Cannabis Withdrawal Syndrome Occurs in Almost Half of Regular Users

May 15, 2020 · Posted in Peer-Reviewed Published Data · Comment 
Photo by Thought Catalog on Unsplash

A recent systematic review and meta-analysis by researcher Anees Bahji and colleagues in the open access medical journal JAMA Network Open describes the symptoms and prevalence of cannabis withdrawal syndrome.

The most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) indicates that cannabis withdrawal syndrome “requires the presence of at least 3 of the following symptoms developing within 7 days of reduced cannabis use: (1) irritability, anger, or aggression; (2) nervousness or anxiety; (3) sleep disturbance; (4) appetite or weight disturbance; (5) restlessness; (6) depressed mood; and (7) somatic symptoms, such as headaches, sweating, nausea, vomiting, or abdominal pain.”

According to Bahji and colleagues, cannabis withdrawal syndrome occurred in 47% of regular users. Higher rates of withdrawal were found among those in clinical settings, those who also used tobacco or other substances, and those who used cannabis daily.

Bahji and colleagues write that while many people believe that cannabis is relatively harmless, it actually has a variety of associated risks. Short-term risks include impaired short-term memory and motor coordination, altered judgment, paranoia, and psychosis. Long-term effects include addiction, altered brain development, poor educational outcomes, cognitive impairment, diminished quality of life, increased risk of chronic respiratory tract and psychotic disorders, injuries, motor vehicle collisions, and suicide.
The researchers warned that users of cannabis may resume cannabis use to allay the depression and anxiety symptoms that are part of the withdrawal syndrome, perpetuating the long-term withdrawal cycle.

Bahji and colleagues suggest that because of the high prevalence of the withdrawal syndrome, doctors should screen patients for cannabis withdrawal, particularly men and frequent cannabis users. They write, “Clinicians should be aware of CWS as it is associated with clinically significant symptoms, which can trigger resumption of cannabis use and serve as negative reinforcement for relapse during a quit attempt.” Doctors can offer support for those reducing their cannabis consumption.

Fish Oil Monotherapy on Depression in Adolescents at High Risk for Bipolar I Disorder: Ambiguity Persists

omega-3 fatty acids
Fish oil supplements

Researcher Robert K. McNamara and colleagues reported in the Journal of Child and Adolescent Psychopharmacology in a 2020 article that 12 weeks of treatment with omega-3 fatty acids in the form of fish oil did not reduce depression symptoms in adolescents at risk for bipolar disorder when compared to placebo. The primary outcome measured was the results of the Childhood Depression Rating Scale-Revised (CDRS-R).

Fish oil did perform better than placebo on two parts of the rating scale: symptom severity and symptom improvement, especially in weeks 11 and 12 of the study. Omega-3 fatty acids increased creatine and choline in the anterior cingulate, and also increased polyunsaturated fatty acids in red blood cells. The treatment was safe and well-tolerated.

A total of 42 patients between the ages of 9 and 21 who had been diagnosed with depression and had at least one parent with bipolar I disorder received either placebo or 3 fish oil capsules per day. Each capsule contained 450?mg EPA, 40?mg docosapentaenoic acid (DPA), and 260?mg DHA for a total daily dose of 2130?mg EPA + DHA.

Editor’s Note: Ambiguity persists about whether omega-3 fatty acids can improve unipolar or bipolar depression, attention-deficit hyperactivity disorder (ADHD), or prevent the progression of schizophrenia symptoms to the full syndrome. Given the lack of side effects, and the documented effects on red blood cells and brain choline, clinical use of these compounds could be considered in some circumstances.

Translocator Protein Levels in Brain Predict Response to Anti-Inflammatory Celecoxib in Major Depressive Disorder

May 5, 2020 · Posted in Brain Imaging, Peer-Reviewed Published Data · Comment 
Photo by Robina Weermeijer on Unsplash

Gliosis describes changes in glia that result from damage to the central nervous system. Researchers can use PET scans (positron emission tomography) to measure the extent of gliosis in the brain. But a new study explored whether these PET scans could instead be used to determine who might respond to a given medication.

Researcher Sophia Attwells and colleagues reported in the journal Biological Psychiatry in 2020 that people with high levels of translocator protein (TSPO), a measure of gliosis and inflammation, had a better antidepressant response to the anti-inflammatory drug celecoxib than patients who started out with lower levels of TSPO.

The study participants, who had treatment-resistant depression, all received 200mg of the anti-inflammatory drug celecoxib twice/day for eight weeks on an open (non-blind) basis. Before they began taking celecoxib, the participants received PET scans to measure translocator protein total distribution volume (TSPO VT) in the prefrontal cortex and the anterior cingulate cortex.

Patients with high levels of TSPO showed greater reductions in depression ratings over the course of the study than those with normal levels of TSPO at baseline.

Attwells and colleagues conclude that “this personalized medicine approach of matching a marker of gliosis to [an anti-inflammatory treatment] …should be applied in early development of novel therapeutics, in particular for [treatment-resistant depression].”

Editor’s Note: These findings are of considerable importance, as they are among the first to indicate that measures of inflammation may predict response to an anti-inflammatory medication such as celecoxib. In a 2013 article in the journal JAMA Psychiatry, Charles L. Raison and colleagues reported that patients with high levels of the peripheral inflammatory marker CRP saw marked improvement in their depression when they received the anti-inflammatory treatment infliximab while those with lower or normal levels of inflammation actually worsened.

Gabapentin is Effective in Alcohol Use Disorder in Patients with Alcohol Withdrawal Symptoms

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Researcher Raymond F. Anton and colleagues reported in the journal JAMA Internal Medicine that compared with placebo, the anticonvulsant medication gabapentin helped people with alcohol use disorders reduce their drinking or abstain from drinking, especially those who had more withdrawal symptoms before treatment.

Ninety-six participants were randomized to receive either placebo or 1200mg/day of gabapentin for 16 weeks.

In the study, 27% of participants who took gabapentin had no heavy drinking days (compared to 9% among those who took placebo) and 18% achieved total abstinence (compared to 4% among those who took placebo). Gabapentin was most effective in those with a history of alcohol withdrawal symptoms. An impressive 41% of participants with high alcohol withdrawal symptoms who took gabapentin achieved total abstinence compared with 1% of participants in the placebo group.

Gabapentin, which is used to treat epilepsy, influences GABA and glutamate transmitters and inhibits the alpha 2gamma-1 voltage sensitive calcium channel, which is upregulated in chronic alcohol exposure.

Better One-Year Clinical Outcomes After Four Weeks of Theta Burst Stimulation for PTSD Than After Two Weeks

April 28, 2020 · Posted in Peer-Reviewed Published Data, Potential Treatments · Comment 
Theta burst stimulation.

In a 2019 article in the journal Neuropsychopharmacology, Nicholas J. Petrosino and colleagues described findings from one year of follow-up with veterans suffering from post-traumatic stress disorder (PTSD) who received intermittent theta burst transcranial magnetic stimulation (iTBS) in a four-week crossover study.

In the first two weeks of the study, half of the 50 participants (who were mostly male and had an average age of 51) received iTBS while the others were given a sham procedure. Then all the participants received iTBS on an open (non-blind) basis for two more weeks.

At one month, those who had received four total weeks of iTBS had better outcomes than those who had received only two weeks of active iTBS. These results were published in the American Journal of Psychiatry in 2019 in an article by Noah S. Philip and colleagues.

The researchers went on to look at longer-term outcomes, namely time until relapse (a major event such as a re-hospitalization or suicide). After one year, those who received four weeks of iTBS went 9 to 11 months without relapsing (296.0 days ± 22.1), while those who received only two weeks of iTBS went 5 to 7 months before relapsing (182.0 days ± 31.9).

It seems that more iTBS may be better than less iTBS for PTSD in both the short and long term.

Cannabis Use in Adolescence Linked to Depression and Suicidality in Young Adulthood

April 24, 2020 · Posted in Peer-Reviewed Published Data, Risk Factors · Comment 
Photo by Louis Hansel @shotsoflouis on Unsplash

In a meta-analysis published in the journal JAMA Psychiatry in 2019, researcher Gabriella Gobbi and colleagues analyzed findings from 11 studies including a total of 23,317 participants and found that cannabis use in adolescence (before age 18) was associated with a significantly increased risk of depression, suicidality, and suicide attempts in young adulthood (between 18 and 32 years of age).

The researchers did not find a link between cannabis use and anxiety.

Editor’s Note: Cannabis use is not as harmless as many teens may believe.

In Animal Model, Long-Term THC Exposure Interferes with Cortical Control of the Nucleus Accumbens

April 21, 2020 · Posted in Peer-Reviewed Published Data, Risk Factors · Comment 
Cannabis plant. Photo by Esteban Lopez on Unsplash

In an article in the journal Biological Psychiatry, researchers Eun-Kyung Hwang and Carl R. Lupica reported that in rats, long-term use of THC (tetrahydrocannabinol) weakens input from the cortex to the reward area of the brain, the nucleus accumbens (NAc). Long-term THC use also strengthens connections to the NAc from emotional control (limbic) regions, such as the basolateral amygdala and ventral hippocampus. Hwang and Lupica reason that this shift from cortical control of the NAc to limbic control likely contributes to the cognitive and psychiatric symptoms associated with cannabis use.

Editor’s Note: Street marijuana largely contains THC rather than CBD, the beneficial, anxiety-reducing component of cannabis. Cannabis products are being decriminalized, but it is important to remember that those with THC are linked to cannabis use disorder and increased susceptibility to psychiatric illness. Patients with bipolar disorder who use marijuana also have a more adverse course of illness than those who do not use it.

One Hit of THC Tied to Psychotic Symptoms in Adults with No History of Mental Illness

April 17, 2020 · Posted in Peer-Reviewed Published Data, Risk Factors · Comment 
A woman rolls a joint. Photo by Thought Catalog on Unsplash

In a meta-analysis published in the journal Lancet Psychiatry, researcher Guy Hindley and colleagues reported that in otherwise healthy adults, a single dose of THC (equivalent to smoking one joint) produced transient psychotic symptoms.

The meta-analysis included 9 studies with a total of 196 participants. The researchers included studies in which participants took tetrahydrocannabinol (THC, the psychoactive component in marijuana) or placebo, and psychotic symptoms were measured.

The researchers also sought out studies in which cannabidiol or CBD was given in combination with THC, but there were not enough of these to derive significant results. CBD does not produce schizophrenia-like symptoms on its own, and some think it may have anti-psychotic effects, but findings on this topic have been mixed.

Taking THC had a large effect size on total psychotic symptoms and negative symptom severity (such as emotional flatness or avolition). It also had an effect on positive symptom severity (for example, hallucinations or delusions). The effects were larger with intravenous administration than with inhaled administration, and tobacco smokers had less severe positive symptoms.

Of four studies that included CBD, only one found that CBD reduced THC-induced psychotic symptoms.

Editor’s Note: Longer-term use of marijuana in adolescents and young adults doubles the risk of psychosis, and other data suggest that chronic use of marijuana at high doses can be associated with new onset of a diagnosis of bipolar disorder or schizophrenia. As cannabis products are being decriminalized around the US, it is worth noting some of the risks of marijuana use, particularly marijuana with a high level of THC.

Early Intervention Works in Schizophrenia: Also Needed in Bipolar Disorder

October 4, 2018 · Posted in Current Treatments, Peer-Reviewed Published Data · Comment 

man

For twenty years, evidence has shown that early intervention can ameliorate many of the adverse consequences of schizophrenia. In a 2018 article in the journal Annual Review of Clinical Psychiatry titled “Transforming the treatment of schizophrenia in the United States: The RAISE Initiative,” Lisa B. Dixon and colleagues described the importance of early intervention in schizophrenia. RAISE stands for Recovery After an Initial Schizophrenia Episode. Dixon and colleagues emphasize that shortening the time that a patient’s psychosis goes untreated, which averages 74 months, is critical to achieving good outcomes. In parallel to these consistent findings, researchers of bipolar disorder (including this editor Robert M. Post and colleagues) have found that an increased length of the interval before treatment is initiated in childhood-onset bipolar disorder is associated with a poor outcome in adulthood.

The RAISE program consists of four interventions: personalized psychopharmacology using a computerized decision support system, individual resilience therapy, family psychoeducation and therapy, and supportive employment and education. Compared with patients receiving standard treatments, patients who participated in the RAISE program showed greater improvements on almost all measures, including the Heinrichs-Carpenter Quality of Life Scale (main outcome), the Calgary Depression Scale for Schizophrenia, the Positive and Negative Syndrome Scale, treatment duration, and engagement in work and school. Moreover, the improvements were more substantial among patients with a shorter duration of untreated psychosis.

Editor’s Note: These findings are of great importance in their own right, but they also have great implications for treatment and research efforts in bipolar disorder. A 2013 randomized study by Lars Kessing and colleagues published in the British Journal of Psychiatry found that in bipolar patients hospitalized for a first or second episode of mania, two years of comprehensive treatment with psychotherapy, pharmacotherapy, and illness education that included mood monitoring and early symptom recognition was vastly superior to typical treatment, and this held true even six years later. In a 2014 article in the Journal of Clinical Psychiatry and a 2016 article in the journal Bipolar Disorders, researcher Jan Marie Kozicky and colleagues reported that in patients hospitalized with a first episode of mania, cognitive functioning and brain imaging abnormalities, respectively, returned to normal over the next year only if the patients experienced no further mood episodes. The message is clear: we must treat the first episode of mania comprehensively to avoid long-term deterioration, which occurs as a function of the number of episodes of mania or depression a patient experiences. However, this early multimodal approach is rarely taken in the US.

In schizophrenia, Dixon and colleagues noted that: “After the RAISE study reports were made available, Congress allocated additional funding to the community mental health …program, leading to growth in the number of…programs across the United States; they were expected to reach 48 states in 2018.”

The contrast between these efforts in schizophrenia and their virtual absence in bipolar disorder is incomprehensible and tragic. Studies in early schizophrenia have been funded for 25 years, while almost none have been funded in bipolar disorder, even in recent years. Community mental health programs for early schizophrenia will soon exist in 48 states; for patients with bipolar disorder there are no programs available in any state that I am aware of. The incidence of bipolar is about three times that of schizophrenia, and the long-term outcomes are often as devastating in bipolar disorder as in schizophrenia. There is a high incidence of drug abuse; social, educational and occupational deficits; and suicide in bipolar disorder. Early intervention with the many safe supplements, nutraceuticals, and well-tolerated drugs that are currently available to adult patients should be studied in young people with bipolar disorder, but such studies neither being funded nor conducted.

The reality is that childhood-onset bipolar disorder is poorly recognized and treated in the US, largely because of a paucity of treatment-related studies and knowledge about the best options for these young patients. If a reader of the BNN knows how to influence advocacy groups, leaders in the Substance Abuse Mental Health Services Administration (SAMHSA) and the National Institutes of Mental Health (NIMH), or influential politicians, it would be useful to take the initiative in bringing some of these deficits and disparities to their attention. Something must be done; ideas about how to do it are welcome. My own efforts to get funding for a childhood-onset bipolar research network in collaboration with such luminaries in the field as David Miklowitz (UCLA), Kiki D. Chang (Stanford University), Boris Birmaher (University of Pittsburg), Benjamin Goldstein (Stonybrook Research Institute), Eric Youngstrom (UNC, Chapel Hill), Soledad Romero (Hospital Clinic of Barcelona), and Josefina Castro Fornieles (University of Barcelona) have not been successful. We will keep trying, but the field needs to reach beyond the many investigators who are advocating for more treatment research to other people with more influence.

Large Finnish Study Finds Lithium is Best at Preventing Re-Hospitalizations in Bipolar Disorder

June 13, 2018 · Posted in Current Treatments, Peer-Reviewed Published Data · Comment 

hospital

A 2018 article in the journal JAMA Psychiatry reports that lithium and long-acting antipsychotic injections were most effective at preventing re-hospitalizations among people with bipolar disorder.

The study by Markku Lähteenvuo and colleagues included 18,018 Finnish patients with bipolar disorder. A national database contained information on any hospitalizations that occurred among the patients and what medications were dispersed to patients.

Among the participants, 54% (9,721 patients) were re-hospitalized at least once over a study period of 16 years. Medications associated with the smallest risk of re-hospitalization for psychiatric reasons were long-acting injections of risperidone, gabapentin, long-acting injections of perphenazine, and lithium carbonate.
When the researchers looked at hospitalizations for any cause (not just psychiatric illness), lithium was associated with the least risk of re-hospitalization, while benzodiazepines had the greatest risk, both for psychiatric re-hospitalization and re-hospitalization for any cause.

Long-acting injectable medications were associated with less risk of re-hospitalization compared to the identical medications delivered orally.

Lähteenvuo and colleagues concluded, “Lithium…should remain as the first line of treatment for bipolar disorder, after decades of underprescription.” They suggest that long-acting injectable medications may be a good alternative to prevent relapse in patients for whom lithium is unsuitable.

Editor’s Note: In addition to lithium’s ability to prevent depressions and manias, it also increases the volume of the hippocampus and protects against a diagnosis of dementia in old age. Lithium decreases the risk for suicide and also increases the length of telomeres, bits on the ends of DNA strands that protect them as they replicate, which are important to the maintenance of both physical and psychiatric health. When lithium is used cautiously to maintain doses below a given patient’s side effects threshold, it is very well tolerated by most individuals.

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