Other Medical Approaches and Emerging Therapies
Cognitive Behavioral Therapy
Cognitive behavioral therapy (CBT) is a non-pharmacologic means of therapy often employed to relieve depression. CBT is typically initiated if primary treatment with antidepressant medications fail, but it is sometimes used as part of first-line treatment alongside antidepressants.
CBT is centered upon the belief that depression is closely linked with negative thinking (i.e. thought patterns that negatively reinforce depressed mood). The goal of CBT is to help the patient recognize and replace negative thinking with more positive, constructive thoughts. CBT has been studied in various settings and has shown efficacy both independently and in combination with other conventional treatment regimens.
A recent review of studies using CBT in treatment resistant depression found that CBT performed as well as pharmacotherapy when used in conjunction with a primary medication, or in cyclical fashion involving switching from pharmacotherapy to CBT and back again (Inoue 2010). This same review also pointed out that when a patient with treatment resistant depression switched antidepressants, greater relief was attained when the switch was accompanied by CBT. A 2010 clinical trial revealed that CBT effectively relieved depression and/or anxiety in patients with chronic obstructive pulmonary disease (Hynninen 2010).
CBT is also effective in young people with depression, and may be preferable over psychotropic drugs for some parents since it lacks harsh side effects. In one trial, CBT was compared to stand-of-care (pharmacotherapy) in children ages 8 – 15. CBT was superior to pharmacotherapy in several aspects, including patient alliance to treatment (Weisz 2009). Moreover, CBT may have an overall cost advantage versus pharmacotherapy (Weisz 2009).
Life Extension suggests that every patient with depression talk with a qualified healthcare provider about cognitive behavioral therapy as an adjuvant, or alternative to pharmacotherapy.
Research supports the use of exercise, primarily aerobic or weight training, as a preventive and adjuvant treatment (used in conjunction with medication) of mood disorders and depression. Some studies have found exercise alone is as effective as medication for relieving depression (Freeman, 2010) and that exercise can reduce depression recurrence rates (Babyak et al 2000). A recent study looked at 202 adults with major depression who either participated in 4 months of exercise, took the medication sertraline, or took a placebo. A one-year follow up showed that exercise was as effective as the medication at relieving depression and that exercise during the follow-up period extended the benefits (Hoffman et al 2011).
Research shows morning light therapy from a light-therapy lamp is effective at treating seasonal affective disorder (seasonal depression), and that it is equally or possibly even more effective than antidepressants, in this type of depression (Freeman, 2010). A study of 98 patients with seasonal depression illustrated this. Depressed subjects were randomly assigned to 8 weeks of therapy with light in the morning (30 minutes, 10,000 lux, and a placebo pill) or 30 minutes of dim light (100 lux and 20 mg of fluoxitine), with both groups experiencing a 67 % response rate (Lam et al 2006).
Light therapy for non-seasonal depression is not well established, although results are promising; light therapy may be more helpful as an adjuvant treatment than as a stand-alone treatment.
Transcranial Magnetic Stimulation
Interestingly, a new procedure called transcranial magnetic stimulation (TMS), which uses magnetic fields to stimulate nerve cells in the brain, is widely researched and showing promising results as a treatment for depression. The FDA has approved TMS for people who have not responded to medication, and it is often compared to the controversial electroconvulsive therapy (ECT). However, it is a possible alternative to ECT, as it is more humane and causes fewer adverse effects.
A recent study of 190 patients with major depression treated with TMS showed a clinically significant improvement in symptoms (George 2010). In a recent review, TMS was concluded to be as effective as cognitive behavioral therapy or pharmacotherapy for relieving depression (Schutter 2011).
TMS is becoming more widely available in hospitals and private practices; however because it is relatively new, it is important to ask how long the treatment has been offered, how many patients have been treated, and what the success rates are.
Complementary Therapies for Depression
Although some physicians routinely screen for underlying hormonal disorders and/ or imbalances as part of depression management, many use hormonal therapy in protocols for depression, most typically do not. Instead, they may consider hormonal imbalances a normal part of aging. Also, many ascribe to the philosophy of looking at studies of averages of population data as opposed to individual cases for potentially beneficial therapeutic programs, which can cause patients who may benefit from hormone restoration to go untreated.
Thyroid dysfunction may be a significantly underappreciated cause of depressive symptoms. In one study, thyroid disorders were associated with a 22% higher likelihood of depression in women (Fuller-Thomson 2011).
Studies have shown that treating subjects within so-called “normal” thyroid hormone levels may still be beneficial. In one such pilot study invloving 17 female patients with depression, 11 (64.7%) saw significant improvement in response to a moderate dose of l-thyroxine (Lojko 2007). Similarly, in a study of 225 subjects with treatment resistant depression, augmenting primary antidepressant therapy with thyroid hormone was found to be roughly as effective as adding a second antidepressant medication for providing relief of symptoms (Fang 2011).
Life Extension suggests maintaining a TSH (thyroid stimulating hormone) of 1 – 2 µIU/mL (typical lab normal range 0.45- 4.5 µIU/mL) to avoid the consequences of subclinical thyroid dysfunction, which may include depression. To learn more about sub-optimal thyroid function and how it may be impacting your life read our Thyroid Regulation protocol.
DHEA is an important steroid hormone often referred to as a neurosteroid because it serves a variety of functions in the brain. DHEA levels decrease with age and stress, and people with depression often have low levels of DHEA. In one study, blood samples from women with a history of depression contained lower levels of select neurosteroids, including DHEA, than women with no depression history (Girdler 2011). Interestingly, experiments showed the women with a history of depression may metabolize progesterone differently than healthy women, reflecting an adaptive effort by the body to compensate for low neurosteroid levels.
A number of studies have examined the role of DHEA in depression, with very encouraging results. DHEA has been shown to modulate serotonin levels in the brains of laboratory animals (Karishma 2002; Abadie 1993). DHEA has also performed well in human trials. DHEA therapy significantly benefited patients with HIV/AIDS and depression (Rabkin 2006). In a randomized, placebo-controlled, double-blind study, researchers studied the effects of 90 mg DHEA daily for 3 weeks and 450 mg daily for 3 weeks as a stand-alone treatment for both mild and severe depression. They found that DHEA therapy resulted in a significant improvement in symptoms compared with the placebo (Schmidt 2005).
Studies indicate that some depressed men have low levels of testosterone (Barrett-Connor 1999; Schweiger 1999). In addition, several clinical trials have shown that testosterone replacement therapy, usually transdermal testosterone gel, can relieve depression in men with low testosterone, metabolic syndrome, and HIV/AIDS (Giltay 2010; Shores 2009; Zarrouf 2009; Pope 2003).
Aging men should maintain their free testosterone level in the youthful range of 20–25 pg/ml to stabilize mood and avert other age-related diseases, such as cardiovascular disease and metabolic syndrome. Men interested in restoring their hormone levels should read Life Extension's Male Hormone Restoration protocol.
Estrogen is critically important for brain function and linked to depression, especially in perimenopausal or postmenopausal women (Grigoriadis 2002). Women using estrogen replacement therapy to alleviate menopause symptoms appear to experience reduced depression (Miller 2002). In some older women being treated for depression, estrogen replacement therapy may actually improve the effects of conventional antidepressants (Schneider 2001).
Estrogen is thought to prevent depression through its association with serotonin regulation in the brain (Osterlund 2010; Joffe 1998; Rubinow 1998). Animal studies show that estrogen may facilitate the effects of antidepressants by modulating serotonin receptors. This suggests that an estrogen imbalance may dampen the efficacy of antidepressant medications (Bethea 1998; Kendall 1982).
Further evidence suggests that estrogen promotes neuroplasticity, the process by which the brain adapts structurally and functionally to new stimuli (Barha 2010; Osterlund 2010). Disturbances in neuroplasticity may lead to recurrent depression (Vidailhet 2010).
Women interested in learning more about the benefits of restoring their hormone levels should read Life Extension's Female Hormone Restoration protocol.
Melatonin is a hormone produced in the pineal gland in the brain; it is involved in sleep-wake function and other circadian rhythms. Melatonin decreases with age and some studies link low levels of melatonin with symptoms of depression.
A double-blind placebo-controlled pilot study of perimenopausal and post-menopausal women who took 3 mg of melatonin at bedtime for 6 months showed significant improvement in depressive symptoms (Bellipanni 2001). Recently, another well-controlled preliminary study looked at 33 participants with major depression and early morning waking who took 6 mg of melatonin for 4 weeks. The results suggested improvement in sleep and depressive symptoms (Serafty 2010).
Studies of the medication agomelatine, which acts upon melatonin receptors in the brain, support melatonin's influences on depression (Green 2011). Some studies suggest that this drug may be as effective as venlafaxine, fluoxetine, and sertraline in reliving depression (Hickie 2011).
Nutrients to Balance Brain Chemistry
Depression is a multifactorial condition, and efficient relief requires addressing multiple neurochemical and metabolic imbalances that may underlie mood disturbances. The nutrients listed in the protocol are categorized according to their evidence-based mechanisms of action in brain health and mood regulation. The categories are:
- Broad-range nervous system function (omega-3 fatty acids, magnesium);
- Neurotransmitter synthesis (SAMe, folate, B12 , B6, tryptophan, 5-HTP, );
- Blood-sugar regulation (chromium, green coffee extract);
- Antioxidant effects (lipoic acid, NAC, selenium); and
- Others (St. John's Wort, vitamin D, zinc, inositol, iron).
Each of these categories is examined below.
Broad-Range Nervous System Effects: Omega-3 Fatty Acids and Magnesium
Omega-3 fatty acids
Omega-3 fatty acids are long-chain polyunsaturated fatty acids found in fish and various oils, such as flaxseed or canola oil (Logan 2003). The brain has a high concentration of polyunsaturated fatty acids, which are found mostly in cell membranes. They affect adaptability of the nervous system, nerve cell conduction and function, and neurotransmitter synthesis (Yehuda 2005; Bourre 1991). Several research models exhibit the influence of omega-3 fatty acids in depression including: (a) dietary studies (Tanskanen 2001); (b) nutritional status studies showing positive effects associated with higher omega-3 to omega-6 fatty acid ratios (Tiemeier 2003); and (c) intervention studies that look at both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) taken as a stand-alone treatment and as an adjunct to medication (Lin 2007).
One investigation showed that adding the omega-3 fatty acid EPA to conventional antidepressant treatment relieved depressive symptoms (Puri 2001). Among children with depression, supplementation with omega-3 fatty acids demonstrated “highly significant” effects on symptom scores (Nemets 2006). In a review article from 2006, researchers analyzed results from six published studies and found that omega-3 fatty acids can reduce symptoms of depression among adults as well (Williams 2006).
Because they are anti-inflammatory, omega-3 fatty acids also reduce the risk of cardiovascular disease, which is highly associated with depression (Burr 1989; Singh 1997). In fact, the American Heart Association recommends fish oil for both preventing an initial heart attack and for preventing a second attack when one has already occurred.
Omega-3 fatty acids are counterbalanced with the inflammatory omega-6 fatty acids. Typically, Americans consume far too many omega-6's and not nearly enough omega-3's.
The ratio of omega-6 to omega-3 fatty acids is important. You can learn your ratio easily with the Omega Score® test. This test can help you assess your risk for depression, heart disease, and other age-related ailments. It can also help you evaluate whether you take enough fish oil or other omega-3 supplements. More information about the importance of maintaining an optimal omega-6 to omega-3 ratio of less than 4:1 can be found in the Life Extension Magazine article entitled “Optimize your Omega-3 Status”.
Magnesium is a cofactor for more than 300 enzymes in the body; it is important for blood-sugar regulation, and has a calming effect on the nervous system (Nadler 1995). Some evidence shows a link between magnesium deficiency and depression (Whittle 2011), and a recent, comprehensive review in the Journal of Medical Hypotheses suggests that magnesium supplementation is a viable approach for depressive symptoms (Eby 2010).
A major hurdle for supplemental magnesium historically has been delivery into the brain. This is a barrier that has limited the ability of typical magnesium supplements to target conditions that arise from within the central nervous system such as depression and anxiety. However, in a recent scientific breakthrough, researchers collaborating from Beijing, Ontario, the University of Texas, and the Massachusetts Institute of Technology have developed a highly advanced form of supplemental magnesium called magnesium-L-threonate.
Magnesium-L-threonate was shown in multiple animal models to not only effectively penetrate deep into the brain, but also to trigger enhancements in learning and memory by optimizing neuronal communication and reinforcing brain structure in key areas of the cortex, the most advanced aspect of the human brain (Slutsky 2010; Abumaria 2011). Since magnesium-L-threonate is readily able to diffuse across the blood brain barrier, while other forms of magnesium are not, it appears to be the ideal form of supplemental magnesium for those with depression of other mood disorders.
Supporting Neurotransmitter Synthesis: Tryptophan and 5-HydroxyTryptophan (5-HTP)
L-tryptophan and 5-hydroxytryptophan (5-HTP) are immediate precursors to serotonin. L-tryptohan is essential for the brain to synthesize serotonin, and several studies have shown that acute tryptophan depletion can cause depression in humans. In fact, some foreign countries license L-tryptophan as an antidepressant (Murphy 2006).
In one study, healthy women given L-tryptophan for 14 days experienced increased recognition of happy faces and words, and decreased recognition of negative words. The research team concluded L-tryptophan had improved the study participants' supply of serotonin in a manner similar to that of SSRIs (Murphy 2006). In another study of the effects of acute tryptophan depletion on healthy women and on patients with bulimia nervosa, both groups were given amino acid mixtures to decrease their plasma L-tryptophan levels. Both groups experienced an increase in depression. (Kaye 2000) Other studies have found L-tryptophan depletion can lead to recurrence of depression in those who are in remission from depression (Booij 2006) or in those with seasonal depression (Neumeister et al 1998).
Methylation (a biochemical building block process for producing neurotransmitters):
Methylation is a process in which a molecule passes a methyl group to another molecule. Methylation is essential to multiple functions in the body, including the production of neurotransmitters. One can supply raw materials to support methylation reactions by supplementing with S-adenosyl-methionine (SAMe) or by providing metabolic cofactors such as folate, vitamin B12, and vitamin B6. These nutrients are necessary for neurotransmitter production and have other regulating effects.
SAMe, which can be found in almost every tissue in the body, assists with production of creatine, glutathione, taurine, L-carnitine, and melatonin.
Research shows SAMe can benefit depressed patients who do not respond to SSRIs. In a well-controlled, 6-week, double-blind trial, 73 subjects with treatment resistant depression were treated with an SSRI plus placebo, or an SSRI plus 1,600 mg SAMe daily. The group receiving the SAMe experienced significantly better response rates and remission compared to the placebo control group (Papakostas 2010). Intriguingly, the group that received SAMe also displayed improved memory function over those receiving placebo. A smaller 6-week study revealed a response rate of 50% and a remission rate of 43% in subjects taking 800–1,600 mg a day of SAMe as an adjunct to their antidepressants (Alpert 2004).
Research shows that low blood levels of folate are associated with depression (Alpert 2000), and may also be predictive of poor response to antidepressant medication (Fava 1997). Clinical trials have also demonstrated that folic acid both relieves depression on its own and enhances the effect of antidepressants. In one study, patients given 500 mcg folic acid daily in conjunction with fluoxetine experienced a significant improvement in depressive symptoms compared with patients receiving the antidepressant alone; women particularly benefited (Coppen 2000). Because relapse is associated with low serum folate, it is important to maintain folate supplementation for a year following a depressive episode (Morris 2003).
The form of supplemental folate is important since a considerable portion of Americans may have a genetic polymorphism that impairs folate metabolism (Willems 2004). In fact, mutations in the gene (MTHFR) that converts folic acid into the active 5-methyltetrahydrofolate (5-MTHF) are associated with depression (Lewis 2006). Therefore, taking supplemental 5-MTHFdirectly, which can cross the blood-brain barrier, may be more effective in supporting healthy neurotransmission and decreasing potentially neurotoxic homocysteine levels.
Vitamin B12 should always be measured in the event of depression (or any other psychological problems) as a vitamin B12 deficiency can be a reversible cause of various neuropsychiatric disorders (Hector 1988). One should also consider whether a vegetarian diet or malabsorption due to celiac disease or gluten enteropathy is a factor in B12 deficiency.
Weaker digestion, reduced absorption of nutrients, and hypochlorhydria (inadequate stomach acid needed to break down proteins that contain vitamin B12) are common in the aging population and associated with a B12 deficiency; B12 levels should be tested in an older person with symptoms of depression. Evidence suggests that the methylcobalamin form of B12may have more beneficial metabolic effects than cyanocobalamin (Sun et al 2005; Bertoglio et al 2010).
Vitamin B6 is a cofactor for the production of most neurotransmitters, but it is particularly important for serotonin synthesis (Baldewicz 2000). B6 levels are often low in women taking oral contraceptives and research has shown that B6 supplementation in these women can improve mood. For example, one study showed 22 women who had depression associated with oral contraceptive use and a B6 deficiency saw significant improvement in their symptoms with B6 supplementation (Adams et al 1973).
A more recent study examined blood levels of pyridoxal-5-phosphate (P5P), a metabolically active form of B6, in the blood of 251 elderly individuals living is Massachusetts. The investigators found that deficient levels of P5P doubled the likelihood of depression in this population. Accordingly, when dietary composition was assessed, those with higher daily B6 intakes were less likely to be depressed (Merete 2008).
Blood sugar regulation and insulin resistance: Chromium and Green Coffee Extract
Recent data link increasing consumption of coffee with decreased risk of depression (Lucas 2011). In fact, this relationship proved to be dose-dependent, meaning that the more coffee study participants drank, the less likely depression would strike them. These findings are corroborated by a similar study conducted in 2010, which supports the link between increasing coffee consumption and decreased depression risk (Ruusunen 2010). Interestingly, this last trial was unable to link caffeine with depression risk, suggesting that other compounds in coffee may be responsible for the mood-elevating effect.
Conventional coffee preparation, which involves roasting the green coffee beans at high temperatures to attain the desired flavor profile, dramatically lowers levels of health-promoting coffee constituents called chlorogenic acids.
Chlorogenic acids have been shown in several studies to aid in controlling blood sugar levels; especially those glucose spikes which occur after a high-carbohydrate meal (Tunnicliffe 2011; Zhang 2011). In a 12-week study, consumption of chlorogenic acid-fortified instant coffee lead to a considerable reduction in body weight when compared to regular instant coffee (Thom 2007). As elevated glucose levels and excess body weight are common among depressives, chlorogenic acids may help combat some symptoms of depression tied to insulin resistance and irregularities in glucose metabolism.
Green coffee, the primary source of chlorogenic acids, cannot be consumed as a beverage due to its extremely bitter taste. Consuming a green coffee extract standardized to chlorogenic acids is an effective means of obtaining biologically active concentrations of chlorogenic acids.
The potential role of chlorogenic acids in mediating the mood boost associated with coffee consumption, and their thoroughly studied antihyperglycemic properties give rise to promising multimodal depression protection.
Chromium has been studied for its role in regulating blood sugar by facilitating the uptake of glucose into cells, and some research indicates that it may be beneficial in depression as well (McCarty 1994).
In one case series of five patients with minor depression, chromium supplementation led to remission (MacLeod 1999). Two other pilot studies found chromium picolinate supplementation benefited atypical depression (Davidson et al 2003; Docherty et al 2005). Finally, although not studied for seasonal depression, chromium may help regulate blood sugar and cravings for sugar and carbohydrates in relation to seasonal depression.
Antioxidant Effects: N-Acetyl-cysteine, Lipoic acid, vitamins C and E, and Selenium
One of the best-researched antioxidants for depression is N-acetyl cysteine (NAC). NAC is a precursor to glutathione, one of the body's most powerful antioxidants. Research has found glutathione depletion and oxidative stress in people with bipolar depression. Two recent studies showed NAC is a safe and effective adjunctive treatment that improves depression in patients with bipolar disorder (Berk 2011).
Although lipoic acid has not been well studied for depression, it is one of the most effective supplemental antioxidants, since it helps recycle other antioxidants, such as vitamin C (May 2010). It also may benefit blood sugar regulation and neurological function, as evidence shows it can help diabetic neuropathy (Jin et al 2007).
In general, antioxidants may help buffer nerve cell damage in cases of chronic or recurrent depression, although they also serve other roles in brain health. For example, the antioxidant vitamin C is an important cofactor in the synthesis of serotonin, norepinephrine, and adrenal hormones that mediate stress. Vitamin E helps protect nerve cell membranes, and low selenium levels are associated with depression (Hawkes WC, Hornbostel L 1996).
St. John's Wort
St. John's wort (Hypericum perforatum) is a medicinal herb used to treat neurological and psychiatric disorders, including depression (Nangia M et al 2000). Compared to a placebo, H. perforatum extract is more effective at targeting mild to moderate depression, and reducing symptoms and recurrence rate (Lecrubier Y et al 2002). Its effectiveness is considered comparable to antidepressant medications, but its actions are more complex (Schrader E et al 2000; Szegedi A et al 2005).
St. John's wort's mechanism of action on depression is not entirely understood, even though it is one of the most researched herbs for depression. St. John's wort has been shown to inhibit serotonin and norephinephrine reuptake, thus increasing their availability at the synapse (Nangia M et al 2000). Other investigators found it influences dopamine and GABA activity. Its antidepressant qualities also can be linked to its antioxidant and anti-inflammatory properties that normalize an overactive hypothalamus-pituitary-adrenal axis and stress response (Butterweck 2003).
While additional research is on-going to identify all of the anti-depressant mechanisms of action, experimental models and clinical trials alike have shown that treatment with St. John's wort delivers positive response rates for mild to moderate depression (Can 2011; Kim 1999; Linde 1996).
Unfortunately, potential side effects associated with St. John's Wort (described at end of this chapter) deprive many depressives of its benefits.
Growing evidence suggests that vitamin D significantly effects depression. This is not surprising in seasonal depression, since the skin synthesizes vitamin D in response to sunlight, which is less available in the winter (Namri et al 2009; Shipowick 2009). However, vitamin D has been found to play other roles in depression. For example, in a study of 7,358 patients age 50 and over with a cardiovascular diagnosis and no a history of depression, low vitamin D levels significantly increased the risk of developing depression (May et al 2010).
Studies also find that vitamin D3 (cholecalciferol) supplementation can improve symptoms of depression. One well-controlled study of 441 overweight and obese participants showed an association between low vitamin D levels and depression. High dose vitamin D supplementation (20,000–40,000 IUs per week or 2,800–6,000 IUs per day) for one year improved mood (Jorde 2008). Another pilot study noted significant improvement in depression in six of nine women with low levels of vitamin D upon supplementation (Shipowick 2009).
Vitamin D's effectiveness may be related to the high prevalence of vitamin-D deficiency in the general population, its importance in blood-sugar regulation, and its importance in overall regulation of genetic activity.
Zinc is a trace element known to help regulate the nervous system (Nowak G 2002) and may be specifically related to depression (Levenson 2006). Increasing evidence shows that decreased blood levels of zinc are associated with depression (Maes M et al 1994, 1997; McLoughlin 1990), and, in depressed subjects, lower levels of zinc are associated with worse depression (Nowak et al 1999). One pilot study of 20 depressed patients also showed that 25 mg a day of zinc augmented benefits of antidepressant medication (Nowak et al 2003).
Animal studies show that antidepressants and electroconvulsive shock treatments change zinc concentrations in areas of the brain associated with depression (Nowak G et al 1999). In further animal research, zinc also was shown to enhance antidepressant effects of imipramine (Kroczka B 2001) and influence serotonin levels and activity in several brain regions (Sairanen 2005).
Inositol levels in the brain and cerebrospinal fluid were found to be lower in subjects with depression. One well-controlled trial showed that taking 12 grams a day of inositol helped relieve symptoms in 39 patients with depression (Levine 1995).
Further research on bipolar depression suggests beneficial influences of inositol (Chengappa 2000). A well-controlled but small trial of 17 participants with bipolar depression showed varied responses. Four of nine patients experienced significant improvement with inositol supplementation compared to zero of eight who took a placebo (Evins 2006).
Inositol, a second-messenger precursor, has important cellular communication functions in the nervous system. Interestingly, inositol is also involved with insulin signaling and function. It therefore may have more of an effect on overweight or obese individuals, as well as those who are insulin resistant, such as those with metabolic syndrome or women with polycystic ovarian syndrome (PCOS). These findings require further research and replication.