Using Light to Improve Sleep and Depression

November 13, 2018 · Posted in Current Treatments, Risk Factors · Comment 
blue-blocking glasses

Blue-blocking glasses

At the 2018 meeting of the North Carolina Psychiatric Association, researcher Chris Aiken described the phenomenon of sleep inertia, when people are awakened from deep sleep by an alarm, rather than waking at the end of a sleep cycle, and are groggy for 15 minutes. Depressed people may stay groggy for 4 hours. A dawn simulator may help. These lights turn on gradually over the course of 30 to 60 minutes, reaching 250 lux while the patient is still asleep. Dawn simulators have worked in eight out of ten controlled clinical trials to help people with seasonal affective disorder, adolescents, and normal adults wake up more easily. They range in cost from $25 to $90 and some brands include PER2LED or LightenUp. Aiken says dawn simulators can improve depression, sleep quality, and cognition.

Evening and nighttime light: Bright lights and blue light, like the light that comes from electronic screens, can shut down the body’s secretion of melatonin, making people awake and alert in the evening when they should be getting sleepy. Dim light or glasses that filter out blue light allow increases in melatonin secretion in the evening, while bright light suppresses it. Missing this early melatonin pulse creates “night owls” who have delayed sleep onset.

Because light still reaches our eyes through our eyelids as we sleep, even low-level light during the night impairs sleep, cognition, and learning, and increases the risk of depression by a hazard ratio of 1.8 (about double the risk). A 2017 study by Kenji Obayashi in the American Journal of Epidemiology found that bedroom light above 5 lux elevated rates of depression in older adults after two years of followup. Living room light averaged around 50 lux and increased depression further.

Lux chart

A slide from Aiken’s presentation shows comparative levels of light

The treatment is turning off TVs, electronic screens, and cellphones in the evening or wearing blue-blocking glasses, which can be found for less than $10. Blue-blocking glasses can increase calmness and reduce anxiety, and even are effective in treating mania. Then, during sleep, wear an eye mask or get light-blocking blinds or curtains for windows. For a complete blackout, use blackout curtains, aluminum foil over windows, electric tape over LED lights, or try sleeping in the basement.

Aiken suggests that to re-instate healthy sleep patterns, people should institute virtual darkness from 6pm to 8am, including wearing blue-blocking glasses when out of bed. Then they should institute total darkness or wear an eye mask when in bed. When symptoms improve, this routine can gradually be shifted to begin later in the evening, such as two hours before bedtime.

Blue light filters are also available for smartphones and tablets including Apple Nightshift mode, Kindle BlueShade, and Android Twilight and Blue Light Filter.

Glasses that filter out blue light include Uvex Ultraspec 2000, 50360X ($7 on Amazon) and Uvex Skyper 351933X ($7-10 on Amazon). The website lowbluelights.com sells blue-blocking glasses from $45 and a variety of other blue-free lighting products such as lightbulbs and flashlights.

Bright light therapy for unipolar and bipolar depression: 30 minutes of bright light (7,500 to 10,000 lux) in the morning can help treat depression in unipolar and bipolar disorder and seasonal affective disorder. The effects usually take 3 to 7 days to set in, but they only last while a patient continues using the bright light in the morning. Researcher Dorothy K. Sit and colleagues found that bright light therapy in the morning sometimes caused hypomanic reactions in people with bipolar disorder, and reported in a 2018 article in the American Journal of Psychiatry that midday light therapy (from noon to 2:30pm) was also effective without this unwanted effect. However, a 2018 article by Ne?e Yorguner Küpeli and colleagues in the journal Psychiatry Research suggested that a half hour of morning light for two weeks was sufficient to bring about improvement in 81% of patients with bipolar disorder and did not cause serious side effects.

Melatonin regimen for sleep onset delay: Melatonin can be used to treat severe night-owls with a very late onset of sleep (for example, going to bed at 2 or 3am and sleeping late into the morning). Melatonin can help with sleep onset to some extent when used at bedtime, but in those with an extreme phase shift, researcher Alfred J. Lewy recommends a regimen of low dose priming with 400–500 micrograms of melatonin at 4pm and then a full dose of 3 milligrams of melatonin at midnight. The 4pm priming dose helps pull back the delayed onset of the body’s secretion of melatonin toward a more normal schedule.

Recent Cannabis Use Linked to Greater Symptoms of Anxiety and Mood Disorders and Less Response to Treatment

November 8, 2018 · Posted in Risk Factors · Comment 

marijuanaIn a 2018 systematic literature review published in the Journal of Clinical Psychiatry, researcher George Mamman and colleagues reported that across 12 studies of people with anxiety and mood disorders, participants who had used cannabis in the previous six months had more symptoms than those who had used less cannabis or no cannabis during that period.

The 12 studies reviewed included a total of 11,959 participants. Four studies looked at post-traumatic stress disorder (PTSD), one at panic disorder, five at bipolar disorder, and 2 at depressive disorder. In addition to finding that recent cannabis use was associated with greater symptoms, the authors of the review also found that in 10 of the 12 studies, recent cannabis use was associated with less symptom improvement in response to treatment for bipolar disorder, depression, and PTSD; including both medication and psychotherapy.

In bipolar disorder, cannabis use was associated with greater symptom severity. Cannabis use for more than one year was linked to more recurrences of mania and shortened time to a recurrence. Compared to participants with no prior use of cannabis, those with a cannabis use disorder had more depressive symptoms, including sleep troubles and loss of interest in activities one had previously enjoyed.

In PTSD, any cannabis use at the beginning of the analysis period and sustained use of cannabis over time were both linked to greater symptom severity in the four months following the beginning of the analysis.

Mammen and colleagues cautioned that these results are limited based on the differences in measurements across the 12 studies, the inpatient populations under study, and the uncontrolled nature of the cannabis the participants accessed on their own time. However, the authors suggest that the findings may inform patients’ and doctors’ conversations about whether or not to use cannabis.

Pilot Study Finds Intravenous Ketamine Improves Tough-to-Treat Adolescent Depression

November 1, 2018 · Posted in Potential Treatments · Comment 

teen depression

A 2018 open study by Kathryn R. Cullen and colleagues in the Journal of Child and Adolescent Psychopharmacology suggests that intravenous ketamine may improve depression in adolescents who have not responded to at least two antidepressants.
Thirteen patients ranging in age from 12 to 18 with treatment-resistant depression were given six ketamine infusions over a period of two weeks, at doses of 0.5 mg/kg of body weight. A 50% drop in scores on the Children’s Depression Rating Scale-Revised (CDRS-R) was considered a good response, and the average drop in participants’ scores was 42.5%. Five of the thirteen participants (38%) met the criteria for a good response. Three of these participants were still in remission at six weeks, while the other two relapsed within two weeks.

Ketamine was fairly well-tolerated by the young participants. Some had temporary dissociative symptoms or blood pressure changes. Higher absolute doses of ketamine were linked to better response.

The response rates in this group were not as good as in some studies of adults. More research using larger sample sizes and placebo controls is needed to optimize dosing and clarify the safety and efficacy of intravenous ketamine in adolescents with tough-to-treat depression, but this is a promising finding in a small number of adolescents.

Curcumin Improves Memory and Depression

October 2, 2018 · Posted in Potential Treatments · Comment 

curcumin

Recent studies suggest that curcumin, the micronutrient in turmeric that gives Indian curry its bright color, may reduce depression and improve memory.

A 2018 study published in the American Journal of Geriatric Psychiatry by Gary Small, director of geriatric psychiatry at UCLA’s Longevity Center, and colleagues found that a curcumin supplement improved mild, age-related memory loss in people without dementia.

Forty adults between the ages of 50 and 90 received either placebo or 90 mg of Theracumin, a bioavailable form of curcumin, twice daily for 18 months. The participants took cognitive tests at the beginning of the study and every 6 months during the study. Thirty of the participants also received positron emission tomography (PET) scans upon beginning and ending the study to evaluate the appearance of plaques and tangles in their brains.

Participants who received curcumin saw improvements in verbal and visual memory and attention over the course of the study compared to those who received placebo. The curcumin participants also saw mild improvements in mood, and less accumulation of amyloid plaques and tau tangles in the amygdala and hypothalamus, brain areas that play a role in memory and emotion. A few participants had mild gastrointestinal effects after taking Theracumin.

In India, where diets are high in curcumin, there is a lower incidence of Alzheimer’s than in the west, and older people also have better cognitive performance than in the west.

Curcumin has anti-inflammatory, antioxidant, and neuroprotective properties. Researchers speculate that curcumin may reduce brain inflammation, which has been implicated in both depression and Alzheimer’s disease.

A 2017 meta-analysis by Qin Xiang Ng and colleagues of 6 studies of curcumin including a total of 377 patients found that the substance has significant antidepressant effects compared to placebo. Half of the studies also reported improvements in anxiety. No adverse events were reported. Ng’s meta-analysis was published in the Journal of the American Medical Directors Association.

Mixed Findings for Intranasal Ketamine

September 13, 2018 · Posted in Potential Treatments · Comment 

intranasal ketamine

The drug ketamine can rapidly and temporarily improve depression when delivered intravenously. Researchers have been working on extending ketamine’s effects and finding easier ways of delivering the medication. One new delivery method under investigation is nasal spray, which could be used repeatedly to extend ketamine’s effects.

Unfortunately, researcher Colleen Loo reported in the Journal of Psychopharmacology in 2018 that a pilot study of self-administered intranasal ketamine for severe depression was suspended when 5 of the 10 participants had side effects that included high blood pressure, psychotic symptoms, and motor incoordination that made them unable to keep using the spray. Early in the four-week study, dosage was adjusted to leave more time between sprays, but this was not enough to prevent the problems with side effects.

Loo said that the nasal spray version of ketamine has complications including variations in absorption among different people and on different days, depending on factors like mucus in the nose and exact application techniques. Its rapid absorption into the bloodstream could lead to high peak levels in certain people.

Loo and colleagues had previously found that elderly patients receiving injections of ketamine under the skin required highly individualized dosing to avoid side effects. This may also be the case with nasal spray.

While Loo’s study found intranasal ketamine infeasible for the moment, Janssen Research and Development, a pharmaceutical company owned by Johnson & Johnson, reported positive results in phase 3 clinical trials of intranasal esketamine (a component of ketamine) at the annual meeting of the American Psychiatric Association in May. Researchers for Janssen reported that intranasal esketamine was highly effective for depression and well-tolerated both in acute treatment and over a year-long period. Janssen is now pursing approval for the drug from the US Food and Drug Administration.

 

Repeated Ketamine Reduces PTSD and Depression in the Short Term

September 11, 2018 · Posted in Comorbidities, Potential Treatments · Comment 

iv ketamine

In a 2018 open study by C. Sophia Albott and colleagues in the Journal of Clinical Psychiatry, veterans with post-traumatic stress disorder (PTSD) and a simultaneous diagnosis of major depression were treated with six infusions of intravenous ketamine over a 12-day period (Mondays, Wednesdays, and Fridays for two weeks).

Ketamine produced large improvements in both conditions. The remission rate was 80.0% for PTSD and 93.3% for depression. The median time to first relapse after the treatment was 41 days for PTSD and 20 days for depression.

One side effect of ketamine was that dissociative symptoms increased temporarily with repeated infusions. PTSD symptoms did not worsen among those participants taking ketamine.

The study was intended to evaluate the efficacy, safety, and durability of repeated ketamine infusions. Ketamine has been used in emergency rooms to rapidly treat depression and suicidality, but the effects of a single infusion fade within days.  Albott and colleagues reported that this treatment scenario with multiple ketamine infusions produced rapid results that lasted longer than single ketamine infusions.

Editor’s Note: While this study found that repeated ketamine infusions were safe, it is possible that long-term use may lead to addiction. Researcher Nolan R. Williams and colleagues reported in a 2018 article in the American Journal of Psychiatry that ketamine works via activation of the opiate receptor.  The drug naloxone, which rapidly reverses opiate overdose, completely blocked ketamine’s antidepressant effects.

 

Longer Periods of Untreated Depression Linked to More Brain Inflammation

June 27, 2018 · Posted in Course of Illness, Risk Factors · Comment 

depressed womanA 2018 study by researchers Elaine Setiawan, Sophia Attwells and colleagues reports that inflammation seems to increase with duration of untreated unipolar depression. This implies that depression may be a progressive illness, and later stage depression may require different treatments than early stage depression, such as those that directly target inflammation.

The study published in the journal The Lancet Psychiatry used positron emission tomography (PET scan) to examines levels of translocator protein in the brain. Higher levels of translocator protein indicate activation of microglia, the brain’s immune cells, which can respond to trauma or injury.

The study included 80 participants between the ages of 18 and 75. Ten had a history of more than 10 years of depression, ten had experienced fewer than 10 years of depression, and 30 comprised a healthy comparison group.

The best predictors of high levels of translocator protein were duration of untreated major depressive disorder, total illness duration, and duration of antidepressant exposure. These three factors explained about half of the variation in translocator protein levels. Those participants whose depression went untreated for 10 years or longer had inflammation levels 29–33% higher than those whose depression was untreated for 9 years or less.

Participants who had received antidepressant treatment appeared to avoid an average yearly increase in the extent of their microglial activation.

The study took place at Canada’s Centre for Addiction and Mental Health.

Editor’s Note: Since inflammation is a predictor of poorer response to antidepressants, these data add a further neurochemical rationale to the already strong clinical rationale for earlier and more sustained antidepressant treatment and prevention. Virtually all treatment guidelines suggest that after two or three prior unipolar depressions, patients should receive long-term (lifelong) antidepressant treatment.

There is now a large body of data, including a 2012 article by this editor Robert M. Post and colleagues in the Journal of Psychiatric Research that too many episodes can hurt the brain, and the current study adds to this perspective. Avoiding preventive treatment for too long may actually foster the development of more episodes and more treatment resistance. A good mantra is “prevent episodes, protect the brain.”

Consensus is now also building that comprehensive long-term treatment is indicated after a first manic episode. A 2013 article by Lars Kessing and colleagues in the British Journal of Psychiatry suggested that high quality initial treatment can improve the long-term course of illness. Moreover, a 2016 article by Jan-Marie Kozicky and colleagues and a 2017 article by Christine Demmo and colleagues, both in the journal Bipolar Disorders, suggest that after a first mania, cognition recovers over the next year only if no further episodes occur in that time.

Three-Minute ‘Theta Burst’ Treatment as Effective as 37-Minute RTMS

May 30, 2018 · Posted in Potential Treatments · Comment 

rTMS treatment

A variation on repeated transcranial magnetic stimulation (rTMS) called intermittent theta burst stimulation (iTBS) may be able to deliver the same benefits in a tenth of the time. RTMS is a non-invasive treatment in which a magnetic coil placed near the skull transmits electrical signals to the brain. It is effective in depression and has been shown to improve aspects of schizophrenia, autism, and addictions as well.

A typical rTMS session lasts for 37.5 minutes and consists of high frequency (10 Hz) stimulation. Access to the treatment remains somewhat limited, so the newer form of iTBS treatment may help more people access treatment by allowing clinicians to treat more patients in a day.

The 2018 study, published by Daniel Blumberger and colleagues in the journal The Lancet, compared iTBS to standard rTMS and evaluated the effectiveness, safety, and tolerability of the new treatment compared to the old. 414 patients aged 18–65 with major depression that had persisted despite treatment with several antidepressant options were randomized to receive either iTBS or rTMS delivered to their left dorsolateral prefrontal cortex. They received the given treatment five days/week for four to six weeks.

Patients who received iTBS showed a nearly identical level of improvement in depression to those who received rTMS. Self-reports of pain intensity were worse among those who received iTBS, but the dropout rate was not higher for that group. Headaches were the most common side effect reported, and rates were similar across both groups. The authors judged iTBS to be a comparable, non-inferior alternative to rTMS for people with major depression.

Among participants who received iTBS, depression improved significantly, with 32 percent reporting a remission of depression symptoms. Those who received standard rTMS had a remission rate of 27 percent.

Treatment Approaches to Childhood-Onset Treatment-Resistant Bipolar Disorder

May 14, 2018 · Posted in Potential Treatments · Comment 

Dear readers interested in the treatment of young children with bipolar disorder and multiple other symptoms: In 2017, BNN Editor Robert M. Post and colleagues published an open access paper in the journal The Primary Care Companion for CNS Disorders titled “A Multi-Symptomatic Child: How to Track and Sequence Treatment.” The article describes a single case of childhood-onset bipolar disorder shared with us via our Child Network, a research program in which parents can create weekly ratings of their children’s mood and behavioral symptoms, and share the long-term results in graphic form with their children’s physicians.

Here we summarize potential treatment approaches for this child, which may be of use to other children with similar symptoms.

We present a 9-year-old girl whose symptoms of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), oppositional behavior, and mania were rated on a weekly basis in the Child Network under a protocol approved by the Johns Hopkins School of Medicine Institutional Review Board. The girl, whose symptoms were rated consistently for almost one year, remained inadequately responsive to lithium, risperidone, and several other medications. We describe a range of other treatment options that could be introduced. The references for the suggestions are available in the full manuscript cited above, and many quotes from the original article are reprinted here directly.

As illustrated in the figure below, after many weeks of severe mania, depression, and ADHD, the child initially appeared to improve with the introduction of 4,800 micrograms per day of lithium orotate (a more potent alternative to lithium carbonate that is marketed as a dietary supplement), in combination with 1 mg per day of guanfacine, and 1 mg per day of melatonin.

mood chart

Despite continued treatment with lithium orotate (up to 9,800 micrograms twice per day), the patient’s oppositional behavior worsened during the period from November 2015 to March 2016, and moderate depression re-emerged in April 2016. Anxiety was also generally less severe from December 2015 to July 2016, and weekly ratings of overall illness remained in the moderate severity range (not illustrated).

In June 2016, the patient began taking risperidone (maximum dose 1.7 mg/day) instead of lithium, and her mania improved from moderate to mild. There was little change in her moderate but fluctuating depression ratings, but her ADHD symptoms got worse.
The patient had been previously diagnosed with bipolar II disorder and anxiety disorders including school phobia, generalized anxiety disorder, and obsessive compulsive disorder.
Given the six weeks of moderate to severe mania that the patient experienced in October and November 2015, she would meet criteria for a diagnosis of bipolar I disorder.

Targeting Symptoms to Achieve Remission

General treatment goals would include: mood stabilization prior to use of ADHD medications, a drug regimen that maximizes tolerability and safety, targeting of residual symptoms with appropriate medications supplemented with nutraceuticals, recognition that complex combination treatment may be necessary, and combined use of medications, family education, and therapy.

Mood Stabilizers and Atypical Antipsychotics to Maximize Antimanic Effects

None of the treatment options in this section are approved by the US Food and Drug Administration for use in children under 10 years of age, so all of the suggestions are “off label.” Further, they may differ from what other investigators in this area of medicine would suggest, especially since evidence-based medicine’s traditional gold standard of randomized placebo-controlled clinical trials is impossible to apply here, given the lack of research in children with bipolar disorder.

As we share in the original article, reintroducing lithium alongside risperidone could be effective, as “combinations were more effective than monotherapy in a study [by] Geller et al. (2012), especially when they involved an atypical antipsychotic such as risperidone. This might include the switch from lithium orotate to lithium carbonate,” the typical treatment for bipolar disorder, on which more research has been done. “Combinations of lithium and valproate were also more effective than either [drug alone]…in the studies of Findling et al. (2006),” and many patients needed stimulants in addition.

“Most children also needed combinations of mood stabilizers (lithium, carbamazepine, valproate) in the study [by] Kowatch et al. (2000).” In a 2017 study by Berk et al. of patients hospitalized for a first mania, randomization to lithium for one year was more effective than quetiapine on almost all outcome measures.

Targeting ADHD

“[The increased] severity of [the child’s] ADHD despite improving mania speaks to the…utility of adding a stimulant to the regimen that already includes…guanfacine,” which is a common non-stimulant treatment for ADHD. “This would be supported by the data of Scheffer et al. (2005) that stimulant augmentation for residual ADHD symptoms does not [worsen] mania, and that the combination of a stimulant and guanfacine may have more favorable effects than stimulants alone.”

However, the consensus in the field is that mood stabilization should be achieved first, before low to moderate (but not high) doses of stimulants are added. “Thus, in the face of an inadequate response to the lithium-risperidone combination in this child, stimulants could be deferred until better mood stabilization was achieved.”

Other Approaches to Mood Stabilization and Anxiety Reduction

“The anticonvulsant mood stabilizers (carbamazepine, lamotrigine, and valproate) each have considerable mood stabilizing and anti-anxiety effects, at least in adults with bipolar disorder. With inadequate mood stabilization of this patient on lithium and risperidone, we would consider the further addition of lamotrigine.

Lamotrigine appears particularly effective in adults with bipolar disorder who have a personal history and a family history of anxiety (as opposed to mood disorders), and it has positive open data in adolescents with bipolar depression and in a controlled study of maintenance (in teenagers 13–17, but not in preteens 10–12) (Findling et al. 2015). With better mood stabilization, anxiety symptoms usually diminish…, and we would pursue these strategies [instead of using] antidepressants for depression and anxiety in young children with bipolar disorder.”

“Carbamazepine appears to be more effective in adults with bipolar who have [no] family history of mood disorders,” unlike lithium, which seems to work better in people who do have a family history of mood disorders.

“While the overall results of oxcarbazepine in childhood mania were negative, they did exceed placebo in the youngest patients (aged 7–12) as opposed to the older adolescents (13–18) (Wagner et al. 2006).

“There are long-acting preparations of both carbamazepine (Equetro) and oxcarbazepine (Oxtellar) that would allow for all nighttime dosing to help with sleep and reduce daytime side effects and sedation. Although data [on] anti-manic and antidepressant effects in adults are stronger for carbamazepine than oxcarbazepine,” there are good reasons to consider oxcarbazepine. First, there is the finding mentioned above that oxcarbazepine worked best in the youngest children. Second, there is a lower incidence of severe white count suppression on oxcarbazepine. Third, it has less of an effect on liver enzymes than carbamazepine. However, low blood sodium levels are more frequent on oxcarbazepine than carbamazepine.

Other Atypical Antipsychotics That May Improve Depression

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Playing Tackle Football Before Age 12 May Be Bad for the Brain

May 3, 2018 · Posted in Risk Factors · Comment 

a football on grass

A 2017 study found that men who began playing American tackle football before age 12 were more likely to have depression, apathy, problems with executive functioning, and behavioral issues in adulthood than their peers who began playing football after age 12. Duration of football play did not seem to matter—those men who stopped playing football after high school were just as likely to be affected in adulthood as those who went on to play football in college or professionally.

The study by Michael L. Alosco and colleagues was published in the journal Translational Psychiatry. It included 214 men (average age 51) who had played football in their youth, but not other contact sports. The men reported their own experiences with depression, apathy, cognitive function, and behavioral regulation. Those who began football before age 12 were twice as likely to report impairment in behavioral regulation, apathy, and executive function than those who began playing later. Those who started younger were also three times more likely to have clinical depression in adulthood than those who started older.

According to Alosco and colleagues, between ages 9 and 12, the brain reaches peak maturation of gray and white matter volume, and synapse and neurotransmitter density also increases. The repeated head injuries that can occur during youth football play during this time may disrupt neurodevelopment, with lasting negative effects.

One drawback to the study was that recruitment was not random—men who volunteered for the study might have done so due to a recognition of their own cognitive problems. However, the results suggest more study is needed, and caution is encouraged when making decisions about youth football participation. Some youth football leagues have begun placing greater limits on the type of contact allowed during play.

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