Mood and anxiety symptoms occur normally in the course of any eventful life and likely have important evolutionary functions. They become pathologic when they interfere with daily functioning, relationships, work or school performance, or other important activities of daily living.
Mood and anxiety disorders are distinct conditions, but their biological underpinnings and clinical presentations frequently overlap.
Major depressive disorder is common and is marked by sadness and loss of interest or pleasure (anhedonia) occurring throughout the vast majority of the time for at least two weeks. Associated symptoms may include poor concentration, excessive feelings of guilt or worthlessness, abnormal sleep patterns, fatigue or loss of energy, appetite disturbance, sexual dysfunction, delusions, psychomotor changes (e.g., slowed thoughts and movements, slumped posture), and/or recurrent thoughts of death. The pathophysiology of depression is believed to involve a combination of abnormal neurotransmitter (e.g., serotonin, norepinephrine, and dopamine) activity, genetic traits, and environmental and psychological factors. According to statistics from the National Institutes of Health, about 7% of all US adults experienced at least one major depressive episode in 2017. The highest prevalence among adults is between ages 18 and 25.
Bipolar disorders include 1 or more manic episodes (when the mood is abnormally elevated, expansive, or irritable) or hypomanic episodes (when manic symptoms are present, but they are mild enough that they do not substantially interfere with a person’s functioning). Associated symptoms may include grandiosity, decreased need for sleep, pressured speech, racing thoughts, distractibility, and risky behavior such as excessive spending and sexual indiscretions. Symptoms of depression and mania often occur together. When this happens, the episode is described as having mixed features.
Anxiety is marked by physiological arousal (muscle 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 mood symptoms are present in up to 40% of primary care patients in the United States. Major depression occurs in about 16% of people (lifetime risk), and medical inpatients have increased prevalence.
The following factors are associated with increased risk:
Sex. There is approximately a two-fold greater incidence of depression in women than in men, independent of country or culture. Lifetime prevalence of major depressive disorder is 10-25% for women and 5-12% for men. In contrast, bipolar I disorder has an equal prevalence in men and women, and manic episodes are more common in men. Women also have a higher incidence of the rapid cycling subtype (> 4 episodes/year) of bipolar disorder than men.
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, minimal contact with others, and limited involvement in community life.
Stressful life events. These include life transitions such as retirement and events of painful loss, such as divorce or the death of a spouse, imprisonment, personal injury or illness, unemployment, or change in financial status.
Coexisting medical illness. Some studies show that up to 30% of patients who present to physicians with a physical symptom had either a depressive or an anxiety disorder. Common coexisting illnesses associated with depression include coronary disease, cancer, neurologic disease, and endocrine disease (e.g., 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 syndrome, Parkinson disease, and cancer. Depression and anxiety often occur concurrently.
Medications. Bronchodilators and theophylline may exacerbate anxiety, as can antidepressants during the first few days of use. Various antihypertensive medications increase anxiety, although beta-blockers can sometimes be used to decrease the physical symptoms. Steroids, psychostimulants (e.g., methylphenidate), over-the-counter medications that contain caffeine, and pseudoephedrine also aggravate anxiety.
Drug intoxication or withdrawal. Drugs that may contribute to symptoms of 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 may in turn lead to a cycle of escalating use.
Suicide attempts are common in individuals with depression or bipolar disorders, as well as in those with other psychiatric illnesses. One-quarter to one-half of bipolar patients attempt suicide, and approximately 15% will die as a result. The mortality rate is increased in elderly patients and those with a rapidly cycling bipolar pattern. Additional risk factors for suicide include the following:
- 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.
- Presence of panic attacks.
- Loss of economic status.
- Loss of social status.
- Victim of bullying.
A detailed history, including psychiatric history, medication use, substance abuse, nutrition, 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 mood and anxiety disorders. Steroids, anticonvulsants, and narcotic use may increase the likelihood of depressive symptoms. Some older antihypertensive medications cause depression that is indistinguishable from primary depression.
All patients should be asked about suicidal ideation, which is common in depression. Suicidality often presents as thoughts without an actual desire to die, or it may be passive (“sometimes I wish I would wake up dead.”) In patients deemed at high risk, however, immediate psychiatric attention (which may include hospitalization) is necessary. High risk is characterized by a well-thought-out plan for dying by suicide, an actual intent to carry out that plan, or making arrangements for one’s death.
Physiologic or laboratory testing is generally not necessary except to evaluate for medical disorders (e.g., thyroid function tests, complete blood count, blood chemistries). A urine toxicology screen may be appropriate in some patients to evaluate for illicit drug use.
Diagnostic criteria for major depressive disorder, bipolar disorder, and generalized anxiety disorder are listed in the Diagnostic and Statistical Manual of Mental Disorders.
Treatment usually includes pharmacologic and nonpharmacologic therapies, along with treatment of any coexisting medical and psychiatric conditions.
For depressive disorders, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and bupropion are most commonly used. Up to 6-8 weeks of treatment are usually necessary before the full benefit of medications is apparent, but improvements may be seen within the first 2 weeks. Successful relief of symptoms occurs in about half of patients who are prescribed an antidepressant. For those who do not get better, serial trials of other antidepressants may successfully identify one that works.
For anxiety disorders, antidepressants, benzodiazepines, and buspirone are commonly used, although long-term use of benzodiazepines should be avoided.
For bipolar disorders, atypical antipsychotics, valproate, lithium, and carbamazepine are used as preventive treatments. Antipsychotics may also be used during exacerbations with or without psychotic features, and hospitalization may be required. Lab work may be required to monitor drug levels and physiological functioning.
Psychotherapy is effective when used alone or in combination with medications, and it improves the outcome of medication treatments. Interpersonal psychotherapy and cognitive-behavioral therapy used alone can be as effective as medications in the acute treatment of mildly to moderately 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. Cognitive-behavioral therapy is also a well-established effective treatment for generalized anxiety disorder. Therapy alone may effectively treat anxiety and mild to moderate depression; however, patients with bipolar disorder require mood stabilizing medication to prevent abnormal mood episodes. Psychotherapy as an adjunctive treatment can further improve outcomes.
Physical exercise has been shown to be effective for the treatment of mild to moderate depression in about half of individuals in research studies. In a 16-week Duke University study of 156 depressed individuals, aged 50 and over, treatment with sertraline, exercise, or both had similar effects. Exercise appears to be effective regardless of whether it is done individually or in a group setting. The response increases with increasing exercise intensity, and exercising three days a week appears to be sufficient to produce an effect.
Apart from its role in treatment, studies also show that exercise may reduce the likelihood that depression will arise in the first place. Overall, exercisers are about 17% less likely to lapse into depression, compared with sedentary people, regardless of age.
The apparent antidepressant effect of exercise has been attributed to anti-inflammatory effects, 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.
Avoidance of caffeine, alcohol, and recreational drugs can help prevent exacerbations of mood disorders and anxiety. In addition, self-hypnosis, meditation, exercise, and relaxation techniques are helpful in treating anxiety disorders.
Due to the evidence that major depression and anxiety disorders are associated with nicotine dependence, referral to a smoking cessation program may be indicated. Treatment with the antidepressant bupropion may facilitate smoking cessation.
Botanical treatments. St. John’s wort is effective in 50-70% of outpatients with mild depression. Results have been mixed for major depression, with some reviews indicating minimal benefits and others suggesting an efficacy similar to antidepressant medications.
Passion flower (Passiflora incarnata), chamomile (Matricaria recutita), and lemon balm (Melissa officinalis) contain flavonoids that bind to benzodiazepine receptors, but evidence of their anxiolytic effects is modest. In double-blind randomized trials, passion flower was as effective as a benzodiazepine for generalized anxiety disorder and also adds to treatment benefits when used as a supplemental treatment.
Kava is an herbal treatment with an apparent anxiolytic effect. However, its safety has not been established. Some kava users have developed liver toxicity, which may have been attributable to excessive doses or to contamination.
It is important to ask patients if they are using any herbal treatments. St. John’s wort, for example, taken at high doses in addition to selective serotonin reuptake inhibitors may cause serotonin syndrome, which is potentially fatal.
The following treatments require more study:
S-adenosylmethionine (SAMe). Elevated concentrations of homocysteine often found in depressed persons (see above) may increase central nervous system levels of S-adenosylhomocysteine, which has been shown to influence monoamine neurotransmitter metabolism. As the sole methyl donor in the central nervous system, SAMe is involved in the creation of monoamine neurotransmitters, membrane phospholipids, and proteins and nucleoproteins. However, available research findings do not yet support supplementation. One study found an increased incidence of mania when SAMe was given to patients with bipolar disorder, so it should be avoided in this population.
Inositol. Inositol, a substance found in many foods (e.g., whole-grain cereals and legumes), is a key intermediate of the phosphatidyl-inositol cycle, a second-messenger system used by several noradrenergic, serotonergic, and cholinergic receptors. Limited studies have suggested that at doses of 8-12 g per day, inositol reduces anxiety symptoms as effectively as selective serotonin reuptake inhibitors, with a low incidence of side effects.
Several nutritional factors may influence mood.
Plant-based diets. Cross-sectional studies tend to show better mood scores among individuals following vegan and vegetarian diets, compared with omnivores, and among those consuming less meat rather than more meat. Similarly, a 9-year Canadian study with almost 300,000 participants showed higher fruit and vegetable intake is associated with lower odds of depression and anxiety.
A healthy body weight. Obesity and mood disorders are often comorbidities, and new research suggests a possible “metabolic-mood syndrome” based on the disorders’ interconnected pathophysiology. Additionally, excess body weight may reduce the efficacy of some medications, pointing out the need for obesity treatment in tandem. Weight loss in obese persons is associated with improvement in mood.
Preventing or treating diabetes. People with type 2 diabetes are more likely to develop depression, compared with the general population. 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. In addition, persons who are depressed are at increased risk for diabetes. A meta-analysis of 9 longitudinal studies found that individuals with major depressive disorder have a 37% increased risk of developing diabetes, compared with other persons.
Complex carbohydrate consumption. Dietary carbohydrate and protein influence the rate at which neurotransmitter precursors enter the central nervous system from the blood. Specifically, carbohydrate-containing meals that raise blood glucose and insulin secretion result in a drop in plasma amino acids. In turn, this means that fewer amino acids compete with tryptophan (a serotonin precursor) for transport through the blood-brain barrier. One study with children found that poor diet generally and low carbohydrate intake specifically were closely associated with depressive symptoms. Weight loss diets that recommend extreme carbohydrate restriction may cause problems for some people who are vulnerable to depression or anxiety. In contrast, artificial sweeteners such as aspartame have been associated with higher levels of depression and anxiety.
Adequate intake of B vitamins. Low blood concentrations of folate and vitamin B12 correlate with depression in the general population. The association between folate and depression may be mediated in part by elevated homocysteine levels, which are frequently found in depressed persons. 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. A common variant of the enzyme 5, 10-methylenetetrahydrofolate reductase (MTHFR) is significantly more common in individuals with elevated homocysteine or depression.
Folic acid is important in the production of tetrahydrobiopterin (BH4), a cofactor in the conversion of phenylalanine to tyrosine and in the hydroxylation of tyrosine and tryptophan, rate-limiting steps in the synthesis of dopamine, norepinephrine, and serotonin. BH4 is also involved in regulating the presynaptic release of neurotransmitters from nerve terminals. Low blood-folate concentrations are associated with significantly greater risk for relapse in persons on antidepressant therapy, and folate status predicts response to antidepressant treatment in the elderly. Some have suggested that a high folate intake may help explain the low prevalence of depression in China. Two clinical trials adding methyltetrahydrofolate (one at 500 μg/day, the other at 15 mg/day) to an antidepressant regimen further reduced depressive symptoms, as indicated by the Hamilton Depression Rating Scale.
Observations that depression is associated with low levels of both vitamin B12 and pyridoxal phosphate indicate that increasing dietary (and perhaps supplemental) intakes of these vitamins may be important in preventing or treating depression. Higher folate intake has been found to be protective against depressive symptoms in men, but a long-term follow-up study on folic acid supplementation in women found no benefit compared with a placebo, despite decreased homocysteine levels. 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.
Omega-3 fatty acids. Depression is associated with lower levels of long-chain omega-3 fatty acids (i.e., eicosapentaenoic and docosahexaenoic acids) in red blood cell membranes. Some, but not all, studies have found that in countries where intake of these fatty acids is higher, depression is less prevalent.
Blood levels of polyunsaturated fatty acids have predicted cerebrospinal fluid levels of both 5-HIAA and HVA. Limited trials have indicated improvements in depression rating scales when fish oils were administered along with standard antidepressants, although a 2015 systematic review found that there is insufficient evidence to recommend supplementation as treatment. These fatty acids may play an anti-inflammatory role, and it is possible that botanical sources of omega-3s, such as flax oil, might have the same effect.
Arachidonic acid is an inflammatory compound found in some foods including eggs, chicken, meat, and fish. It has been found that high levels can impair a person’s emotional state.
See Basic Diet Orders chapter.
What to Tell the Family
It is important for the family to understand that mood disorder symptoms are not simply volitional or temporary states of mind that can be easily changed. Depression in particular may arise from other medical conditions and may indicate a need for additional treatment. Although they are medical disorders, depression, anxiety, and bipolar illnesses respond well in many cases to medication, psychotherapy, and nutritional intervention, which will often include a role for the family. Combining nutrition, pharmacologic, and psychotherapeutic treatments may be particularly effective. Family members can also assist the patient in informing the physician of worsening behavioral status.
National Institute of Mental Health. Prevalence of Major Depressive Episode Among Adults. https://www.nimh.nih.gov/health/statistics/major-depression.shtml#part_155... Accessed April 15, 2020.
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