Overview and Risk Factors
Mood and anxiety symptoms occur normally in the course of any eventful life and likely have important evolutionary functions. However, they become pathologic when they interfere with daily functioning, maintenance of relationships, work or school performance, and other important activities of life.
Depressive and anxiety disorders are distinct conditions, but their biological underpinnings and clinical presentations frequently overlap. Because the nutritional considerations related to these disorders are similar, the conditions are described in a single chapter.
Depression is a common syndrome marked by sadness, hopelessness, and apathy. Associated symptoms may include poor concentration, excessive guilt, sleep disturbance, appetite disturbance, sexual dysfunction, delusions, and psychomotor changes (eg, slowed thoughts and movements, slurred speech, slumped posture). The pathophysiology of depression is believed to involve a combination of abnormal neurotransmitter (eg, serotonin and norepinephrine) activity, hormonal (eg, cortisol) abnormalities, genetic traits, and environmental and psychological factors.
Anxiety is marked by physiological arousal (motor tension, autonomic hyperactivity) and psychological arousal (excessive worry, increased vigilance). Norepinephrine, serotonin, and gamma-aminobutyric acid (GABA) may be involved in its pathophysiology, and both genetic predispositions and environmental factors are believed to play a role.
Significant depressive symptoms are present in up to 40% of primary care patients in the United States. Major depression occurs in up to 10% of primary care patients and up to 15% of medical inpatients. The following factors are associated with increased risk:
Gender. Females are more likely to be diagnosed with a depressive disorder.
Family history. It is important to consider both diagnosed and undiagnosed indicators of mood disorder, especially in first-degree relatives.
Inadequate social supports. Examples include living alone or having few friends.
Stressful life events. These might include retirement or the death of a loved one.
Coexisting illness. Some studies show that up to 30% of patients who present to physicians with a physical symptom had either a depressive or anxiety disorder.1 Common coexisting illnesses associated with depression include coronary disease, cancer, neurologic disease, and endocrine disease (eg, hypothyroidism). Common coexisting illnesses associated with anxiety include angina, myocardial infarction, arrhythmias, congestive heart failure, mitral valve prolapse, asthma, chronic obstructive pulmonary disease (COPD), hyperthyroidism, hypoglycemia, Cushing's syndrome, Parkinson's disease, and cancer.
Medications. Drugs associated with anxiety include bronchodilators, antidepressants (anxiety symptoms associated with starting an antidepressant usually abate after several weeks of use), various antihypertensive medications (although beta-blockers are sometimes used to decrease the physical symptoms of anxiety), steroids, psychostimulants (eg, Ritalin), over-the-counter medications that contain caffeine, and pseudoephedrine.
Drug intoxication or withdrawal. Drugs that may contribute to anxiety include caffeine, alcohol, cannabis, cocaine, methamphetamine, and nicotine. Some medications that are used to treat anxiety, notably benzodiazepines, can cause rebound anxiety, in which individuals feel more anxious after the medication wears off than they did before taking it. This often leads to a cycle of escalating use.
Suicide is a risk in depressive illnesses, as in other psychiatric conditions. Among the risk factors for suicide are:
- A history of suicide attempts.
- Suicidal ideation.
- Family history of suicide or attempts.
- Access to weapons.
- Substance abuse.
- Underlying medical illness.
- Male gender.
- Increasing age.
A detailed history, including psychiatric history, medication use, substance abuse, and social history, should be taken for all patients. Physical examination should include a thorough neurologic examination and should rule out disorders that are associated with depression or anxiety, especially cardiac and endocrine disease.
Particular attention should be paid to medication history, as many medications may contribute to depressive and anxiety disorders. Isotretinoin, for example, is under investigation for its contribution to depression and suicidal ideation, and some older antihypertensive medications cause depression that is indistinguishable from primary depression.
All patients should be asked about suicidal ideation. In patients deemed at risk, immediate psychiatric attention is necessary, which may include hospitalization. The lifetime risk of suicide in depressed patients is about 15%.
Physiological or laboratory testing is generally not necessary, except to evaluate for medical disorders (eg, electrocardiogram, thyroid function tests, complete blood count, blood chemistries). A urine toxicology screen may be appropriate in some patients to evaluate for drug use.
Diagnosis of Major Depressive Disorder
According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnosis of a major depressive episode includes at least five of the following symptoms occurring on most days within the same 2-week period, and representing a change from previous functioning, causing significant distress or impairment, and not accounted for by effects of a medication, substance abuse, or bereavement2:
- Depressed mood most of the day, nearly every day.
- Markedly diminished interest in or pleasure from most activities.
- Significant weight loss or gain, or change in appetite.
- Altered sleep patterns (insomnia or hypersomnia).
- Psychomotor agitation or retardation observable to others.
- Fatigue or loss of energy.
- Feelings of worthlessness or excessive guilt.
- Diminished ability to think or concentrate; indecisiveness.
- Recurrent thoughts of death or suicidal ideation, plan, or attempt.
Diagnosis of Generalized Anxiety Disorder
Generalized anxiety disorder is characterized by excessive anxiety and worry occurring more days than not for at least 6 months. The patient finds it difficult to control the worry and has at least three of the following symptoms:
- Difficulty concentrating or mind going blank.
- Muscle tension.
- Sleep disturbance.
The anxiety or physical symptoms cause clinically significant distress or impairment in social, occupational, or other areas of function, and the disturbance is not due to a medical condition or substance abuse.2
Treatment usually includes pharmacologic and nonpharmacologic therapies, along with treatment of any coexisting medical and psychiatric conditions.
A wide variety of antidepressant and anxiolytic medications are available. For depressive disorders, selective serotonin reuptake inhibitors and tricyclic antidepressants are most commonly used. In many cases, several weeks of therapy are necessary before medications take effect. Successful relief of symptoms occurs in about half of patients. For anxiety disorders, antidepressants, benzodiazepines, and buspirone are commonly used.
Psychotherapy may be effective used alone or in combination with medications, and improves the outcome of medication treatments. Interpersonal psychotherapy and cognitive-behavioral therapy can be as effective as medications in the acute treatment of depressed outpatients, and the latter has an enduring effect that reduces the risk for relapse. Treatment with a combination of medication and psychotherapy may enhance the probability of response over either treatment alone, especially in persons with chronic depression.3 Cognitive-behavioral therapy is also a well-established effective treatment for generalized anxiety disorder.4
Studies suggest that exercise may be as efficacious as medications for the treatment of depression over both the short term and long term. The apparent antidepressant effect of exercise has been attributed to the correction of dysregulation of the central monoamines, reduction of stress-induced hypothalamic-pituitary axis hyperactivity, distraction from negative emotions, and improvement in self-esteem and self-efficacy.5
Caffeine avoidance, self-hypnosis, meditation, exercise, and relaxation techniques are helpful in treating anxiety disorders.6
Due to the evidence that major depression and anxiety disorders are associated with nicotine dependence,7 referral to a smoking cessation program may be indicated. Treatment with certain antidepressants (eg, bupropion) may facilitate smoking cessation.8
Diet may influence mood in several ways. Certain amino acids and other nutrients act as cofactors in the production of neurotransmitters. Dietary carbohydrate and protein influence the rate at which neurotransmitter precursors enter the central nervous system from the blood. Caffeine and alcohol, of course, have pronounced nervous system effects. Weight loss in obese persons is associated with improvement in mood.9
Diabetes is associated with depression. Presumably, this is primarily because diabetes and its complications are likely contributors to depressive symptoms. However, poor metabolic control may exacerbate depression and diminish the response to antidepressants, and clinical studies have shown that, as metabolic control improves, so does depression.10 In addition, persons who are depressed are at increased risk for diabetes. A 2006 meta-analysis of 9 longitudinal studies found that individuals with major depressive disorder have a 37% increased risk of developing diabetes, compared to other persons.11
The following nutrients are under investigation for their role in mood disorders:
Folate and Other B-Vitamins
Low blood concentrations of folate and vitamin B12 correlate with depression in the general population.12 The association between folate and depression may be mediated in part by elevated homocysteine levels, which are frequently found in depressed persons.12,13 High plasma homocysteine has been associated with reduced levels of cerebrospinal fluid amine metabolites 5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and 3-methyl, 4-hydroxy phenylglycol.14
A common variant of the enzyme 5, 10-methylenetetrahydrofolate reductase (MTHFR) is significantly more common in individuals with elevated homocysteine or depression.15
Folic acid is important in the production of tetrahydrobiopterin (BH4), a co-factor in the conversion of phenylalanine to tyrosine and in the hydroxylation of tyrosine and tryptophan, rate-limiting steps in the synthesis of dopamine, norephinephrine, and serotonin. BH4 is also involved in regulating the presynaptic release of neurotransmitters from nerve terminals.14 Low blood-folate concentrations are associated with significantly greater risk for relapse in persons on antidepressant therapy,16 and folate status predicts response to antidepressant treatment in the elderly.17 Two clinical trials adding methyltetrahydrofolate (one at 500 Âµg/d; the other at 15 mg/d) to an antidepressant regimen further reduced depressive symptoms, as indicated by the Hamilton Depression Rating Scale.18
Observations that depression is associated with low levels of both vitamin B1219 and pyridoxal phosphate20 indicate that increasing dietary (and perhaps supplemental) intakes of these vitamins may be important in preventing or treating depression. Limited evidence suggests that geriatric patients with depression and cognitive dysfunction respond better to antidepressant medication when given supplemental vitamins B1, B2, and B6, compared with antidepressant treatment alone.21
These observations may help explain why consuming a traditional Chinese diet, which is high in folate, with resulting high blood levels of this vitamin, is associated with lower rates of major depression.12
Omega-3 Fatty Acids
Depression is associated with lower levels of long-chain omega-3 fatty acids (ie, eicosapentanoic and docosahexanoic acids) in red blood cell membranes.22 Some, but not all, studies have found that in countries where intake of these fatty acids is higher, depression is less prevalent.23 Among individuals in the Arctic, the abandonment of traditional diets high in omega-3 fatty acids has been associated with increasing rates of depression and anxiety,24 although other biological and social factors may confound this interpretation.
Blood levels of polyunsaturated fatty acids predicted cerebrospinal fluid levels of both 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA).25 Controlled clinical trials have found improvements in depression rating scales when fish oils were administered with standard antidepressants.23,26,27 It is not known whether botanical sources of omega-3s, such as flax oil, have the same effect.
St. John's Wort is effective in 50% to 70% of outpatients with mild depression.28 However, minimal beneficial effects are found in larger studies in patients with major depression.29 Passion flower (Passiflora incarnata), chamomile (Matricaria recutita), and lemon balm (Melissa officianalis) contain flavonoids that bind to benzodiazepine receptors, but only preliminary evidence supports their anxiolytic effects at this time.6,28 Kava is an herbal treatment with evidence of a significant anxiolytic effect. However, it is no longer available, due to reports of liver failure in rare cases when high doses were taken.
The following treatments may be helpful, but require more study:
Elevated concentrations of homocysteine often found in depressed persons may increase central nervous system (CNS) levels of S-adenosylhomocysteine, which has been shown to inhibit monoamine neurotransmitter metabolism. As the sole methyl donor in the CNS, SAMe is involved in the creation of monoamine neurotransmitters, membrane phospholipids, and proteins and nucleoproteins. Also, in limited trials SAMe has shown effects similar to those of medication in treating depression.30 SAMe may have the advantages of a faster onset of action and fewer side effects, compared with selective serotonin reuptake inhibitors.31
Inositol, a substance found in many foods (e.g., whole grain cereals, legumes) is a key intermediate of the phosphatidyl-inositol (PI) cycle, a second-messenger system used by several noradrenergic, serotonergic, and cholinergic receptors. Interest in inositol stems from the complaints of side effects caused by anxiolytic medications, leading patients to discontinue treatment and experience relapse.28 Limited studies have suggested that at doses of 12-18 grams per day inositol reduces anxiety symptoms as effectively as selective serotonin reuptake inhibitors, with a low incidence of side effects.32,33
What to Tell the Family
Depression and anxiety are not simply volitional or temporary states of mind that can be easily changed. Depression in particular may arise from other diseases, and the presence of both disorders may indicate a need for more aggressive patient monitoring. Although they are medical disorders, depression and anxiety respond well in many cases to both medication and psychotherapy, and combining these treatments may be particularly effective. The role of folate and other nutrients is under investigation.
1. Kroenke K, Jackson JL, Chamberlin J. Depressive and anxiety disorders in patients presenting with physical complaints: clinical predictors and outcome. Am J Med. 1997;103:339-347.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Arlington, Va: American Psychiatric Association; 1994.
3. Hollon SD, Jarrett RB, Nierenberg AA, Thase ME, Trivedi M, Rush AJ. Psychotherapy and medication in the treatment of adult and geriatric depression: which monotherapy or combined treatment? J Clin Psychiatry. 2005;66:455-468.
11. Knol MJ, Twisk JWR, Beekman ATF, Heine RJ, Snoek FJ, Pouwer F. Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis. Diabetologia [serial online]. 2006;49:837-845. Accessed March 7, 2006
13. Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003;60:618-626.
16. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry. 2004;65:1096-1098.
21. Bell IR, Edman JS, Morrow FD, et al. Brief communication. Vitamin B1, B2, and B6 augmentation of tricyclic antidepressant treatment in geriatric depression with cognitive dysfunction. J Am Coll Nutr. 1992;11:159-163.
22. Maes M, Christophe A, Delanghe J, Altamura C, Neels H, Meltzer HY. Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res. 1999;85:275-291.
24. McGrath-Hanna NK, Greene DM, Tavernier RJ, Bult-Ito A. Diet and mental health in the Arctic: is diet an important risk factor for mental health in circumpolar peoples?:a review. Int J Circumpolar Health. 2003;62:228-241.
25. Hibbeln JR, Linnoila M, Umhau JC, Rawlings R, George DT, Salem N Jr. Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics. Biol Psychiatry. 1998;44:235-242.
27. Peet M, Horrobin DF. Dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002;59:913-919.