Lithium FDA-Approved for Bipolar Disorder in Children 7–17
In April 2019, the US Food and Drug Administration approved lithium for both the acute treatment of mania and for ongoing maintenance treatment of bipolar disorder in children and adolescents aged 7 to 17. Combined analysis of several studies indicates that lithium is effective and well-tolerated in both children and adolescents with bipolar disorder, both for acute treatment and to prevent bipolar episodes.
Early Predictors of Suicide and Lithium as an Anti-Suicide Drug
At the 2019 meeting of the International Society for Bipolar Disorders, researcher Gin S. Malhi discussed early predictors of suicide in people with bipolar disorder, such as younger age of illness onset, early life stressors, and family history of suicide. Impulsivity, hopelessness, cognitive deficits and substance use are risk factors, both for suicide in general and for an imminent suicide attempt. Proximal risk factors that indicate someone may make a suicide attempt soon include: mood swings, rapid cycling, increased depression, hospitalization, and severe anxiety.
Editor’s Note: Among all psychotropic drugs, lithium has the best data supporting its anti-suicide effects, both at therapeutic doses in patients with bipolar disorder and at trace levels in the water supply in the general population. People who live in locations where more lithium is naturally present in the water supply have lower rates of suicide than those who live in places with less lithium in the water. Malhi also noted that the antioxidant N-acetylcysteine (NAC), which has positive effects on mood and habitual behaviors, can reduce the incidence of lithium-induced dysfunction of the kidneys.
Family History of Lithium Response A Potent Predictor of Lithium Effectiveness
Researcher Martin Alda and colleagues reported at a 2018 scientific meeting that a family history of good response to lithium is highly predictive of response to lithium in a current bipolar patient. A good prospective response to lithium was seen in 68.6% of patients with a family member who responded well to lithium. Only 22% of those without a family member with a positive lithium response responded well to lithium.
Editor’s Note: Other predictors of a good response to lithium include: a family history of mood disorder, classical euphoric mania with clear-cut well intervals between episodes, lack of a simultaneous anxiety or substance abuse disorder, starting lithium early rather than late in the course of illness after many episodes or rapid cycling has occurred, and a sequential pattern of episodes of mania followed by depression, and then an interval of wellness (i.e. M-D-I rather than D-M-I). Even in those without these characteristics, lithium has many benefits including neuroprotection, reduction of suicide risk, and improved medical health (perhaps through its ability to increase the length of telomeres which are bits of DNA at the end of each chromosome). Longer telomeres are protective, while people with shorter ones may be vulnerable to some medical and psychiatric illnesses.
Baseline Levels of CRP Could Help Predict Clinical Response to Different Treatments
C-reactive protein (CRP)
C-reactive protein, or CRP, is a marker or inflammation that has been linked to depression and other illnesses. People with high levels of CRP respond differently to medications than people with lower CRP, so assessing CRP levels may help determine which medications are best to treat a given patient.
High baseline levels of CRP (3–5pg/ml) predict a poor response to selective serotonin reuptake inhibitor antidepressants (SSRIs) and to psychotherapy, and are associated with increased risk of recurrent depression, heart attack, and stroke.
However, high baseline CRP predicts a better response to the antidepressants nortriptyline and bupropion. High CRP is also associated with better antidepressant response to infliximab (a monoclonal antibody that inhibits the inflammatory cytokine TNF alpha), while low levels of CRP predict worsening depression upon taking infliximab.
High baseline CRP also predicts good antidepressant response to intravenous ketamine (which works rapidly to improve treatment-resistant depression), minocycline (an anti-inflammatory antibiotic that decreases microglial activation), L-methylfolate (a supplement that can treat folate deficiency), N-acetylcysteine (an antioxidant that can improve depression, pathological habits, and addictions), and omega-3 fatty acids (except in people with low levels of DHA).
High baseline CRP also predicts a good response to the antipsychotic drug lurasidone (marketed under the trade name Latuda) in bipolar depression. In people with high baseline CRP, lurasidone’s positive results have a huge effect size of 0.85, while in people with low CRP (<3pg/ml) the improvement on lurasidone has a smaller effect size (0.35).
In personal communications with this editor (Robert M. Post) in 2018, experts in the field (Charles L. Raison and Vladimir Maletic) agreed that assessing baseline CRP levels in a given patient could help determine optimal strategies to treat their depression and predict the patient’s responsiveness to different treatment approaches.
At a 2018 scientific meeting, researchers Cynthia Shannon, Thomas Weickert, and colleagues reported that high baseline levels of CRP were associated with symptom improvement in patients with schizophrenia when they were treated with the drug canakinumab (marketed under the trade name Ilaris). Canakinumab is a human monoclonal antibody that targets the inflammatory cytokine interleukin-1 beta (Il-1b). Il-1b is elevated in a subgroup of patients with depression, bipolar disorder, or schizophrenia, and CRP levels are an indication of the associated inflammation.
Lithium Superior to Other Mood Stabilizers in a Longitudinal Study of Bipolar Youth
At a late-2018 scientific meeting, researcher Danella Hafeman and colleagues reported some results of the Course and Outcome of Bipolar Youth (COBY) study. The study includes long-term follow up of 413 youth with bipolar disorder, who ranged in age from 7 to 17 years old. Hafeman and colleagues reported that taking lithium more than 75% of the time was linked to fewer suicide attempts, fewer depressive symptoms, and fewer psychosocial difficulties than taking another mood stabilizer (such as an atypical antipsychotic, lamotrigine, or valproic acid) more than 75% of the time after adjusting for demographic variables.
Despite the limitations of observational studies such as this one, the authors concluded, “Our findings are consistent with studies in adult populations, showing that lithium (compared to other mood stabilizers) is associated with decreased suicidality, less depression, and better psychosocial functioning. Given the paucity of evidence regarding lithium in children and adolescents, these findings have important clinical implications for the pharmacological management of youth with [bipolar disorder].”
Editor’s Note: These observations are consistent with several other studies. Researcher Barbara Geller and colleagues observed in eight years of follow up of children diagnosed with bipolar disorder that those who were treated with lithium spent more time in remission than those who took other medicines. A randomized controlled study by researcher Robert Findling and colleagues documented that maintenance lithium treatment was more effective than placebo at preventing bipolar episodes. Together, these data suggest that lithium should be used more often in the long-term treatment of children with bipolar disorder.
Way ahead of his time in about 1993, the renowned child psychiatrist Dennis Cantwell said something like this: “If I had an adolescent child with a first manic episode, I would have him stay on lithium for the rest of his life.” He seems to have been prescient, as evidence of the many benefits of lithium over other alternatives in the treatment of both children and adults has been accumulating.
An open-access review article this editor (Robert M. Post) published in the journal Neuropsychopharmacology in 2017, “The New News about Lithium: An Underutilized Treatment in the United States,” argues that lithium’s many benefits have been underestimated, while its side effects have been overestimated. It is my view that it would be beneficial if lithium were more often included in the treatment regimen of adults as well as children and adolescents with bipolar disorder.
Lithium has an astounding range of effectiveness. It prevents recurrent depressions and suicide (even in those with unipolar depression), increases hippocampal and cortical volume, protects memory, and increases the length of telomeres (the end portions of chromosomes that protect them as they replicate). In multiple animal models of neurological diseases, it has also been found to be neuroprotective and to reduce the size of brain lesions.
Risk of Suicide in People with Bipolar Disorder: Lowest with Lithium, Highest with Antidepressants
Researcher Markku Lähteenvuo and colleagues reported in the journal JAMA Psychiatry in early 2018 that long-acting injectable antipsychotics and lithium were best at preventing re-hospitalization in 18,018 bipolar patients in Finland who received an average of more than 7 years of follow up. Lähteenvuo and colleagues have now gone on to analyze suicide data from the same cohort of patients with bipolar disorder, and report that those taking lithium had the lowest rate of suicide, while those taking valproate had the next lowest suicide rate. Those patients with bipolar disorder who were treated with antidepressants had the greatest suicide rate. The suicide rate was particularly high for those once-hospitalized patients taking the MAO inhibitor antidepressant meclobemide, which is not approved for use in the US. Increased rates of suicide were also seen with use of sedatives and benzodiazepines.
Editor’s Note: Evidence continues to mount that lithium should be the definitive first line therapy in bipolar disorder for a multitude of reasons (as this editor Robert M. Post reviewed in an open-access article in the journal Neuropsychopharmacology in 2017). Still, lithium is not often prescribed for people with bipolar disorder in the US, and this does not seem to be in these patients’ best interests.
Use of antidepressants in bipolar disorder has remained controversial, but it is common in clinical practice despite a lack of evidence that it is effective, and the presence of some evidence that it is actually harmful. Antidepressant use in a person with bipolar disorder may cause switching into mania, cycle acceleration, dysphoria induction, and even suicide.
Clinicians should take these data seriously and overcome the impulse (leftover from treating unipolar depression) to use unimodal antidepressants as first line or adjunctive therapy for bipolar depression. Antidepressants are only effective in the long term in about 15% of patients with bipolar depression, and now it appears antidepressant use also carries an additional risk of suicide.
High Baseline Levels Of C-Reactive Protein Predict Better Response To Lurasidone in Bipolar Depression
In a study presented at the 2017 meeting of the International Society for Affective Disorders, Charlies L. Raison and colleagues examined whether baseline levels of the inflammatory marker C-reactive protein (CRP) affected antidepressant response to the antipsychotic drug lurasidone in bipolar depression. The participants were divided into three double-blind groups: one received 20–60mg/day of lurasidone, another received 80–120 mg/day of lurasidone, and the third received placebo over a period of six weeks. The effect was dramatic—in people with CRP levels above 5 mg/L at the beginning of the study, lurasidone (at either dosage level) had a very large effect size (d=0.85), while in people with baseline CRP levels below 5 mg/L the effect size was smaller (d=0.35).
Interestingly, 118 of the participants (24.5%) had CRP levels above 5mg/L at baseline, indicating a substantial amount of inflammation was present in a quarter of the bipolar depressed patients. Higher levels of CRP at baseline were correlated with better improvement on specific items on the Montgomery–Åsberg Depression Rating Scale (MADRS): “lassitude” (or lack of energy), “apparent sadness,” “reported sadness,” and “pessimistic thoughts.” Raison and colleagues concluded: “These findings suggest that the efficacy of lurasidone in patients with bipolar depression may in part be linked to the inflammatory status of patients prior to treatment. If confirmed in prospective investigations, [the results of a wide-range CRP assay] may prove useful as a predictive biomarker that could help optimize the use of lurasidone for the treatment of patients with bipolar depression.”
Editor’s Note: In many instances, high levels of CRP predict a poor response to treatment (such as to selective serotonin reuptake inhibitor antidepressants (SSRIs) in unipolar depression), so these findings are of considerable interest. They also suggest the untested possibility that lurasidone has anti-inflammatory effects, as those with high levels of inflammation at baseline often respond better to drugs with direct anti-inflammatory effects such as celecoxib (Celebrex) or the antioxidant N-acetylcysteine (NAC).
Inflammation is Associated with Antidepressant Treatment Resistance
Researcher Ebrahim Haroon and colleagues report in a 2018 issue of Psychoneuroendocrinology that people whose depression failed to respond to at least three different antidepressants in their current episode of depression had higher levels of inflammation than those who had fewer than three failed antidepressant trials.
The researchers found that patients who had not responded to antidepressants had higher levels of the inflammatory markers TNF-alpha, TNF-alpha receptor 2, and Il-6. The inflammatory marker CRP was also significantly elevated in these patients when statistical analyses that excluded body mass index (BMI) were used.
Haroon and colleagues reported that a third of all patients with major depressive disorder fail to respond to currently available antidepressant treatments, and that inflammation may be to blame because it interferes with the neurotransmitter systems that antidepressants target.
Editor’s Note: These data indirectly support the use of anti-inflammatory drugs to augment the effects of antidepressants in patients with treatment resistant depression. A caution that may be very important is to assess evidence of inflammation at baseline, as some data suggest that people with low CRP may, for example, do more poorly with a blocker of TNF-alpha, while people with high CRP at baseline (over 3 pg/ml) show good improvement.
Using Light to Improve Sleep and Depression
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.
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.
Cannabidiol Drug Approved For Rare and Severe Types of Epilepsy
In June, the US Food and Drug Administration (FDA) for the first time approved a drug derived completely from the cannabis plant. The drug, Epidiolex, a syrup, contains cannabidiol, the cannabis component that has been found to treat certain ailments. In a news release, the FDA stated that cannabidiol does not cause intoxication or a ‘high’. Tetrahydrocannabinol, or THC, is the cannabis component that makes people high, impairs cognition, and can induce paranoia.
The approval led, in September, to the Drug Enforcement Agency re-classifying FDA-approved drugs containing cannabidiol derived from cannabis and less than 0.1% THC as schedule V controlled substances. So far only Epidiolex meets these criteria. Cannabis had previously been classified as a schedule I controlled substance, in the same legal category as heroin, LSD, or ecstasy.
Epidiolex is now approved to treat two rare, severe types of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients aged two years and older. It is the first FDA-approved treatment for Dravet syndrome, a genetic condition that appears in the first year of life when babies develop fever-related seizures. Other types of seizures, even including a continuous seizure state, can occur later.
Lennox-Gastaut syndrome also develops in young children, usually between the ages of three and five. They have multiple types of seizures with debilitating consequences.
In three randomized, double-blind, placebo-controlled clinical trials that included a total of 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome, the drug reduced the frequency of patients’ seizures compared to placebo.
Side effects of Epidiolex include sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections. The FDA also warned in its approval that “[a]s is true for all drugs that treat epilepsy, the most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks.” The drug is produced by GW Pharmaceuticals, which has already gained approval outside the US for a cannabis-based drug to treat multiple sclerosis.
Editor’s Note: It is important for readers to know that most marijuana available in the US contains mostly THC with minimal cannabidiol.
