Irritability is common in unipolar depression. Emslie suggested that if a child’s irritability is severe and the child destroys objects and denies being irritable, bipolar disorder might be likely. Irritable unipolar depressed children will generally acknowledge being irritable.
Emslie reported that 96% of youth in his randomized placebo-controlled studies of selective serotonin reuptake inhibitor antidepressants (SSRIs) recovered from their unipolar depression, but 46.6% relapsed. Those children with residual depressive symptoms were at double the risk for relapse into a depression compared to those who remitted completely. In those without residual depressive symptoms, there were no relapses if the children stayed on their medications.
Children were excluded from Emslie’s study if they had a positive family history of bipolar disorder, and perhaps because of this, very few participants switched into mania with antidepressants.
MORAL: Treat to remission and stay on the antidepressants associated with the remission. This has previously been found to be important for adults as well. (Emslie added that he would advise that a child stay on an antidepressant for at least a year after a remission was achieved, and longer if the child had difficulties in academic performance or relationships at school.)
Children with unipolar major depression who had a few manic symptoms at a subsyndromal level had poorer outcomes in Emslie’s study. The presence of subsyndromal manic symptoms in bipolar depressed adults is a risk factor for increased switching into mania when antidepressants are added to a mood stabilizer.
Comorbid substance abuse is another risk factor for poor outcome in childhood depression.
A symposium at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) examined long-term outcomes of childhood onset disorders, including bipolar disorder, unipolar depression, ADHD, and anxiety disorder.
The Course of Childhood Onset Depression
Gabrielle Carlson presented the work of Karen Wagner on unipolar depression, in which there was a 15.3% incidence of unipolar depression in female adolescents, and 7.7% incidence in males. The overall incidence increased with age; from 8.4% in children aged 13, to 12.6% in children age 15 and 21.4% in children age 17. Average duration of a depressive episode was 17 months. While 85% recovered, 40% of those who recovered experienced a recurrence.
Carlson also presented data from Barbara Geller indicating that among children hospitalized with pre-pubertal onset of depression, 33% eventually were diagnosed with bipolar I disorder. If diagnoses of bipolar II and BP-NOS were included, the rate at which these children who got depressed before puberty eventually developing a bipolar disorder increased to an astonishingly high 49%. Thus, very early onset depression has a 50/50 chance of predicting an eventual bipolar disorder diagnosis.
Predictors of a more difficult course of depressive illness presentation were: earliest onset, more than 3 episodes, longer duration of depressive illness, and a positive family history. Those with early-onset depression had more suicidality, smoking, drug abuse, alcoholism, and an increased incidence of not having children when they became adults.
The Treatment for Adolescents with Depression Study (TADS) performed at the National Institute of Mental Health compared antidepressant response to fluoxetine, cognitive behavioral therapy (CBT), or the combination of fluoxetine plus CBT. Early in the study, the combination was most effective, with response in 39% of the children, compared to 24% for fluoxetine and 19% for CBT alone. However, after 3 years of follow up, all of the groups showed a relatively similar percent response: 60% for the combination; 55% for fluoxetine; and 64% for CBT.
In 2008, Michael Berk and colleagues showed that N-acetylcysteine (NAC) is effective as an adjunctive treatment for bipolar depression. At the 2012 meeting of the International Congress of Neuropsychopharmacology, Berk reported that NAC (1000 mg twice a day) was also effective in unipolar depression, significantly beating placebo in a randomized double-blind 12-week study.
Editor’s Note: NAC has a broad spectrum of clinical efficacy in bipolar and unipolar depression, negative symptoms of schizophrenia (such as apathy and withdrawal), irritability in autism, trichotillomania (compulsive hair-pulling), gambling addiction, obsessive-compulsive disorder, and many substance-abuse disorders, such as cocaine, heroin, alcohol, and marijuana.
How can one substance do all this? NAC has antioxidant effects, it turns into glutathione (an antioxidant that is the body’s main defense against oxidative stress and free radicals), it has neuroprotective effects (causing neurite sprouting), and it re-regulates glutamate in the reward area of the brain, the nucleus accumbens. Berk believes it is NAC’s antioxidant properties that produce its positive effects in such a range of illnesses, while this editor (Robert M. Post) favors the glutamate mechanism (as discussed in BNN Volume 14, Issue 1 from 2010 and Volume 16, Issue 1 from 2012) as an explanation of NAC’s effects.
Whatever its mechanism turns out to be, NAC is worthy of consideration as an adjunctive treatment. It is readily available from health food stores without a prescription, relatively inexpensive (less than $20 for 100 pills), and relatively well-tolerated. Minor gastrointestinal upsets were the most common reported side effect in the Berk’s clinical trial. However, this editor has had one patient experience a worsening of psychosis.
Editor Robert M. Post’s Personal Opinion About NAC
With the usual caveat that all treatment strategies discussed in the BNN must be evaluated and administered by a physician, it may be useful to consider adding NAC to a treatment regimen for a patient struggling with recurrent unipolar or bipolar depression, and/or a comorbid substance use disorder. Using conventional treatments early in the course of these disorders for acute treatment and for long-term prevention would be the first approach. For less than satisfactory acute responses, conventional adjunctive treatments (as recommended in treatment guidelines elsewhere) might be considered along with NAC, which in some cases can have a delayed onset of action. (Three months may be required to see maximal effects in bipolar disorder.)
As we’ve written before, the popular media has sometimes questioned the efficacy of antidepressants for unipolar depression. A reanalysis of data from previous controlled trials of fluoxetine and venlafaxine that was recently published in the Archives of General Psychiatry provides new evidence that these drugs are significantly more efficacious than placebo in youth, adult, and geriatric populations with major depressive disorder.
The researchers concluded,
To our knowledge, this is the first research synthesis in this area to use complete longitudinal person-level data from a large set of published and unpublished studies. The results do not support previous findings that antidepressants show little benefit except for severe depression. The antidepressants fluoxetine and venlafaxine are efficacious for major depressive disorder in all age groups, although more so in youths and adults compared with geriatric patients. Baseline severity was not significantly related to degree of treatment advantage over placebo.
Wednesday we reviewed new data that shows that despite the FDA warning that antidepressants can increase suicidal ideation among young people in the first few months they are taken, antidepressants actually reduce acute suicidal ideation and decrease suicidal acts. As we described last year in our article on five myths about antidepressants, antidepressant treatment in recurrent unipolar depression is important to patients’ long-term wellbeing, cognitive functioning, and even life expectancy.
Untreated depression, and particularly untreated recurrent depression, carries high risks not only for lethality by suicide, but also for increases in medical mortality, particularly from cardiovascular disease. In addition to these medical risks, data from many studies suggest that a higher number of prior depressions is associated with increased cognitive dysfunction, and recent large data sets from a case registry in Denmark indicate that patients with four or more prior unipolar or bipolar depressive episodes have double the risk of receiving a diagnosis of dementia in old age. Thus, depressions are dangerous for a patient’s psychological, medical, and cognitive health.
Antidepressants Are Highly Effective in Depression Prevention
In 1992 researcher John Davis completed a meta-analysis of all antidepressant data available at the time in unipolar depression studies and not only found that antidepressant continuation was more effective than placebo in reducing the likelihood of later depressions, but also calculated that the statistical likelihood that this finding was due to chance was minuscule, i.e., p<10-34. John Geddes and colleagues in a meta-analysis in 2003 indicated that there was an approximate 70% reduction in the risk of depressive recurrences with antidepressant continuation compared with discontinuation.
Treatment of a first or second episode of unipolar depression is recommended for six to nine months following achievement of remission. After a third episode, all treatment guidelines of which this editor is aware recommend long-term preventive treatment with antidepressants, particularly if episodes have been severe or close together temporally. This long-term antidepressant continuation for prophylaxis is much like long-term treatment of high blood pressure or high cholesterol recommended for those with or at high risk for cardiovascular disease.
There is some evidence that cognitive behavior therapy reduces the risk for depressive recurrence in those discontinuing antidepressant treatment, but it appears maximally beneficial to engage both psychotherapeutic and pharmacological treatment to prevent future episodes. Read more
Researcher A. Kahn reported at the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in Boca Raton in 2011 that severely depressed and suicidal patients taking citalopram (Celexa) or a combination of citalopram and low dose lithium experienced improvements in depression and suicidal thoughts. This study was unusual because most clinical trials exclude actively suicidal patients. In the group of subjects receiving citalopram plus lithium (300 mg/day and achieving 0.5 mEq/l or higher), there were several indications of better anti-suicide effects than in those on citalopram alone. The authors concluded that with appropriate doses, antidepressants plus lithium may prospectively reduce suicidal thoughts, and that it is possible to conduct clinical trials in severely depressed and suicidal patients if adequate safety measures are included.
Surprisingly, improvement in suicidal ideation preceded improvement in depressed mood per se.
Editor’s note: The study reported here suggests that in those with high suicidal ideation scores at baseline, antidepressants with or without lithium may quickly bring about anti-suicidal effects on thoughts, desires, and behaviors. Whether these effects occur reliably in studies in other groups of patients and in younger individuals remains to be established.
These data are an interesting contrast to data on antidepressant use in those with low levels of suicidality at baseline. A number of studies have suggested that in children and adolescents who were exposed to an antidepressant, a small percentage experienced increases in suicidal ideation in the first two months of treatment compared to patients taking placebo. This led to a Federal Drug Administration (FDA) warning (directed at all patients taking antidepressants) that increases in suicidal ideation and action may occur upon starting antidepressants.
It is important to note that the warning does not refer to completed suicides; the data set that led to the FDA warning included no completed suicides. More than 70% of those with suicidal ideation do not make an attempt, and the vast majority of attempts do not result in a completed suicide.
Most of the studies that found the slight increase in suicidal ideation in some patients after beginning antidepressant treatment actively excluded acutely suicidal patients. Since the study of citalopram and lithium above used a population of severely depressed and suicidal patients and found that antidepressants improved suicidality, it appears important to consider a patient’s baseline state when considering psychiatric interventions. In another example, there is an interesting difference between the way depressed patients and non-depressed normal volunteers respond to one night’s sleep deprivation: depressed patients often show dramatic improvement, while normal volunteers tend to feel worse.
More Evidence that Antidepressants Prevent Suicide in Unipolar Depression
A new study by DeLeon published in the Journal of Clinical Psychiatry in 2011 found that during periods of life when unipolar patients were taking antidepressants (compared to times when they were not taking them) the patients experienced 20% fewer suicidal acts or completed suicides. Read more
Sherwood Brown and colleagues from the University of Texas Southwestern Medical Center have completed a successful placebo-controlled trial of citicoline for bipolar and unipolar depression with comorbid methamphetamine dependence. Forty-eight participants with methamphetamine dependence and either unipolar or bipolar depression were randomized to either citicoline (2000 mg/day) or placebo for 12 weeks. Those receiving citicoline had significantly greater improvement in scores on the Inventory of Depressive Symptoms compared with those who received placebo, and patients receiving citicoline stayed in the study significantly longer, with completion rates of 41% on citicoline and 15% on placebo.
In 2007, the same team of investigators reported in the Journal of Clinical Psychopharmacology that citicoline had positive effects in bipolar patients with cocaine dependence, who experienced significant decreases in cocaine use and fewer cocaine-positive urine tests while taking citicoline.
If you have unipolar depression or bipolar disorder and are having trouble stabilizing your mood, we recommend nightly charting of mood, medications and side effects on the easy-to-use Monthly Mood Chart Personal Calendar (pictured below) or the National Institute of Mental Health Life Chart (NIMH-LCM), both of which are available for download.
Click on the Life Charts tab above to download the personal calendar, which includes space for rating mood, functioning, hours of sleep, life events, side effects, and other symptoms such as anxiety. Then bring the chart to each visit with your physician to help in the assessment of treatments.
Life charting can help determine which medications are working partially and need to be augmented further, and which need to be eliminated because of side effects. Since there are now many potential treatments for depression and bipolar disorder (some FDA-approved and some not), a careful assessment of how well each new treatment works for a particular patient is essential to finding the optimal treatment regimen.
A number of studies presented at the 4th Biennial Conference of the International Society for Bipolar Disorders conference in Sao Paulo, Brazil in March reported new data relevant to inflammation and oxidative stress. Both inflammation and oxidative stress increase risk of cardiovascular disorders, and patients with inadequately treated mood disorders lose 10 or more years of life expectancy from cardiovascular disorders compared to the general population. Inflammation and oxidative stress may also contribute to the symptoms, evolution, and progression of the mood disorders themselves.
It is possible that these two processes could become new targets for therapeutic intervention in addition to more traditional psychopharmacological drugs that primarily target the neurotransmitters dopamine, norepinephrine, serotonin, and the neurotrophic factor BDNF. Read more
Low dose thyroid replacement treatment with T3 (Cytomel) (25-37.5 µg) is typically recommended for acute antidepressant augmentation in unipolar and bipolar depression. This approach has few side effects and works even in those with normal thyroid function at baseline.
Some data also supports the use of relatively high (supraphysiological) doses of T4 (Synthroid) late in the treatment of highly treatment-resistant patients with unipolar and bipolar disorder. These supra-physiological doses of T4 typically ranged from 300-500 µg/day, producing a free thyroxine index of 150% of normal. This is usually moderately well tolerated, although minor degrees of sweating, tachycardia (fast heartbeat), and other signs of hyperthyroidism can accompany this regimen. If this approach is employed, it is particularly important to increase the dose of T4 (Synthroid) very slowly because of its relatively long half-life—about 12 days. (That is, if a patient takes a high dose of T4 and then stops their medication completely, 12 days later blood levels will only have decreased to half of what they originally were.)
Findings about high-dose T4 for women with treatment-resistant bipolar illness after the jump. Read more