New discoveries in neuroanatomy are helping clarify what addiction looks like in the brain. Peter Kalivas of the Medical University of South Carolina reported at the 2013 meeting of the Society of Biological Psychiatry that most drugs of abuse alter glutamate levels and the plasticity of synapses in the nucleus accumbens, the reward area of the brain. Glutamate is the main excitatory neurotransmitter in the brain, and compulsive habits may be associated with increased release of glutamate in this brain area.
During chronic cocaine administration, for example, the neurons in the nucleus accumbens lose their adaptive flexibility and their ability to respond to signals from the prefrontal cortex. Normally, low levels of stimulation would induce long-term depression (LTD) while high levels of stimulation would induce long-term potentiation (LTP). These are long-term changes in the strength of a synapse, which allow the brain to change with learning and memory. When long-term potentiation and long-term depression are no longer possible, memory and new learning in response to messages from the prefrontal cortex are diminished.
Given this absence of flexible responding, animals extinguished from cocaine self-administration (when a lever they had pressed to receive cocaine ceases to provide cocaine) are highly susceptible to cocaine reinstatement if a stressor is presented or if a signal appears that suggests the availability of cocaine. This cocaine reinstatement is associated with high levels of glutamate in the nucleus accumbens, so Kalivas reasoned accurately that lowering these levels would be associated with a lesser likelihood of cocaine reinstatement.
The drug N-acetylcysteine (NAC), which is available from health food stores, decreases the amount of glutamate in the nucleus accumbens by inducing a glutamate transporter in glial cells that helps clear excess synaptic glutamate. In Kalivas’ research, NAC prevented cocaine reinstatement, cocaine-induced anatomical changes in spine shape (bigger, stubby spines), and the loss of long-term potentiation and long-term depression in the nucleus accumbens.
The findings on NAC in animal studies led to a series of important small placebo-controlled clinical trials in people with a variety of addictions, and positive results have been found using NAC in people addicted to opiates, cocaine, alcohol, marijuana, and gambling. It also decreases hair-pulling in trichotillomania and reduces stereotypy and irritability in children with autism.
NAC also appears to be effective in the treatment of unipolar and bipolar depressed patients in placebo-controlled trials by Australian researcher Michael Berk. Thus, NAC could be useful for patients with affective disorders who are also having difficulties with comorbid substance use.
Some antibiotics (that are not commonly available) also induce the glutamate transporter and glial cells of the nucleus accumbens, offering a potential new approach to treating some addictions.
Among the hundreds of posters, workshops, clinical perspectives, and symposia presented over five days at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), there were almost no posters or presentations on new approaches to treatment (either with drugs or therapy) for children with bipolar disorder.
As we have repeatedly emphasized in the BNN and in research publications, this deficiency has adverse consequences for the many hundreds of thousands of children and adolescents in the US with unequivocal diagnoses of bipolar disorder. Suicide is now the second leading cause of death in adolescents 13 to 17 years of age in the US. Most of these young people have a mood disorder. Bipolar disorder carries with it not only a substantial risk of suicide, but also the potential for a lifetime of dysfunction, disability, and medical comorbidity if it is inadequately treated.
Please advocate for more treatment research for childhood onset bipolar disorder. A whole generation of children, their parents, and their physicians desperately need more treatment information.
A mutation in a gene related to circadian rhythms may help explain bipolar disorder. Animals with a mutation in the gene, known as CLOCK, typically exhibit behaviors that mimic human mania, such as increased locomotor activity and decreased anxiety.
Stress can lead to depression in bipolar patients, so researcher Nicole Edgar et al. exposed animals with the mutated “manic” version of the CLOCK gene to unpredictable chronic mild stress. The stress brought about decreased locomotor activity and increased anxiety, mimicking a switch into depression. These data suggest that alterations in CLOCK genes may provide a useful model for both mania and depression.
The research was presented at the 2013 meeting of the Society of Biological Psychiatry, and the abstract (#471) can be found in the meeting supplement, Volume 73, Number 9S of the journal Biological Psychiatry.
In another abstract (#472) at the same meeting, researcher Wilbur Williams et al. reported that alterations in related clock genes (that result in decreases in the proteins CRY-1 and SIRT1) are associated with manic-like behavior that could be reversed using lithium. These data further suggest that clock genes may provide a useful model for bipolar disorder.
Barbara Gracious of Ohio State University became interested in the inflammatory marker CRP through studying vitamin D3 deficiency. Vitamin D is a neurosteroid, and low levels of it have been associated with risk of schizophrenia, cardiovascular disease (heart attack), diabetes, mood disorders, cognitive deficits, autoimmune disease, and obesity. High CRP levels are related to low vitamin D, to obesity, and to other inflammatory markers such as IL-6 and TNF alpha.
Gracious measured these levels of CRP in 621 children participating in the Longitudinal Study of Manic Symptoms (LAMS), who were followed up for many years. She found that those with higher levels of CRP developed a mood episode approximately two years earlier than those with normal levels. CRP binds phosphocholine, which activates complement, a kind of protein that induces inflammation. CRP is elevated in 14% to 53% of patients with depression and anxiety.
Copeland et al. reported in the American Journal of Psychiatry in 2012 that after a first depression, high CRP was associated with relapse. CRP also increases in adolescent females (who are at increased risk for depression).
Editor’s Note: These findings suggest the potential importance not only of using CRP as an indicator of depression risk, but also of targeting CRP levels in the hopes of reducing risk of a mood episode in children with elevated inflammatory markers. Supplementing vitamin D3 in those with low levels would be a good place to start, as would preventing or treating obesity and promoting good sleep hygiene and exercise. The potential role of medications with direct anti-inflammatory effects such as aspirin (acetylsalicylic acid) or minocycline deserves further study.
Balanced diet, exercise, and good sleep habits may be easier said (or recommended) than done. Such lifestyle advice must be delivered with motivational interviewing, and instilled through practice, positive feedback, encouragement, and more practice. In children in general, and especially in those at high risk for a mood episode due to a family history of a unipolar or bipolar mood disorder, starting things off right from the outset with good diet, exercise, and sleep routines would be highly recommended. The benefits for long-term health and wellbeing could be enormous.
The results of good health behaviors may be mediated through several pathways. They could lessen inflammation and obesity, increase brain-derived neurotrophic factor (BDNF, which is important for new synapses and long-term memory) and neurogenesis (both of which are increased by exercise), and even lengthen the telomeres that cap the ends of each strand of DNA (short ones are associated with a variety of medical and psychiatric illnesses).
Cognitive behavioral therapy may improve both depression symptoms and inflammatory bowel disease. At a symposium on early-onset depression at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Eva Szigethy of the University of Pittsburg discussed depression in inflammatory bowel disease (IBD), i.e. Crohn’s disease or ulcerative colitis. Depression and bipolar disorder are often associated with elevated inflammatory markers, such as IL-1b, IL-2, IL-6, INF gamma, TNF alpha, and CRP (C-reactive protein). This kind of inflammation can cause symptoms like decreased appetite, fatigue, anhedonia (loss of pleasure in activities one once enjoyed), and motor slowing.
In children with IBD randomized to cognitive behavioral therapy or just routine supportive care, the somatic symptoms of those receiving cognitive behavioral therapy improved, as did their IBD.
Other treatments may also target both depression and inflammation. Szigethy noted that there is some evidence that the TNF alpha–inhibiting anti-inflammatory drug infliximab has some antidepressant effects in those with high CRP and in patients with the autoimmune condition psoriasis. She indicated that the antidepressant bupropion decreases depression and inflammation in IBD and that bupropion has anti–TNF alpha effects (at least in animals).
Currently levels of inflammation are measured with blood drawn from a vein, but new techniques may be more child-friendly. These include measuring inflammatory markers in hair (which reflects levels over the previous two weeks), saliva, or with a drop of blood from a pinprick (as used by researcher Ben Goldstein).
At a symposium on early-onset depression at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Betsy Kennard described a course of cognitive behavioral therapy tailored to eliminating residual symptoms in children with unipolar depression who had no family history of a parent with bipolar disorder. In the same study Graham Emslie discussed, the investigators considered cognitive behavioral therapy for the treatment of childhood- and adolescent-onset depression.
The therapy was aimed at achieving health and wellbeing and focusing on positive attributes and strengths in the child, and it was designed to be a shorter than usual course (i.e. four weekly sessions, then four every other week, and one at three months). This regimen typically also included three to five family sessions. Other key components of the therapy included anticipating and dealing with stressors, setting goals, and practicing all the skills learned.
On a visual timeline, children identified and wrote down past stressors, how they felt when depressed, their automatic cognitions, ways they would know when they were feeling down again (i.e. feeling isolated, angry at parents, etc.), their strengths and skills, what obstacles to feeling better existed and how to circumvent them, and their long-term goals.
The therapy was based on the research of Martin Seligman and Giovanni A. Fava, plus Rye’s Six S’s (soothing, self-healing, social, success, spiritual, and self-acceptance). The children participated in practice and skill-building in each domain. Sleep hygiene and exercise were emphasized. The idea of “making it stick” was made concrete with phrases on sticky notes taken home and put up on a mirror. Postcards were even sent between sessions as reminders and for encouragement.
Editor’s Note: Most depressed kids don’t get completely well (only about 20% after an acute course of medication). Something must be added. This kind of specialized cognitive behavior therapy works and keeps patients from relapsing. This study included only those children with unipolar depression whose parents did not have bipolar disorder. However, Emslie noted that depressed children of a bipolar parent also had an exceedingly low rate of switching into mania (2 to 4%) in his experience, so fluoxetine followed by cognitive behavioral therapy might be considered for treating unipolar depressed children of a bipolar parent.
Once children have developed bipolar disorder, evidenced by hypomania or mania followed by depression, antidepressants are to be avoided in favor of mood stabilizers and atypical antipsychotics, since there is a higher switch rate in these youth when they are prescribed antidepressant monotherapy.
Since children with bipolar disorder are at such high risk for continued symptoms and relapses, the strategy of adding cognitive behavioral therapy to their successful drug treatment would appear appropriate for them as well as those with unipolar depression, especially since there is a large positive literature on the efficacy of cognitive behavioral therapy, psychoeducation, and Family Focused Therapy (FFT) in children and adults with bipolar depression. As noted previously, FFT is very effective for children at high risk because of a parent with bipolar disorder and who are already symptomatic with anxiety, depression or BP-NOS.
Moral of the story: getting kids with unipolar or bipolar depression well and keeping them well is a difficult endeavor that requires specialized, combined medication and therapy approaches and follow-up education and therapy. This is for sure. The hope would also be that good early and long-term intervention would yield a more benign course of recurrent unipolar or bipolar disorder than would treatment as usual (which all too often consists of medication only).
At a symposium on early-onset depression at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Graham Emslie of the University of Texas Southwestern Medical Center discussed the role of cognitive behavioral therapy in the long-term treatment of child-and adolescent-onset unipolar depression.
In Emslie’s research, the combination of the antidepressant fluoxetine and cognitive behavioral therapy reduced depressive relapses in children. Using the two treatments together did not speed onset of antidepressant response compared to fluoxetine alone, but once children responded to the medication, the addition of cognitive behavioral therapy reduced relapses over the next year compared to fluoxetine alone (even though the cognitive behavioral therapy ended after the first six months).
Emslie likened the use of cognitive behavioral therapy to the course of rehabilitation that often follows a major surgery and is meant to sustain or enhance the good effects of surgery. Getting patients to full remission (well and with no residual symptoms) was the key to staying well.
At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Vilma Gabbay of the Mount Sinai School of Medicine reiterated the findings from the TORDIA (Treatment of SSRI-Resistant Depression in Adolescents) study that 20% of young people with depression remained resistant to treatment, childhood-onset depression was more likely to be recurrent and more difficult than adult-onset depression in the long run, and suicide was the second leading cause of death in 12- to 17-year-olds in 2010 according to a Centers for Disease Control report in May 2013. Anhedonia (a loss of pleasure in activities once enjoyed) was the most difficult symptom to treat in adolescents.
Gabbay carefully explained some of the rationales for using ketamine in young people with depression. The presence of inflammation is a poor prognosis factor, and ketamine has anti-inflammatory effects, decreasing levels of inflammatory markers CRP, TNF-alpha, and Il-6.Given that ketamine has been widely used as an anesthetic for surgical procedures, its safety in children has already been demonstrated. Ketamine did not appear to cause behavioral sensitization (that is, increased effect upon repetition) in a report by Cho et al. in 2005 that included 295 patients.
As noted previously, Papolos et al. reported in a 2012 article in the Journal of Affective Disorders that intranasal ketamine at doses of 50 to 120 mg was well-tolerated and had positive clinical effects in 6- to 19-year-olds with the fear of harm subtype of bipolar disorder that had been highly resistant to treatment with more conventional drugs.
Gabbay reluctantly endorsed further cautious controlled trials in children and adolescents, in light of ketamine’s suggested efficacy and good safety profile, which stands in contrast to its popular reputation as a party drug or “Special K.”
Editor’s Note: The discussant of the symposium, Neal Ryan of Western Psychiatric Institute and Clinic, added an exquisitely brief discussion suggesting that ketamine should ultimately be studied in combination with behavioral and psychotherapeutic procedures to see if its therapeutic effects could be enhanced. He made this suggestion based on the data that ketamine has important synaptic effects, increasing brain-derived neurotrophic factor (BDNF), which is important for healthy cells and long-term memory, and reverting thin dendritic spines caused by stress back to their normal mushroom shape. This editor (Robert Post) could not be more in agreement.
In a recent study, ketamine performed better than an active comparator on several measures in adults with post-traumatic stress disorder (PTSD). Since ketamine has noticeable dissociative effects, researchers have looked for another drug with mind-altering effects that would be a more appropriate comparator than placebo.
At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Adriana Feder of Mount Sinai Hospital reported on the randomized study in those with PTSD, in which intravenous ketamine was compared to intravenous midazolam, a potent benzodiazepine that produces anti-anxiety and sedating effects. Murrough et al. previously showed that intravenous ketamine was superior to midazolam in treatment-resistant depression.
In the randomized study Feder described, the participants had suffered PTSD from a physical or sexual assault and had been ill for 12 to 14 years. Those who received ketamine improved more, in some instances for as long as two weeks (ketamine’s blood levels disappear after a few hours, and its clinical antidepressant effects usually last only a few days). Reports of side effects included three patients with blood pressure increases requiring treatment with propranolol, and four patients who each had a transient episode of vomiting.
These controlled data parallel previous open observations. When ketamine was used as a surgical anesthetic during operations on burn patients, only 26.9% subsequently reported PTSD compared to 46.4% who developed PTSD when an alternative to ketamine was used as the anesthetic.
At the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Kyle Lapidus of Mount Sinai Hospital reviewed the literature from controlled studies on the efficacy of intravenous (IV) ketamine at a dosage of 0.5 mg/kg over a 40-minute infusion for adults with treatment-resistant depression (with consistent response rates of 50% or more), and suggested that intranasal ketamine may also be effective.
Ketamine is a strong blocker of the glutamate NMDA receptor. At high doses (6 to 12 mg/kg) it is an anesthetic, at slightly lower doses (3 to 4 mg/kg) it is psychotomimetic (causing psychotic symptoms) and is sometimes used as a drug of abuse, and at very low doses it is a rapidly acting antidepressant, often bringing about results within 2 hours. Antidepressant effects typically last 3 to 5 days, so the question of how to sustain these effects is a major one for the field.
Murrough et al. reported in Biological Psychiatry in 2012 that five subsequent infusions of ketamine sustained the initial antidepressant response and appeared to be well tolerated by the patients. Another NMDA antagonist, riluzole (used for the treatment of ALS or Lou Gehrig’s disease), did not sustain the acute effects of ketamine, and now lithium is being studied as a possible strategy for doing so.
The bioavailability of ketamine in the body depends on the way it is administered. Compared to IV administration, intramuscular (IM) administration is painful but results in 93% of the bioavailability of IV ketamine. Intranasal (IN) administration results in 25-50% of the bioavailability of IV administration, while oral administration results in only 16-20% of the bioavailability of IV administration, so Lapidus chose to study the IN route. He compared intranasal ketamine at doses of 50mg (administered in a mist ) to 0.5 ml of intranasal saline. Both were given in two infusions seven days apart. Lapidus observed good antidepressant effects and good tolerability. Papolos et al. had reported earlier that intranasal ketamine had good effects in a small open trial in treatment-resistant childhood onset bipolar disorder.
Editor’s Note: Further studies of the efficacy and tolerability of intranasal ketamine are eagerly awaited.