normotensive patients, nitroprusside has minimal effect on blood pressure, and cyanide accumulation is a theoretical concern but occurs only after 72 hours or more of continuous infusion. In treating schizophrenia, the infusion dose is 0.5 mg/kg/minute for four hours.

In the initial trial published in JAMA Psychiatry, Hallak’s team used the Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale (PANSS) as outcome measures. A significant effect on certain components occurred within the first two to three hours of treatment, and improvement endured for four weeks. All the patients were also receiving an antipsychotic other than clozapine.

I met with Jaime, Joao Paulo and their team at the University of Sao Paulo Hospital in Ribeirao Preto and was able to observe a treatment. When I first met the patient, whose infusion had begun 10 minutes before, she appeared anxious and tended to avoid eye contact. When I returned 90 minutes later, she was engaged in an art activity and was eager to show me what she had created. She smiled broadly and even tested her English vocabulary a little. The researchers said that they often see an improvement in the patients’ affect over the course of the infusion, and they are trying to find ways to measure this more objectively. Although data are still limited, the effect in treatment-resistant patients tends to be more delayed.

Further studies of nitrous prusside in Ribeiroa Preto are underway, including for treatment-resistant patients, some on clozapine, and on neurophysiologic effects as detected with fMRI and event-related potential. Because the benefits of the treatment begin to wane after four weeks, they are planning a controlled trial of weekly nitrous prusside infusions for four weeks followed by 60 days of observation.
Reference
Hallak JEC, Maia-de-Oliveira JP, Abroa J, et al. Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside: A Randomized, Double-blind, Placebo-Controlled Trial. JAMA Psychiatry. 2013;70:668-676. Abstract
Photo: Left to right: Dr. Jaime Hallak, Dr. Joao Paolo Maia-de-Oliveira, Juliana Almeida (audiologist), their patient and her mother

Health Care is a Human Right

On July 19th, 2014, Dr. Randall White was invited to speak at  The Western Washington Chapter of Physicians for a National Health Program’s Ninth Annual Public Meeting. This year’s theme was: “Health Care is a Human Right: Making it Real in Washington State.” As a physician who has practiced both in Canada and the US, Randall brings a unique perspective to the table. Dr. White is a known advocate for health care equality, and stresses that financial access to health care is a major source of inequality. He says “Inequality has greater effects on Health Care than the actions of doctors and caregivers. In Canada, Health Care is a human right.” He goes on to encourage his American colleagues to continue to strive for universal health care.

MicroRNA: a new frontier in schizophrenia?

A large consortium of researchers in Europe, North American and Australia performed a genome-wide association study (GWAS) of single-nucleotide polymorphisms, which are uncommon variants of genes, among people with schizophrenia in two stages. In the first stage, a discovery analysis of pre-existing GWAS cohorts, they included, 9,394 people with schizophrenia and 12,462 controls, all of European ancestry. In the second-stage independent replication, they used a sample of 8,442 cases and 21,397 controls. In the combined stage-1-and-2 dataset, five alleles had a significant and novel association with schizophrenia, whereas two alleles identified in previous research had significant association. The most robustly newly associated allele was rs1625579 on chromosome 1p21.3, in intron 3 of AK094607. This region codes for the primary transcript of MIR137, a microRNA involved in adult neurogenesis and neuronal maturation. Two previous studies cited in the present report found an association of this regulatory mechanism with schizophrenia. Moreover, four genes identified as possibly associated with schizophrenia in the present study are targets of MIR137.

Although the evidence is circumstantial, the researchers assert a possible pathophysiologic role for the MIR137 mechanism in schizophrenia. Linkage studies, an older approach to identify candidate genes, have identified schizophrenia-related genes such as DISC1, and studies of patients with copy-number variants such as 22q11 deletion syndrome have suggested additional genetic etiologies of psychosis. The heterogeneity of “the group of schizophrenias,” as Bleuler called this disorder (2), is being borne out in genetic research, and psychiatrists should pay attention. We can hope that such work will bear fruit in improved treatments for our patients.

References

1. The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011.18;43:969-976. Full text

2. Bleuler, Eugen. Dementia praecox or the group of schizophrenias. Leipzig, Germany; 1911.

Health Care is a Human Right: Making it Real in Washington State

We are pleased to announce that Dr. Randall White has been invited to be the third speaker at The Western Washington Chapter of Physicians for a National Health Program’s Ninth Annual Public Meeting. This year’s theme is: “Health Care is a Human Right: Making it Real in Washington State”, and includes a promising keynote to be delivered by Kshama Sawant, PHD, Seattle City Council Member. Sawant champions the rights of the working poor and disenfranchised, and is most recently recognized for her work on the successful $15Now campaign, a grass-roots living wage campaign.

Another highlight will be Philip Caper, MD, who was a staff member on Senator Edward Kennedy’s US Senate Labor and Human Resources Subcommittee on Health, a PNHP national Board Member and active in Maine AllCare.

Randall will be contributing “Remarks from a Canadian / American Perspective.” He will mention how commercialized mental health care compromises quality, provides less service for the severely mentally ill, and has been implicated in known corruption in the U.S.

We hope you will join us!

Attending the event? Or following from home? Use hashtag #HCHR2014 and @BCPsychosis

Saturday, July 19th, at 7PM at
Kane Hall Room 120, on the University of Washington Campus
Admission is free and open to the public.
There is free parking beneath Kane Hall.

Dr. Vila receives award at American Psychiatric Association 2014 meeting

Dr. Fidel Vila-Rodriguez, a BC Psychosis Program psychiatrist, received an American Psychiatric Foundation Early Academic Career Award on Schizophrenia Research at the APA Annual Meeting in New York in May, 2014. To learn about Dr. Vila’s research, visit his lab Web site NINET.CA.

Estradiol for treatment-resistant schizophrenia

Researchers from Australia have conducted the first controlled trial of estrogen in premenopausal women with treatment-resistant psychosis (1). They recruited 183 women with schizophrenia or schizoaffective disorder who were not pregnant, lactating, or postmenopausal; and who had no history of breast cancer, endocrine disorders, migraine with aura, or thromboembolism. Patients with acute mania were excluded. Patients were randomly assigned to receive either transdermal estradiol 100 mcg daily, transdermal estradiol 200 mcg daily, or placebo patch. The primary outcome measure during the 56-day trial was the Positive and Negative Syndrome Scale (PANSS). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), the Repeatable Battery of Neuropsychological Status, adverse-effects monitoring, and serum estradiol concentration at the baseline and during treatment.

The baseline demographic, illness, and treatment characteristics did not differ among the placebo, 100 mcg-estradiol, and 200-mcg estradiol groups. Most subjects were outpatients, and the three groups had mean PANSS total scores of 72-75. Compared with the placebo group, both treatment groups had significant increases in serum estradiol concentration; and greater decreases in mean PANSS positive, general, and total scores. The effect size for positive symptoms, however, was 0.0 for the 100 mcg group and 0.44 for the 200 mcg group, which reflected a mean 3.3-point reduction in PANSS-positive score with the higher dose. No significant treatment effect was found for negative symptoms or cognition. The only significant adverse effect was an increase of irregular menses in the 200 mcg group compared with the placebo group.

The investigators acknowledge that this trial was short-term and that the risks of thromboembolism and endometrial carcinoma may accumulate during longer-duration therapy. Raloxifene, a selective estrogen receptor modulator, entails a lower risk of these adverse effects. In 2011, investigators from Spain reported on a randomized trial of 16 postmenopausal women who had significant mean reduction of positive, negative, and general symptoms compared with a comparable placebo group (2). Case reports exist of raloxifene use in premenopausal women with treatment-resistant schizophrenia (3,4), but controlled trials in this population have not been published.

References

1. Kulkarni J, Gavrilidis E, Wang W. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age. Molecular Psychiatry. Published online 15 Apr 2014. Abstract

2. Usall J, Huerta-Ramos E, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2011;72(11):1552-1557. Abstract

3. Raveendranathan D, Shivakumar V, Jayaram N, Rao NP, Venkatasubramanian G. Beneficial effects of add-on raloxifene in schizophrenia. Arch Womens Ment Health. 2012;15(2):147-148. Abstract

4. Shivakumar V, Venkatasubramanian G. Successful use of adjuvant raloxifene treatment in clozapine-resistant schizophrenia. Indian J Psychiatry. 2012;54(4):394. Full text

A Meta-Analysis of CBT for Medication-Resistant Psychosis

A team of BC psychologists has performed the first meta-analysis of cognitive-behavioral therapy for medication-resistant psychosis. The 16 published studies that met their inclusion criteria comprised 12 trials and 639 individual patients. Medication resistance was defined as inadequate response of positive symptoms to at least one medication at adequate dose and duration, or treatment with clozapine. All the trials entailed assignment to either individual CBT for 10 to 24 sessions, or to a control intervention such as treatment as usual, psychoeducation or befriending. Four trials lacked masked raters. Outcome measures were typically PANSS or BPRS, and most studies had a follow-up assessment 3 to 18 months after completion of treatment. Based on pooled outcome data, effect size was derived with Hedge’s g.

For improving positive symptoms, the effect size of CBT compared to control intervention at the end of treatment was 0.47. At follow-up 3-18 months after treatment, the effect size was 0.41. Among studies with an outcome measurement for general psychopathology, such as depression and anxiety, the effect sizes were 0.52 at treatment end and 0.40 at follow-up. According to the researchers, excluding studies without masked raters did not significantly change the effect sizes.

This meta-analysis yielded a medium effect size for time-limited CBT in medication-treated patients with residual positive symptoms. The results suggest improvement may be maintained beyond a year. These were not necessarily treatment-resistant patients as typically defined, although some were on clozapine. Research on other important outcomes such as hospital admission, psychosocial functioning, and suicide would help determine the place of CBT in managing treatment-resistant psychosis.

Reference

Burns AM, Erickson DH, Brenner CA. Cognitive-behavioral therapy for medication-resistant psychosis: a meta-analytic review. Psychiatr Serv. Published online 1 Apr 2014. Abstract