N-acetylcysteine (NAC), an antioxidant sold in health food stores, has several beneficial effects on brain and behavior. It improves depression and can reduce cravings for cocaine, alcohol, marijuana, and nicotine, and can also help control habit-driven behaviors such as gambling, compulsive hair-pulling, and symptoms of obsessive-compulsive disorder (OCD).
New research, particularly by researcher Nascaa and colleagues in 2014 and 2016, has identified a related compound, acetyl-l-carnitine (ALC), as an anti-stressor and antidepressant in animals, and researchers have begun to explore its use in people. ALC has been found to improve mitochondrial function and improve recovery from peripheral nerve damage. ALC also inhibits the release of glutamate, which can prevent depressive behaviors following stress.
A 2004 study by P. Ruggenenti and colleagues in the journal Hypertension found that in people, 1 gm of ALC taken twice daily safely improved arterial hypertension, insulin resistance, impaired glucose tolerance, and low levels of adiponectin in the blood (a risk factor for diabetes) in subjects at increased cardiovascular risk.
In a 2014 article in the Journal of Psychiatric Research, researcher S.M. Wang and colleagues reviewed evidence that ALC improves mild depression. Two randomized clinical trials indicated that ALC was more effective than placebo for mild depression. Two other randomized clinical trials showed that ALC was as effective as the antidepressants fluoxetine and amisulpride for mild depression. The supplement was as tolerable as placebo and better tolerated than fluoxetine and amisulpride. Wang and colleagues suggested that more clinical trials are needed to confirm that ALC is effective in depression.
Editor’s Note: If further clinical trials confirm the antidepressant effects of ALC, it could represent a new way to treat chronic stress and depression and regulate insulin. Together these effects could reduce the cardiovascular risks that accompany depression.
At the 2017 meeting of the American College of Psychiatrists, researchers Charles L. Raison and Vladimir Maletic gave a plenary lecture on the role of inflammation in depression. Meta-analyses have confirmed that inflammatory markers including Il-1, Il-6, TNF alpha, and CRP are elevated in about 1/3 of depressed patients. However, Raison and Maletic made the point that anti-inflammatory medications are not for everyone. While patients with elevated levels of CRP at baseline responded to an anti–TNF alpha antibody, patients with low CRP values at baseline actually got worse.
Raison and Maletic cited three studies that have also linked CRP to differential response to traditional antidepressants. In unipolar depression, those with low CRP respond well to selective serotonin reuptake inhibitor (SSRI) antidepressants, while those with elevated blood levels of CRP seem to respond better to a dopamine-active antidepressant such as bupropion or a noradrenergic-active antidepressant such as nortriptyline or the serotonin norepinephrine reuptake inhibitor (SNRI) antidepressant duloxetine. Patients with high inflammation at baseline also seem to respond better to intravenous ketamine and oral doses of omega-3 fatty acids.
Studies of animals have suggested that inflammation throughout the body is implicated in depression. Studies in which rodents are repeatedly defeated by larger animals show that these animals have increased inflammation from lymphocites (a type of white blood cells) in the blood, and monocytes (another type of white blood cells) from the bone marrow and spleen. This inflammation can induce depression-like behaviors in the rodents, which is prevented if the inflammatory mechanisms are blocked. These data suggest that depression is not just in the brain—inflammation from all over the body plays an important role.
Inflammation can interfere with the balance of neurotransmitters in the brain, making antidepressants less effective. Anti-inflammatory treatments (such as those used to treat rheumatoid arthritis) may help. In a 2016 meta-analysis published in the journal Molecular Psychiatry, researchers led by Nils Kappelmann analyzed the results of 20 clinical trials of chronic inflammatory conditions where depressive symptoms were also recorded. In a subset of 7 clinical trials that compared anti-inflammatory treatment to placebo, they found that anti-inflammatory treatment improved depressive symptoms significantly compared to placebo.
The anti-inflammatory drugs studied most often targeted the inflammatory marker tumor necrosis factor (TNF) alpha using an antibody. Some of the anti-inflammatory drugs that improved depressive symptoms were adalimumab, etanercept, infliximab, and tocilizumab.
The researchers also found that those participants with the most inflammation when they began treatment saw the largest improvement in their depression after taking anti-inflammatory treatments.
Kappelmann and colleagues suggest that inflammation may cause depression, and that anti-inflammatory drugs may be useful in the treatment of depression in people with high inflammation.
A large study of retired Americans found that those with high levels of the inflammatory marker C-reactive protein in the blood had more depression and anxiety. Higher CRP also predicted severity of depression and anxiety four years later.
The study, by researchers Joy E. Lin and Aoife O’Donovan, included 18,603 people over age 50 from the Health and Retirement Study. It was presented at the 2016 meeting of the Society of Biological Psychiatry.
Lin and O’Donovan hope that treating or preventing inflammation may be the key to preventing symptoms of depression and anxiety.
A recent study shows that psychotherapy can not only improve depression symptoms, but may also reduce the inflammation that often accompanies them.
Researcher Jean Pierre Oses and colleagues randomly assigned participants with depression to receive Supportive-Expressive psychodynamic therapy, which is designed to help patients understand conflictual relationship patterns, or an alternative therapy. Among the 47 participants who received Supportive-Expressive therapy, depression improved significantly after 16 sessions, and blood levels of the inflammatory markers interleukin-6 and TNF alpha also dropped.
The research was presented at the 2016 meeting of the Society of Biological Psychiatry.
In new research presented at the 2016 meeting of the Society of Biological Psychiatry, researcher Tracy Barbour and colleagues revealed that youth with a family history of depression showed more amygdala activation in response to a threat than people without a family history of depression. This amygdala hyperactivity was linked to low resilience to stress and predicted worsening depressive symptoms over the following year.
In the study, 72 non-depressed youth were shown images of cars or human faces or cars that seemed to loom in a threatening way. Brain scans showed increased amygdala activity in participants with a family history of depression compared to those without such a history.
The amygdala is an almond-shaped part of the brain in the temporal lobe that has been linked to emotional reactions and memory, decision-making, and anxiety.
A recent study suggests that women who experienced moderate or severe abuse in childhood secrete less oxytocin while breastfeeding their own children. Oxytocin is a hormone that promotes emotional bonding. The study included 53 women. They breastfed their newborn children while blood samples were collected from the women via IV. Those women with a history of moderate or severe abuse (emotional, physical, or sexual) or neglect (emotional or physical) had lower measures of oxytocin in their blood during breastfeeding than women with no history or abuse in childhood or a history of mild abuse.
A history of abuse or neglect was more common among women with current depression compared to women with a history of depression or anxiety. Women who had never experienced depression or anxiety were least likely to have a history of abuse or neglect.
The study by Alison Steube and colleagues, presented at the 2016 meeting of the Society of Biological Psychiatry, suggests that traumatic events that occur during childhood may have long-lasting effects. These experiences may modulate the secretion of oxytocin in adulthood. Low oxytocin has been linked to depression.
A large study in Denmark suggests that taking selective serotonin reuptake inhibitor (SSRI) antidepressants alongside cholesterol-lowering statin drugs improved depression more than SSRIs alone. The findings, by Ole Köhler and colleagues were reported in the American Journal of Psychiatry in 2016.
The study included 872,216 people in Denmark’s national health care database who took SSRIs between 1997 and 2012. The most common SSRIs were citalopram, sertraline, and escitalopram. Of these people taking SSRIs, 13.0% also took a statin drug, typically simvastatin. Those patients who were taking both an SSRI and a statin were less likely than those taking an SSRI alone to be hospitalized for any psychiatric problem, or for depression specifically.
Depression is known to be correlated with inflammation throughout the body. Statins reduce this inflammation as well as lowering cholesterol. A 2013 study by Ahmad Ghanizadeh and Arvin Hedayati in the journal Depression and Anxiety showed that the SSRI fluoxetine and the statin lovastatin reduced depression severity compared to fluoxetine alone.
The combination of SSRIs and statins did not seem to reduce deaths or suicidal behavior compared to SSRIs alone. Statins have some side effects, but combining them with antidepressants did not increase the risks associated with their use.
A 2016 article by Heli Malm and colleagues in the Journal of the American Academy of Child and Adolescent Psychiatry suggests that in utero exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants may increase the risk of depression in adolescence. However, the study included potentially confounding factors. It is possible that women who took SSRIs during pregnancy had more severe depression than those who went unmedicated during pregnancy. The mothers in the study who took SSRIs also had more comorbid conditions such as substance abuse.
Editor’s Note: Women should balance the risks and benefits of antidepressant use during pregnancy, since depression itself can have adverse effects on both mother and fetus. It has recently been established that SSRI use during pregnancy does not cause birth defects, so women with depression that has not responded to non-pharmaceutical interventions such as psychotherapy, omega-3 fatty acid supplementation, exercise, mindfulness, and repeated transcranial magnetic stimulation (rTMS) may still want to consider SSRIs.
In August 2011, the US Food and Drug Administration issued a warning that doses of the selective serotonin reuptake inhibitor (SSRI) antidepressant citalopram (Celexa) that exceeded 40mg/day could prolong the QT interval, a measure of heart rate used to diagnose abnormal heart rhythms. A study of records from the Veterans Health Administration showed that 35,848 veterans whose dose of citalopram was reduced from an average of 64mg/day to under 40mg/day faced increased deaths, hospitalizations for any cause, and hospitalizations for depression specifically after the reductions.
The FDA warning meant to prevent heart problems had the unintended consequence of increasing hospitalizations and deaths among the veterans affected. These findings by Thomas S. Rector and colleagues were published in the American Journal of Psychiatry in 2016.
Editor’s Note: There are some similarities between this case and findings by researchers Andrew Nierenberg and Andrew Stoll, who noticed that patients taking 40mg/day of fluoxetine (Prozac) had better long-term outcomes than those taking 20mg/day, even though those taking 40mg were more ill and more likely to relapse at the start of the study.
Researchers Ellen Frank and David Kupfer found that 90% of unipolar depressed patients relapsed when their antidepressant doses were halved, even though they had been stable for 5 years before the change.
These and the findings from Rector and colleagues lead this editor to believe that reducing the dosage of effective treatments should not be done without reason—that is, in the absence of side effects, or simply to achieve the minimal effective dose. Dose reductions without cause not only may increase the risk of relapse, but may also put the patient at increased risk of developing tolerance to the medication, for example hastening the onset of ‘Prozac poop-out.’
When long-term maintenance drug therapy is going well, it may be best to be conservative and stay the course. Conversely, in the absence of a good long-term response, be as active and creative as possible to achieve mood stabilization.