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Depression and comorbid medical illness: therapeutic and diagnostic challenges.

It is estimated that major depressive disorder exists in 36% of patients with coexistent medical conditions and may be more common in hospitalized and elderly patients. (1) This discussion addresses comorbidities in patients with depression and provides treatment strategies for clinicians.

Absent in the general discussion are the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). These agents may have value in treating specific comorbid illnesses (ie, chronic pain syndromes); however, their toxicity makes them inappropriate as first-line medications for depression.

* AGE OF PATIENT AND RISK FOR DEPRESSION AND COMORBIDITIES

Children and adolescents Diagnosis of depression among children and adolescents is often missed. It may be masked by medical or psychiatric comorbidities. (2,3) Parents may not express psychosocial concerns regarding their children to pediatricians, who may not respond. (4) Possibly, 1% to 2% of children and 5% to 8% of adolescents may be affected. (5)

Evaluating the pediatric patient. Various medical conditions can present as depression (eg, anemia, brain injuries, chronic headaches, diabetes, drug abuse, epilepsy, infectious mononucleosis, hypothyroidism, Lyme disease, (6) renal disease, Wilson's disease). Baseline laboratory studies should be considered to rule out organic components of the illness. (7,8)

Treatment strategies. Most of the available treatment strategies are based on data derived from studies with adults. Children are better placebo responders than adults (over 50% in most trials) (9) and benefit highly from structured psychotherapy with support and education for both patient and family.

Limited evidence from clinical trials regarding antidepressants to children. Limited evidence-based research has focused on SSRIs in children. Thus far, fluoxetine, (10) paroxetine, (11) and most recently sertraline (12) are the only antidepressants that have been shown in controlled trials to be effective in children. Caution is indicated regarding paroxetine for patients with major depressive disorder younger than 18 years of age because of a possible increase in suicidal thinking, although no increase in suicides has been documented. (13)

Most antidepressant agents are not FDA-approved for patients under age 18; however, fluoxetine has received approval for use in children ages 7 to 17. (13) Prompt referral and close collaboration with mental health professionals is of the utmost importance in the adolescent who becomes socially disruptive or makes comments of a suicidal nature.

Depression in the elderly

Depression in the elderly often goes undiagnosed and untreated. The prevalence in patients aged more than 65 years can be as high as 30% in outpatient setting and 40% in hospitalized patients. (14) Cognitive impairment can often cloud the differential diagnosis. Depression can simulate dementia: both are associated with memory loss, concentration difficulties, irritability, agitation and distractibility. (15) Medical conditions that become more common with aging are associated with depressive disorders: Up to 50% of cardiac, renal, Parkinsonian, post-stroke, chronic pain, and rheumatoid arthritis patients develop comorbid depressive disorders. (16,17)

Common signs of depression in the elderly that may be overlooked are diminished self-care, increased irritability, and social withdrawal with psychomotor retardation, all of which can impact daily activities, independent living, and compliance with other medical regimens. The greatest risk factors for depression are age over 75, cognitive dysfunction, and severe chronic medical illness.

Barriers to effective screening. Screening may be limited by cognitive impairment. The Mini-Mental State Exam (MMSE) is commonly used for screening global cognitive function. A score of less than 15 cannot be screened with the usual intruments.

An estimated 10% to 30% of the geriatric population will develop mental symptoms as a result of an unrecognized, undiagnosed, and potentially correctable medical condition. (17) Anemia, hypothyroidism, atypical anginal symptoms, pancreatic cancer, hyponatremia, Cushing's disease, post-herpetic neuralgia, and vitamin B12 deficiency are all associated with psychiatric symptoms. (16,17)

Role of multiple medications in diagnosis or onset of symptoms. Multiple medications (including over-the-counter medications) may increase the elderly patient's risk for drug-drug interactions, which may unmask early dementia or produce symptoms of depression, delirium, or mania. (18) Among the many medications that commonly cause psychiatric symptoms in the elderly are steroids, anticholinergics, benzodiazepines, cimetidine, and interferon. (19)

Age-related factors that affect drug accumulation and elimination in the elderly. Age-related pharmacodynamic changes may affect treatment response. The elderly have a higher fat percentage, less volume fat of distribution, less muscle mass, and less total body water. These factors can cause a higher concentration of liposoluble drugs in the brain. (20) Decreased plasma protein levels may lead to diminished drug binding and increased levels of free active drug. Decreased size of both the liver and the kidneys can also inhibit drug elimination and promote drug accumulation.

Alterations in pre- and postreceptor reactivity can affect neurotransmitter levels and target tissue responsiveness. For instance, as the brain ages, reduction of dopamine levels in the central nervous system can increase the risk of extrapyramidal symptoms from neuroleptics, selective serotonin reuptake inhibitors (SSRIs), and other antidepressant drugs. Also, reduced levels of gamma-aminobutyric acid may increase the elderly patient's sensitivity to ethanol. (20)

Issues in selecting an appropriate agent for elderly patients. Bupropion, mirtazapine, nefazodone, SSRIs, and venlafaxine are all effective and considered reasonably safe. For the severely depressed, the clinician may consider adjuvant psychostimulants (for the patient with lethargic depression), which have been proved effective in open-label and small clinical trials. (21,22)

Iatrogenic complications. The elderly are particularly prone to iatrogenic complications. Nearly 25% of elderly patients who take SSRIs or venlafaxine develop below-normal sodium levels. (23,24) The syndrome of inappropriate antidiuretic hormone is a relatively common side effect of SSRIs and, when severe, can be associated with mental status changes, such as confusion, lethargy, and seizures. Thus, serum sodium levels should be evaluated prior to and 4 weeks after starting therapy with these agents. (23,24)

Large case control studies have demonstrated the increased risk of falls among elderly patients taking antidepressants (equally among SSRIs and TCAs). (25) Tremors, extra-pyramidal symptoms, somnolence, and even delirium may occur. When chronic medical illness forms the basis for treatment-resistant depression (cancer, post-stroke, chronic pain, etc), the patient should be referred to a geriatric psychiatrist.

* ANXIETY DISORDERS AS A COMORBID CONDITION WITH DEPRESSION

Primary anxiety disorders (ie, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, specific phobic disorder, and post-traumatic stress disorder)--as opposed to depression with anxiety--should be considered in choosing an antidepressant.

Primary anxiety disorders and depression

In patients with primary anxiety disorders, anxiety usually precedes the onset of any depressive symptoms, and it is treated as a separate problem. First-line treatment considerations should normally include selective or nonserotonin modulating agents (SSRIs, mirtazapine, nefazodone and venlafaxine).

The SSRIs have well-established efficacy in this therapeutic area, as documented in reviews in the United States and Europe. (26-28)

Primary depression with anxiety

Patients who have depression with anxiety typically experience anxiety symptoms that surface concurrently with depressive ones. Effective first-line agents include bupropion, SSRIs, or venlafaxine. (29-31) The efficacy of the SSRIs has been well supported in reviews demonstrating that the SSRIs were as effective as the older TCAs, but with a much more acceptable safety profile. (26,27)

Evidence from the clinical trials. Bupropion (sustained release formula) and the SSRI sertraline showed comparable antidepressant and anxiolytic activity after 16 weeks of therapy in a 248-patient randomized, double-blind, placebo-controlled study of patients with primary depression. (29)

Venlafaxine was effective in a 1998 meta-analysis of 6 short-term trials (3 placebo-controlled, and 3 active-drug-controlled). (32)

Potential side effects of agents. Clinicians should note that akathisia (restlessness) is a possible short-term side effect of SSRIs in the treatment of depression with anxiety. Similarly, an uneasy energized feeling is a possible short-term side effect with venlafaxine and bupropion. Although this transient restlessness usually wears off, some patients may require temporary coadministration of another agent, such as a benzodiazepine, to ensure continued compliance. This bridging agent will ultimately be discontinued once the patient has demonstrated a positive response to the antidepressant.

* DEPRESSION, CARDIOVASCULAR DISEASE, AND POSTMYOCARDIAL INFARCTION

Depression is a strong independent risk factor for ischemic heart disease. Regardless of cardiac status and history, depressed patients exhibit significant alterations in platelet physiology that may increase risk for thrombus formation. (33) Depression frequently remains undiagnosed and untreated in patients with cardiovascular disease (75% depression diagnoses missed), and only half of the 25% correctly diagnosed are ultimately treated for comorbid depression. (34)

Missed diagnosis of depression in patients with cardiac disease

Symptom overlap may be a factor in missed diagnoses. For example, fatigue and insomnia can present as symptoms of cardiac illness, but they are also commonly associated with depression. The patient may not report significant depressive symptoms. Additionally, physicians may have concerns regarding potential antidepressant side effects and thus may be reluctant to use additional pharmacotherapy for depression.

Depression after acute MI

Depression has a negative prognostic effect on mortality when it develops following an acute myocardial infarction (MI). As many as 65% of patients report symptoms of depression following an acute MI, with 15% to 22% developing major depressive disorder. (35) Cardiac patients with depression are also less likely to comply with overall treatment, to take their low-dose aspirin, to follow up with cardiac rehabilitation, to stop smoking, and to return to regular activities as quickly as nondepressed patients. (35,36)

Evidence from clinical trials: patients with cardiovascular disease and depression

The increased cardiac risk in patients with depression and hopelessness was established as a risk factor independent of established risk factors (ie, hypertension, smoking, hyperlipidemia and family history) (36) in a study of 2832 patients with no known pre-existing cardiovascular disease at baseline. Individuals were assessed for symptoms of depression and followed prospectively for 12 years. The risk of fatal and nonfatal cardiac events was directly related to the severity of depression. Other studies similar results. (37,38)

The outcome in the Myocardial Infarction and Depression-Intervention Trial (MIND-IT) (34) will address the relationship between cardiac events following an MI in depressed patients treated in the intervention arm (mirtazapine or citalopram) vs those depressed patients followed for care as usual treatment. Currently, 2140 patients have been randomized and will be followed for 27 months.

Treatment strategies for patients with cardiac disease and depression

It is currently unknown whether aggressively treating depression in the cardiac patient can improve survival. (39) Treating depression has been shown to increase compliance with cardiac regimens and can improve global functioning of the patient. (40)

Psychosocial treatment for these patients should include short-term practical cognitive-behavior therapy; expectations and limitations of their illness with respect to exercise activity, sexual activity, work, and hobbies should be all addressed on an individual basis both from a short-term and long-term perspective.

Safety and efficacy are main considerations when selecting an antidepressant for depression during the post-MI period. Overall efficacy differs little among antidepressant agents, whereas adverse events may differ significantly.

Use of antidepressants in post-MI patients: evidence from clinical trials

The use of sertraline, bupropion, and, to a lesser extent, mirtazapine and nefazodone has been studied in post-MI patients. In the largest randomized, placebo-controlled trial sertraline demonstrated safety in 369 patients with acute heart disease who had experienced major depression after cardiac hospitalization (for MI or unstable angina), (42) although drug efficacy was significant only in the subgroup of patients with a Hamilton-Depression Scale score (42) of over 18 and 2 previous episodes of depression.

This suggests that pharmacologic treatment may have tendency toward cardioprotective effects without any evidence of drug-induced adverse cardiac events. Drug therapy may be indicated for those patients with more severe states of depression or where a previous history of depression exists. Perhaps only effective early diagnosis and supportive psychosocial intervention may be all that is needed in the mild depression following a myocardial infarction. (43, 44)

Bupropion has been evaluated in 1 small, open-label trial that addressed cardiovascular safety. (45) As a smoking-cessation aid, bupropion demonstrated both safety and efficacy in nondepressed patients during the 2-week period after an MI episode. (46) The authors proposed that bupropion may also help reduce cardiac risk in those patients with a nicotine addiction (see Addictions in patients with depression, page S28).

* DIABETES AND DEPRESSION

Patients with diabetes are 2 to 3 times as likely to experience depression as those without diabetes. (47) According to the NIMH, depression has a more serious progression in persons with diabetes, is linked to a higher rate of depression relapse, is associated with more diabetes-related medical complications, and engenders higher healthcare costs than depression in persons without diabetes. (48) Severity of depression also correlates positively with both the degree of hyperglycemia and the presence of diabetic neuropathy. (16,51) Patients with diabetes have a significantly higher risk for heart disease and stroke. (49) Additionally, patients with depression and diabetes tend to present with mostly somatic complaints. (16)

Conditions associated with diabetes that may be affected by treatment for depression

Adults with type 2 diabetes commonly have insulin resistance and obesity. Obesity, sexual dysfunction, ischemic heart disease, and painful peripheral neuropathies are common complications of diabetes. These conditions may be aggravated by some pharmacologic agents used in the treatment of depression.

Cognitive behavioral therapy in patients with diabetes and depression

Cognitive behavioral therapy (CBT) has been effective in reducing glycosolated hemoglobin levels (at 6 months) following a 10-week study where all the patients received diabetes education but only the treatment arm received individualized CBT. (50)

Pharmacologic agents: Absence of data from clinical trials

No long-term trials have assessed the effect of any particular antidepressant in people with depression who have diabetes, IHD, diabetic neuropathy, or obesity. The only antidepressant that is not associated with weight gain, however, is bupropion. It also features no anticholinergic or hypotensive side effects.

Both fluoxetine and sertraline have been reported to have a favorable short-term effect on glycosolated hemoglobin levels (6 months) in this patient population. (51,52) SSRIs may be associated with significant weight gain with long-term use. For some patients with depression and diabetes, these SSRI-related adverse effects may complicate therapy and have a negative effect on compliance.

In a 2002 review of advances in diabetic neuropathy, Simmons and Feldman concluded diabetic neuropathic pain could be effectively treated with bupropion, together with the antiepileptic drug lamotrigine. (53)

* OBESITY AND DEPRESSION

While the relationship between depression and severe obesity is unclear, several studies show that severely obese patients are at high risk for depression. In a study of 487 patients who had gastric-restrictive weight-loss surgery, significant postoperative weight loss was associated with a fall in Beck Depression Inventory scores, with a mean +/- SD score of 7.8 +/- 6.5 at 1 year and 9.6 +/- 7.7 at 4 years. (54)

Recently, more than 2000 adults with major depression were followed for 5 years in a prospective, observational study. Obesity (body mass index [greater than or equal to] 30) at baseline was associated with an increased risk of depression 5 years later, even after controlling for covariates such as gender, marital status, education, social support, physical health problems, and functional limitations. (55)

Weight gain in patients with depression: effects of pharmacologic agents

In obese patients diagnosed with depression, the physician should consider the risk of antidepressant-related weight gain when initiating therapy. A review of the literature demonstrates that SSRIs have repeatedly been shown to result in weight gain with long-term use. (56) In a review of short-term and long-term studies of SSRI-related weight gain, Sussman and Ginsberg concluded that of those patients who gained weight on SSRI therapy, it was "typical for increases up to and exceeding 20 pounds." (57,58) Certainly not everyone gains weight while taking SSRIs and the mechanism of action behind SSRI-induced weight gain remains to be clarified. It has been hypothesized that weight gain results from desensitization and possible deregulation of 5-H[T.sub.2c] receptors involved in appetite control (58) or the indirect negative effect of serotonin on dopamine neurotransmission. (57-61)

While serotonergic agents seem to stimulate appetite and reduce satiety, dopamine-enhancing agents such as bupropion appear to reduce cravings and suppress appetite, which may benefit depressed obese patients. Also, obese depressed patients may benefit from the energizing action of bupropion's dopaminergic activity.

Several longitudinal studies have evaluated bupropion in the treatment of obese individuals without depression. (62) An 8-week, randomized, double-blind, placebo-controlled study of 50 overweight and obese women (who did not experience depression) demonstrated that bupropion was associated with greater weight loss (approximately 5% of body weight) than was placebo (approximately 1% of body weight). (63) In a longer placebo-controlled study, bupropion facilitated weight loss compared with placebo in a group of 193 obese adults treated with medication and dietary modifications for a 26-week period. (62)

Another trial followed 400 non-obese patients with major depression for 52 weeks. Long-term bupropion treatment was associated with average weight loss of 1.4 kg. When the distribution of the weight loss was examined, it was found that weight loss was greatest in those patients who were heaviest at baseline. (64)

* CHRONIC PAIN AND DEPRESSION

It has been reported that 30% to 54% percent of patients with chronic pain have recurrent episodes of major depression, 30% to 40% will develop dysthymia, 28% develop depression with an adjustment disorder, and 15% to 20% develop alcohol and illicit drug abuse. Early, effective treatment of both the chronic pain and the comorbid depression has been shown to improve functional, social, and work status. (65)

Additionally, depression reduces pain threshold and tolerance, and increases pain ratings. Patients often have significant autonomic hyperactivity with increased skeletal muscle tension, insomnia, comorbid anxiety, comorbid substance abuse with narcotic habituation, and pain-inadvertent behavior. (66)

Chronic arthritis and depression

Studies suggest that more than 50% of patients with rheumatoid arthritis experience depressive symptoms and anxiety symptoms as well. These patients have higher pain scores and are more difficult to manage than nondepressed arthritic patients. (66) They should be treated aggressively and compassionately. Antiinflammatory agents, muscle relaxants, and opiates can all independently cause depressive symptoms.

Selecting the most appropriate agent for depression with comorbid chronic pain

TCAs have been used and studied extensively in patients with comorbid depression and chronic pain. The norepinephrine component seems to have a more significant pain-modulating role than the serotonergic effects. TCAs have performed better than SSRIs for chronic pain patients. (67,68) Their analgesic effects are independent of antidepressant effects. Desipramine, however, may not be appropriate because of its strong anticholinergic and antihistamine effects.

Both bupropion and venlafaxine have significant norepinephrine effect and have been shown in limited trials to be effective for the treatment of chronic pain. (67,68) These drugs play a secondary role as therapeutic agents in chronic pain, yet a primary role in the major depressive patient with comorbid pain.

* MIGRAINE AND DEPRESSION

The lifetime prevalence of major depression is 3 times higher in patients with migraine than in the general population. Migraine headache can also be comorbid for bipolar spectrum, panic disorder, and social phobia, suggesting a neurochemical correlation. A therapeutic regard for the headache disorder may be important in choosing an antidepressant.

Evidence from clinical trials

Evidence from at least 2 studies supports a growing interest in the use of SSRIs as prophylactic agents in migraine therapy. In a double-blind, placebo-controlled study of fluoxetine in 53 patients with migraine, the frequency of migraine attacks decreased by 52% in patients who received fluoxetine, as compared with an only 27% reduction among patients who received placebo. (69) These findings were consistent with those of an earlier pilot study by Adly et al, which showed a significant reduction in migraine headache "scores" (derived from variables such as headache intensity and duration) in patients who received fiuoxetine compared with placebo. (70)

The authors recommend the use of both SSRIs and TCAs. Only amitriptyline has demonstrated benefit in large, randomized, placebo-controlled trials. (71,72) The panel would use doxepin or nortriptyline only as augmentation tools and in small doses (10-50 mg) for the patient with disrupted sleep patterns and not as the primary agent. SSRIs, such as fluoxetine, paroxetine, and sertraline, were most often used based on favorable side-effect profile and not on established efficacy.

* SEIZURE DISORDER IN PATIENTS WITH DEPRESSION

Depressive disorders are the most common type of psychiatric comorbidity in patients with epilepsy. (73) Patients with partial complex seizure disorders of temporal- and frontal-lobe origin are at high risk for depression, as are patients whose seizures are poorly controlled. Evidence suggests that depression may actually precede seizure disorder in some patients with primary and generalized epilepsy, (73) and in patients with complex partial seizures. (74) Patients with seizure disorders have 4 to 5 times greater incidence of major depressive disorder and 4 times the incidence of suicide than normal controls.

These patients may tend to minimize their complaints to avoid further stigmatization of their illness. They often present with atypical features of depression. The physician may fear that antidepressant medication may lower the seizure threshold and worsen seizure control.

Most antidepressant drugs are safe in patients with epilepsy. Overall, the severity of depressive disorders in patients with epilepsy is milder than that of the major depressive disorder, yet due to the chronicity, they had a significant overall negative impact on their quality of life. (73-74) Unfortunately, many patients develop symptom tolerance and perceive their dysphoria as part of their epileptic state.

Evidence from the clinical trials: Antiepileptic drugs and antidepressant activity

Certain antiepileptic drugs might have some antidepressant activity, including carbamazepine, gabapentin, lamotrigine, or valproic acid. Of these, only lamotrigine has demonstrated this activity in clinical trials involving patients with depressive illness (specifically, bipolar depression). (76-77)

Observational studies, case reports, and data from controlled trials suggest that some antiepileptic drugs may provoke depressive symptoms, including benzodiazepines, phenobarbital, phenytoin, primidone, topiramate, (73) vigabatrin, and tiagabine. (78)

Evidence regarding use of antidepressants in patients with epilepsy. While all antidepressants incrementally increase seizure risk in the nonepileptic depressed patient, little is known of the effect on patients with epilepsy. EEG activity was examined in 23 depressed patients and after 4 weeks of treatment with paroxetine 30 mg/d. (79) No significant differences were observed between treatment and placebo groups. Citalopram also has no effect on EEG activity.

A short review concluded that fluoxetine, paroxetine, sertraline, or trazodone should be used as first-line treatment in patients with epilepsy. (80) SSRIs (fluoxetine, paroxetine, and fluvoxamine, and, to a lesser degree, sertraline) have been associated with a comparatively lower risk of seizure induction. (81) SSRI-related P450 cytochrome inhibition may influence the metabolism of older antiepileptic drugs, such as phenytoin and carbamazepine. This inhibition may increase serum levels. When managing a patient at risk for seizure, one should refer to the SSRI's prescribing information and carefully review the seizure risk profile of the product.

Bupropion is contraindicated for patients with seizure disorders. Bupropion administration has been linked to an increased risk of seizure, probably as a result of pharmacologic factors related to the rapidity of titration of this drug and the peak trough levels experienced by the patient.

Although electroconvulsive therapy is a well-tolerated treatment and may be considered, it has not been specifically looked at for efficacy or safety in depressed patients with epilepsy.

* ATTENTION DEFICIT HYPERACTIVITY DISORDER AND DEPRESSION

Estimates of comorbid depression in attention deficit hyperactivity disorder (ADHD) vary in the literature, ranging from not at all to as high as 15% to 74% of cases. The clinician should be alert to possible major depressive disorder in their ADHD patients. (82)

ADHD and depression are comorbid 30% to 40% of the time and may have overlapping symptoms. Careful evaluation of the course of symptoms must precede any treatment decisions. If both disorders are present, the first line of treatment is a stimulant.

Biochemical basis of ADHD

An imbalance in cerebral catecholamine metabolism may form the biochemical basis of the disorder. Successful treatments appear to enhance synaptic levels of catecholamines (dopamine and norepinephrine) in the striatal tracts of the cerebral cortex. This is believed to be the basic mechanism of action of the popular stimulant medications (methylphenidate, pemoline, and dextroamphetamine) which remain the most commonly used treatments for ADHD in adults and children. (83)

Treatment options for depression and comorbid ADHD

Antidepressants with a noradrenergic mechanism of action, such as TCAs and bupropion, have been shown to be effective in treating ADHD. Preliminary evidence indicates that venlafaxine and nefazodone may be effective in treating ADHD. In contrast, SSRI antidepressants have not proven to be effective for ADHD symptoms. Spencer et al (84) found that desipramine--based on meta-analysis of 5 trials involving 170 ADHD patients--produced similar efficacy to methyphenidate, yet significantly higher adverse effects, including possible sudden collapse or death in children, presumably of cardiac cause. Because of this, most child and adolescent psychiatrists have limited its use.

Several randomized clinical trials support the efficacy of bupropion in ADHD. (85-88) Based on these considerations, stimulant use remains the initial therapeutic step in treating the comorbid, depressed ADHD patient. When adults with ADHD are diagnosed with comorbid depression, these patients may derive special benefit from medications such as bupropion that enhance dopaminergic and norepinephrine neurotransmission. Bupropion has also proved efficacious in clinical trials in the pediatric population. (86,90)

If symptoms of major depressive disorder and ADHD persist despite the trial of stimulant therapy, then bupropion should be the first-line agent for the treatment of residual comorbid depressive disorder symptoms in these treatment resistant patients. This is due to its ability to treat both the depressive component and possibly the ADHD comorbidity. (87-90)

* ADDICTIONS IN PATIENTS WITH DEPRESSION

Importance of addressing substance abuse first

Treatment of a patient with depression and comorbid substance abuse requires meeting 2 objectives: to address the underlying substance abuse and to treat the patient's depression. The physician may need to temporarily postpone a conclusive diagnosis in order to distinguish symptoms of true mood disorders from a reversible "organic depression" produced by an abused substance's direct toxicity or withdrawal effects. This brief diagnostic waiting period is necessitated by the fact that 4 weeks of abstinence is required before an accurate diagnosis of depression can be determined, (91) although alcohol-related or drug-induced withdrawal states can be associated with depressive symptoms for up to 6 months following drug cessation. An extended period of withdrawal symptoms is particularly common in patients with cocaine-induced anhedonia, and in those experiencing sleep disturbance following alcohol cessation.

Treating depression in this population

Once the acute effects of substance intoxication/withdrawal have been resolved, current recommendations call for treating depression and addiction concurrently and aggressively (92) because successful treatment of the substance-related disorder (including alcoholism) often ameliorates symptoms of depression. This is evidenced by the fact that, even without medication, the remission rate for depression is very high in successfully treated addicts who developed secondary depression while abusing substances.

For patients with primary depression and comorbid substance abuse, a patient's depressive symptoms do not usually abate with abstinence. Thus, pharmacologic treatment of depression is generally required. Important demographic information can be obtained from studies looking at dual diagnosis. Drake and Wallach found that the patients were generally younger, male, aggressive, suicidal, noncompliant, and less able to manage daily living activities. (93)

The treatment approach for patients with comorbid substance abuse problems should be tailored to the chronic medical model, not simply viewed as a social problem. The medical literature supports the combined approach of antidepressant therapy and outpatient counseling for patients with depression and comorbid substance abuse. Ideally, abstinence from all substances of abuse should be achieved prior to attempting to manage a patient's depressive symptoms, since it is unlikely that a patient will respond to any antidepressant if he or she is currently using a substance of abuse. (94)

Alcohol abuse: Association with psychiatric complications

Alcohol abuse is associated with myriad psychiatric complications in the acute inebriated state and in the acute withdrawal state. The acute intoxicated state may cause aggressiveness, depression, and suicide. The withdrawal may bring delirium, hallucinosis, seizures, or tremor. These patients may need to be hospitalized in the presence of a history of previous delerium tremens (DTs), seizures during withdrawals, head trauma, delirium, pancreatitis, suicide risk, or a fever of greater than 101[degrees]F. Many severe depressions are alcohol-induced organic mood syndromes and improve spontaneously with prolonged abstinence. (98) In 1 study, severely depressed alcoholic patients remitted after 2 weeks of unmedicated sobriety. (99)

Evidence from clinical trials

While data regarding response to specific agents are limited, 1 trial (99) studied the effect of fluoxetine on alcohol consumption in 20 men with chronic dependence. After a 1-month, double-blind, placebo-controlled trial period, they found that the fluoxetine group had 15% lower alcohol intake.

* FEMALE LIFE-CYCLE EVENTS

Peak prevalence of depression in women occurs between the ages of 18 and 44, with the average age of occurrence in the mid-20s. During childhood, the prevalence of depression is roughly equivalent for males and females, but it rises significantly among girls in the adolescent years. Evidence suggests that progesterone and estrogen may influence the synthesis, metabolism, and catabolism of neurotransmitters such as serotonin and norepinephrine. In addition, birth control pills, steroids, and progestins have all been associated with depression. Mood disorders unique to women--such as postpartum depression and premenstrual dysphoric disorder--appear to have an etiologic link to changes in hormone levels.

Lifestyle factors may also play a role in triggering the onset of depression in women. Married women have an increased risk for depression, possibly because of marital discord, domestic violence, or death of a spouse. Sexual abuse, history of abortion or miscarriage, or the death of a child may be important contributory factors.

A woman with depression may present with vague somatic symptoms such as fatigue, lack of motivation, stress headaches, muscle pains, insomnia, and difficulty concentrating. (100,101) Symptoms may initially surface during female life-cycle events such as pregnancy, menstruation, and menopause--all of which may be associated with an increased risk of depression. Each event has specific considerations that should be carefully reviewed.

Premenstrual dysphoric disorder

It is important to differentiate premenstrual dysphoric disorder (PMDD) (4% incidence in women) from a minor depressive disorder. Key factors associated with the diagnosis of PMDD include the following:

* The patient's symptoms have occurred during most menstrual cycles

* Symptoms have been clearly documented for at least 2 consecutive menstrual cycles

* Any mood changes are temporary, occurring only in the time period between the luteal phase and the onset of menstruation.

Verifying the cyclic nature of a patient's symptoms is imperative in establishing a diagnosis of PMDD. If a patient's symptoms are not cyclic, then the diagnosis is more likely to be minor depression. Patients with minor depression may be treated with any first-line agent, while true PMDD (which, technically, is not classified as a true depressive disorder) responds very well to SSRIs. For example, in a large, double-blind trial, Steiner et al (102) reported that 20-60 mg of fluoxetine taken daily through 6 menstrual cycles improved mood symptoms in 53% of the cycles compared with improvement in 28% of the cycles with placebo. In another open trial, Freeman et al (103) reported symptomatic improvement with nefazodone. Improvement in symptoms occurred by the end of the first cycle of treatment and was maintained for the entire course of treatment.

Pregnancy and post-pregnancy

Although pregnancy is not a risk factor for major depression, symptoms of minor depression are often exhibited by expectant mothers. Women at most risk during their pregnancies are those with histories of substance abuse and poor social support (eg, the single mother).

After delivery, postpartum depression (PPD) presents with minor transient symptoms in 50% to 80% of women; the majority of these patients will not require medication. Ten percent, however, will develop major depression. These patients may be first-time mothers and may not recognize that these symptoms are abnormal, or they may be reluctant to admit to feeling depressed due to the possibility of the stigma attached to not being a "good mother."

Women at the greatest risk for PPD are those with a history of PPD, or a strong family history of depression or PMDD. It is important to recognize symptoms of depression in the new mother, since it may have a negative impact on mother-child bonding and adversely affect early childhood development.

Treatment of PPD includes counseling, support, and medication. With regards to the treatment of major depression during pregnancy, all of the SSRIs are Class C, as described by the Food and Drug Administration. They have been repeatedly shown not to be teratogenic but carry the C rating due to a slight increase in the risk of premature labor. Venlafaxine, mirtazapine, and nefazodone are also Class C. Bupropion is rated Class B in pregnancy. The risks, benefits, and alternatives of using any medication in pregnancy must be carefully weighed and discussed with the patient.

IMPORTANCE OF SMOKING CESSATION FOR PATIENTS WITH DEPRESSION

In a review of strategies for treatment of patients with depression and nicotine addition, Nunes et al reported that nicotine may function as an antidepressant in some patients. Additionally, patients with a history of depression may have more difficulty with smoking cessation than patients who have never been depressed. Smoking cessation itself may trigger depression. (94) Nicotine may also exacerbate depression with long-term use. Therefore, smoking cessation should be considered for incorporation in long-term treatment programs for substance abuse. (95)

Currently, bupropion is the only non-nicotine pharmacologic agent approved for the management of smoking cessation. (96) A noncompetitive inhibitor of nicotinic acetylcholine receptors, this agent appears to interfere with the addictive actions of nicotine. It may also activate the brain's reward-reinforcement circuit--a dopaminergic pathway. (97)

A recent review from researchers at the Mayo Nicotine Dependence Center reported that, when used as a treatment for tobacco dependence, bupropion approximately doubles abstinence rates compared with placebo. (96) Other reports suggest that long-term treatment with bupropion may act to reduce or delay smoking relapse. (96) Furthermore, bupropion has been found to be especially effective in the significant number of smokers who suffer from a depression with features of anxiety; however, patients with comorbid primary anxiety disorders may not respond favorably to bupropion therapy.

Impact of antidepressants on breastfeeding In severe or moderately resistant depression, the use of antidepressants is not contraindicated during breastfeeding. (101) Safety studies have shown the lowest concentration of medication present in breast milk when using paroxetine and fluvoxamine; (104) however, all of the second-generation antidepressants (but not the older MAOIs) are considered safe for breastfeeding mothers, with the exception of nefazodone. (104-106)

Menopause

The use of serotonergic antidepressants to reduce the severity and frequency of hot flashes (as opposed to sweating) is being considered an alternative treatment to hormone therapy. (107-109) The side-effect profiles of these medications, however, do not exactly match the menopausal woman's common complaints of increasing weight and decreasing libido. Options in treating a depressed menopausal woman therefore include the use of a serotonergic antidepressant with a separate therapeutic strategy for libido and weight issues or the use of bupropion with separate therapeutic strategy for the complaint of hot flashes.

POTENTIAL FOR DRUG-DRUG INTERACTIONS

Potential drug-drug and drug-disease interactions may affect treatment decisions. The cytochrome P450 enzymes--3A4, 2D6, 1A2, 2C9, and 2Ci--are involved in drug metabolism. Antidepressants most commonly affect 2D6 and can also affect 3A4. The inhibitory effect of antidepressants on 2D6 is summarized below and appears in the FDA-approved package insert sheets.

In vitro studies have classified fluoxetine and paroxetine as direct or significant 2D6 inhibitors; bupropion and sertraline as 2D6 inhibitors; and citalopram, escitalopram, mirtazapine, nefazodone, and venlafaxine as weak or non-2D6 inhibitors.

In vivo studies using desipramine (dependent on 2D6 for its degradation) have shown fluoxetine, paroxetine, and bupropion have a greater than 200% increase area under the concentration curve (AUC); escitalopram, a 100% increase; citalopram and venlafaxine, a 35% to 50% increase; nefazodone, no change. Sertraline and mirtazapine have not been studied. Important substrates of 2D6 include atomoxetine, dextromethorphan, hydrocodone, mexiletine, paroxetine, propafenone, propranolol, TCAs, and timolol.

Nefazodone is a potent inhibitor of 3A4, increasing alprazolam and buspirone's AUC by 200% and 5,000%, respectively. St. John's wort is an inducer of 3A4 and can decrease the AUC of warfarin. Fluvoxamine, by inhibiting 2C9, can increase the AUC of warfarin. (41)

The cytochrome P450 enzyme 2D6 (CYP2D6) inhibitors may diminish the efficacy of narcotics, affecting the analgesic properties of hydrocodone and dihydrocodeine. Since oxycodone and methadone do not require CYP2D6 for activation, these 2 drugs may be considered as suitable alternatives. (41) SSRIs such as fluoxetine block the conversion of codeine to its more active metabolite morphine, and may have a negative effect on analgesic activity.

REFERENCES

(1.) Katon W, Schulberg H. Epidemiology of depression in primary care. Gen Hosp Psychiatry 1992; 14(4):237-247.

(2.) Kovacs M, Goldston D, Gatsonis C. Suicidal behaviors and childhood-onset depressive disorders: a longitudinal investigation. J Am Acad Adolesc Psychiatry 1993; 32(1):8-20.

(3.) Emslie GJ, Mayes TL, Laptook RS, Batt M. Predictors of response to treatment in children and adolescents with mood disorders. Psychiatr Clin North Am 2003: 26(2):435-456.

(4.) Cassidy LJ. Approaches to recognition and management of childhood psychiatric disorders in pediatric primary care. Pediatr Clin North Am 1998; 45:1037-1052.

(5.) Son SE, Kirchner JT. Depression in children and adolescents. Am Fam Physician 2000; 62(10):2297-2308, 2311-2312.

(6.) Fallon BA. The underdiagnosis of neuropsychiatric Lyme disease in children and adults. Psychiatr Clin North Am 1998; 21(3):693-703.

(7.) Weller EB, Weller RA, Svadjian H. Mood disorders. In: Lewis M, ed. Child and adolescent psychiatry: a comprehensive textbook. Baltimore, MD: Williams and Wilkins, 1996; 650-655.

(8.) Jellenik MS, Snyder JB. Depression and suicide in children and adolescents. Pediatr Rev 1998; 19:255-264.

(9.) Birmaher B, Ryan ND, Williamson DE, Brent DA. Kaufman J, Dahl RE, et al. Childhood and adolescent depression: a review of the past 10 years. Part 1. J Am Acad Child Adolesc Psychiatry 1996;35:1427-1439.

(10.) Emslie GJ, Rush AJ, Weinberg WA, et al. Double-blind, randomized placebo-controlled trial of fluoxetine in depressed children and adolescents. Arch Gen Psychiatry 1997; 54:1031-1037.

(11.) Keller MB. Efficacy of paroxetine in the treatment of adolescent major depressive disorder: a randomized controlled trial. J. Am Acad Child Adolesc Psychiatry 2001: 40:762-772.

(12.) Wagner K, Ambrosini P, Rynn M, et al. Sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 2003; 290(8):1033-1041.

(13.) FDA Talk Paper, 2003. Available at http://www.fda.gov/ bbs/topics/answers/2003/ANSO1234.html.

(14.) Agency for Health Care Policy and Research. Depression in primary care, volume 2. Treatment of major depression: Clinical Practice Guideline Number 5. Rockville, MD: Dept of Health and Human Services: 1997.

(15.) Conn DK. Other dementias and mental disorders due to general medical conditions. In: Sadavoy J, Lazarus LW, Jarvik LF, Grossberg GT, eds. Comprehensive review of Geriatric Psychiatry-II. Washington, DC: American Psychiatric Press; 1996.

(16.) Franco-Bronson K. The management of treatment-resistant depression in the medically ill. Psychiatr Clin North Am 1996; 19(2):329-50.

(17.) Marsh CM. Psychiatric presentations of medical illness. Psychiatr Clin North Amer 1997; 20(1):181-204.

(18.) Hubbard JR, Levenson JL, Patrick GA. Psychiatric side effects associated with the ten most commonly dispensed prescription drugs: a review. J Fam Pract 1991: 33(2):177-186.

(19.) Kohn R. Beta-blockers an important cause of depression: a medical myth without evidence. Med Health R I 2001; 84(3):92-95.

(20.) Kompoliti K, Goetz CG. Neuropharmacology in the elderly. Neurol Clin 1998; 16(3):559-610.

(21.) Stoll AL, Pillay SS, Diamond L, Workum SB, Cole JO. Methylphenidate augmentation of serotonin selective reuptake inhibitors: a case series. J Clin Psychiatry 1996; 57(2):72-76.

(22.) Wallace AE. Double-blind, placebo-controlled trial of methylphenidate in older, depressed, medically ill patients. Am J Psychiatry 1995; 152(6):929-931.

(23.) Kirby D, Harrigan S, Ames D. Hyponatraemia in elderly psychiatric patients treated with Selective Serotonin Reuptake Inhibitors and venlafaxine: a retrospective controlled study in an inpatient unit. Int J Geriatr Psychiatry 2002; 17(3):231-237.

(24.) Bouman WP, Pinner G, Johnson H. Incidence of selective serotonin reuptake inhibitor (SSRI) induced hyponatraemia due to the syndrome of inappropriate antidiuretic hormone (SIADH) secretion in the elderly. Int J Geriatr Psychiatry 1998; 13(1):12-15.

(25.) Liu B, Anderson G, Mittman, To T, Axcell T, Shear N. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 1998; 351(9112):1303-1307.

(26.) Nutt D. Treatment of depression and concomitant anxiety. Eur Neuropsychopharmacol 2000; 10 Suppl 4:S433-437.

(27.) Montgomery SA, Judge R. Treatment of depression with associated anxiety: comparisons of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl 2000; 403:9-16.

(28.) Dunner D, Kumar R. Paroxetine: a review of clinical experience. Pharmacopsychiatry 1998: 31(3):89-101.

(29.) Rush AJ, Trivedi MH, Carmody TJ, et al. Response in relation to baseline anxiety levels in major depressive disorder treated with bupropion sustained release or sertraline. Neuropsychopharmacol 2001; 25(1): 131-188.

(30.) Nierenberg AA, Alpert JE, Pava 3, Rosenbaum JF, Fava M. Course and treatment of atypical depression. J Clin Psychiatry 1998; 59 Suppl 18:5-9.

(31.) Dilsaver SC, Qamar AB, Del Medico VJ. The efficacy of bupropion in winter depression: results of an open trial. J Clin Psychiatry 1992; 53(7):252-255.

(32.) Rudolph RL, Entsuah R, Chitra R. A meta-analysis of the effects of venlafaxine on anxiety associated with depression. J Clin Psychopharmacol 1998; 18(2):136-144.

(33.) Musselman DL, Tomer A, Manatunga AK, et al. Exaggerated platelet reactivity in major depression. Am J Psychiatry 1996; 153(10):1313-1317.

(34.) van den Brink RHS, van Melle JP, Honig A, et al. Treatment of depression after myocardial infarction and the effects on cardiac prognosis and quality of life: rationale and outline of the Myocardial INfarction and Depression-Intervention Trial (MIND-IT). Am Heart J 2002; 144(2):219-225.

(35.) Carney RM, Freedland KE, Eisen SA, Rich MW, Jaffe AS. Major depression and medication adherence in elderly patients with coronary artery disease. Health Psychology 1995; 14(1):88-90.

(36.) Anda R, Williamson D, Jones, et al. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology 1993; 4:285-294

(37.) Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6-month survival. JAMA 1993; 4:295-294.

(38.) Lesperance F, Frasure-Smith N, Talajic M. Major depression before and after myocardial infarction: its nature and consequences. Psychosom Med 1996; 58(2):99-110.

(39.) Steeds RP. Treating depression has been shown to increase compliance with cardiac regimens and can improve global functioning of the patient. Eur Heart J 2001; 21(6):427-429.

(40.) Block SD. Perspectives on care at the close of life. Psychological considerations, growth, and transcendence at the end of life: the art of the possible. JAMA 2001; 285(22):2898-2905.

(41.) Hansten P. A guide to patient management: the top 100 drug interactions, Year 2000. H&H Publications; 2000.

(42.) Glassman AH, O'Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288(6):701-709.

(43.) Frasure-Smith N. Social support, depression, and mortality during the first year after myocardial infarction. Circulation 2000; 101(16):1919-1924.

(44.) Writing Committee for the ENRICHD Investigators. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the enhancing recovery in coronary artery disease patients (ENRICHD) randomized trial. JAMA 2003; 289(23):3106-3116.

(45.) Roose SP, Dalack GW, Glassman AH, Woodring S, Walsh BT, Giardina EG. Cardiovascular effects of bupropion in depressed patients with

heart disease. Am J Psychiatry 1991; 148(4):512-516.

(46.) Ludvig J, Eisenberg M. Smoking cessation: options for patients. Perspectives in Cardiology 2002; October 39-44.

(47.) Carney C. Diabetes mellitus and major depressive disorder: an overview of prevalence, complications, and treatment. Depress Anxiety 1998; 7(4)149-157.

(48.) National Institute of Mental Health. The strategic plan for mood disorders research. Washington, DC: NIMH; 2002.

(49.) Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999; 1134-1146.

(50.) Lustman PJ, Clouse RE, Tankosic T. Managing depression in patients with diabetes. Primary Care Special Edition 2001; 5(1):19-21.

(51.) Goodnick PJ, Henry J, Buki V. Treatment of depression in patients with diabetes mellitus. J Clin Psychiatry 1995; 56(4):128-136.

(52.) Goodnick PJ. Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy. Ann Clin Psychiatry 2001; 13(1):31-41.

(53.) Simmons Z, Feldman EL Update on diabetic neuropathy. Curr Opin Neurol 2002; 15(5):595-603.

(54.) Dixon JB, Dixon ME, O'Brien PE. Depression in association with severe obesity: changes with weight loss. Arch Intern Med 2003; 163(17):2058-2065.

(55.) Roberts RE, Deleger S, Strawbridge WJ, Kaplan GA. Prospective association between obesity and depression: evidence from the Alameda County Study. Int J Obes 2003; 27:514-521.

(56.) Fava M. Weight gain and antidepressants. J Clin Psychiatry 2000; 61(Suppl: 11):31-47.

(57.) Sussman N, Ginsberg DL. Weight gain associated with SSRIs. Primary Psychiatry 1998; 5:28-37.

(58.) Richelson E. Weight gain on SSRIs: a paradox? Primary Psychiatry 1998; 5:40-41.

(59.) Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psych 1996; 153(4):466-476.

(60.) Alcantara AG. A possible dopaminergic mechanism in the serotonergic antidepressant-induced sexual dysfunctions J Sex Marital Ther 1999; 25(2):125-129.

(61.) Dewey SL, Smith GS, Logan J, et al. Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in vivo microdialysis. J Neurosci 1995; 15:821-829.

(62.) Jain AK, Kaplan RA, Gadde KM, et al. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res 2002; 10:1049-1056.

(63.) Gadde KM, Parker CB, Maner LG, et al. Bupropion for weight loss: an investigation of efficacy and tolerability in overweight and obese women. Obes Res 2001; 9:544-551.

(64.) Croft H, Houser TL, Jamerson BD, et al. Effect on body weight of bupropion sustained-release in patients with major depression treated for 52 weeks. Clin Ther 2002; 24(4):662-672.

(65.) Fishbain DA. Approaches to treatment decisions for psychiatric comorbidity in the management of the chronic pain patient. Med Clin North Amer 1999; 83(3):737-760.

(66.) Hagglund KJ, Haley WE, Reveille JD, Alarcon GS. Predicting individual differences in pain and functional impairment among patients with rheumatoid arthritis. Arthritis Rheum 1989; 32(7):851-858.

(67.) Semenchuk MR, Davis B. Efficacy of sustained-release bupropion in neuropathic pain: an open-label study. Clin J Pain 2000; 16(1):6-11.

(68.) Tasmuth T, Hartel B, Kalso E. Venlafaxine in neuropathic pain following treatment of breast cancer. Eur J Pain 2002; 6(1):17-24,

(69.) Steiner TJ, Ahmed F, Findley LJ, MacGregor EA, Wilkinson M. S-fluoxetine in the prophylaxis of migraine: a phase 11 double-blind randomized placebo-controlled study. Cephalalgia 1998; 18(5):283-286.

(70.) Adly C, Straumanis J, Chesson A. Fluoxetine prophylaxis of migraine. Headache 1992; 32(2):101-104.

(71.) Silberstein SD, Lipton RB. Overview of diagnosis and treatment of migraine. Neurol 1994; 44(10 Suppl 7):S6-16.

(72.) Merikangas KR, Stevens DE. Comorbidity of migraine and psychiatric disorders. Neurol Clin 1997; 15(1):115-123.

(73.) Kanner A, Balabanov A. Depression and epilepsy: how closely related are they? Neurol 2002; 58:8 Suppl 5:S27-39.

(75.) Wiegartz P, Seidenberg M, Woodard A, Gidal B, Hermann B. Co-morbid psychiatric disorder in chronic epilepsy: recognition and etiology of depression. Neurol 1999; 53(5 Suppl 2):S3-8.

(76.) Calabrese JR, Bowden CL, McElroy SL, et al. Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder. Am J Psychiatry 1999; 156(7):1019-1023.

(77.) Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000; 20(6):607-614.

(78.) Harden CL. The co-morbidity of depression and epilepsy: epidemiology, etiology, and treatment. Neurol 2002; 59:6 Suppl 4:S48-55.

(79.) Sedgwick EM, Edwards JG. Assessment of electroencephalographic changes during treatment with psychotropic drugs. Neuropharmacol 1984; 23(2B):265-267.

(80.) Duncan J. Modern treatment strategies for patients with epilepsy: a review. J R Soc Med 1991; 84(3):159-162.

(81.) Curran S, de Pauw K. Selecting an antidepressant for use in a patient with epilepsy. Drug Safety 1998; 18(2):125-133.

(82.) Alpert JE, Maddocks A, Nierenberg AA, et al. Attention deficit hyperactivity disorder in childhood among adults with major depression. Psychiatry Res 1996; 62(3):213-219.

(83.) Searight HR, Burke JM, Rottnek F. Adult ADHD: evaluation and treatment in family medicine. Am Fam Physician 2000; 62(9):2077-2086, 2091-2092.

(84.) Spencer T. Attention-deficit/hyperactivity disorder and comorbidity. Pediatr Clin North Am 1999; 46(5):915-927.

(85.) Casat CD, Pleasants DZ, Fleet JVW. A double-blind trial of bupropion in children with attention deficit disorder. Psychopharmacol Bull 1987; 23:120-122.

(87.) Barrickman LL, Perry PJ, Allen AJ, et al. Bupropion versus methylphenidate in the treatment of attention deficit disorder. J Am Acad Child Adolesc Psychiatry 1995; 34(5):649-657.

(88.) Conners CK, Casat CD, Gualtieri CT, et al. Bupropion hydrochloride in attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 1996; 35:1314-1321.

(89.) Wilens TE, Spencer TJ, Biederman J, et al. A controlled clinical trial of bupropion for attention deficit hyperactivity disorder in adults. Am J Psychiatry 2001; 158(2):282-288.

(90.) Davis WB, Bentivoglio P, Racusin R, Brown KM, Bostic JQ, Wiley L. Bupropion sustained release in adolescents with comorbid attention-deficit/hyperactivity disorder and depression. J Am Acad Child Adolesc Psychiatry 2001; 40(3):307-314.

(91.) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: APA; 2000.

(92.) Mason BJ, Kocsis JH, Ritvo EC, Cutler RB. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression. JAMA 1996; 275(10):761-767.

(93.) Drake RE, Wallach MA, Hoffman JS. Housing instability and homelessness among aftercare patients of an urban state hospital. Hosp Community Psychiatry 1989; 40(1):46-51.

(94.) Nunes EV, Deliyannides D, Donovan S, McGrath PJ. The management of treatment resistance in depressed patients with substance abuse disorders. Psych Clin North Amer 1996; 19(2):311-325.

(95.) Glassman AH, Covey LS, Dalack GW, et al. Smoking cessation, clonidine, and vulnerability to nicotine among dependent smokers. Clin Pharmacol Ther 1993; 54(6):670-679.

(96.) Hays JT, Ebbert JO. Bupropion for the treatment of tobacco dependence: guidelines for balancing risks and benefits. CNS Drugs 2003; 17(2):71-83.

(97.) Nestler EJ. Cellular and molecular mechanisms of addiction. In: Charney DS, Nestler EJ, Bunney BS, eds. Neurobiology of Mental Illness. New York: Oxford University Press; 1999: 578-590.

(98.) Dackis CA, Gold MS, Pottash AL, Sweeney DR. Evaluating depression in alcoholics. Psychiatry Res 1986 17(2):105-109.

(99.) Gorelick DA, Paredes A. Effect of fluoxetine on alcohol consumption in male alcoholics. Alcohol Clin Exp Res 1992; 16(2):261-265.

(100.) Szewczyk M, Chennault SA. Women's health. Depression and related disorders. Prim Care 1997; 24(1):83-101.

(101.) Epperson CN. Postpartum major depression: detection and treatment. Am Faro Phys 1999; 59(8):2247-2254, 2259-2260.

(102.) Steiner M, Steinberg S, Stewart D, et al. Fluoxetine in the treatment of premenstrual dysphoria. Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group. N Engl J Med 1995 332(23):1529-1534.

(103.) Freeman EW, Richels K, Sondheimer SJ, Denis A, Pfeirfer S, Weil S. Nefazodone in the treatment of premenstrual syndrome: a preliminary study. J Clin Psychopharmacol 1994; 14(3):180-186.

(104.) Henrick V, Fukuchi A, Altschuler L, Widawski M, Wertheimer A, Brunhuber MV. Use of sertraline, paroxetine and fluvoxamine by nursing women. Br J Psychiatry 2001; 179:163-166.

(105.) Baab SW, Peindl KS, Pointek CM, Wisner KL. Serum bupropion levels in 2 breastfeeding mother-infant pairs. J Clin Psychiatry 2002; 63(10):910.

(106.) Yapp P, Ilett KF, Kristensen JH, Hackett LE Paeh M J, Pampono J. Drowsiness and poor feeding in a breast-fed infant: association with nefazodone and its metabolites. Ann Pharmacother 2000; 34(11):1269-1272.

(107.) Joffe H, Soares CN, Cohen LS. Assessment and treatment of hot flashes and menopausal mood disturbance. Psychiatr Clin North Am 2003; 26(3):553-580.

(108.) Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003; 289(21):2827-2834.

(109.) Soares CN, Poitras JR, Prouty J, Alexander AB, Shifren JL, Cohen LS. Efficacy of citalopram as a monotherapy or as an adjunctive treatment to estrogen therapy for perimenopausal and postmenopausal women with depression and vasomotor symptoms. J Clin Psychiatry 2003; 64(4):473-479.

Adam Keller Ashton, MD

Clinical Professor of Psychiatry

SUNY at Buffalo School of Medicine

Buffalo, NY

Dr Ashton is a clinical associate professor of Psychiatry at the State University of New York in Buffalo, and is in fulltime private practice with the Buffalo Medical Group. He has written extensively for psychiatric journals on treatment-induced sexual dysfunction. He is a distinguished clinical fellow of the American Psychiatric Association.

Dr Ashton received his medical degree from the State University of New York at Buffalo School of Medicine after completing his master's degree at the same facility. He completed his residency also at the State University of New York at Buffalo with subsequent training in sex therapy at the Robert Wood Johnson School of Medicine in New Jersey.

Dale A. O'Mello, MD

Associate Professor

Department of Psychiatry

Michigan State University

Lansing, MI

Dr D'Mello is an associate professor in the department of psychiatry at Michigan State University. Dr D'Mello is the medical director for MSU Inpatient Psychiatry at St. Lawrence Hospital and serves on the editorial board for Journal of Psychotic Disorders. Dr D'Mello is a member of the American Psychiatric Association and the American Academy of Clinical Psychiatrists. He has a special interest in pharmacologic management of psychotic disorders and biological and social concomitants of major psychoses and affective disorders.

Dr D'Mello received his medical degree from Bombay University, Bombay, India and completed his residency in psychiatry at Michigan State University in East Lansing.

Bezalel Dantz, MD

Assistant Professor of Clinical Medicine and Psychiatry

University of Chicago

Chicago, IL

Dr Dantz is an assistant professor of clinical medicine and psychiatry at the University of Chicago. He is the director of the Behavioral Medicine Clinic at the University of Chicago Hospital and is a primary care physician there as well. His main interest is in training non-psychiatric clinicians to recognize and treat mental health disorders. He lectures on the interface between medical and psychiatric disorders, and writes about psychiatric aspects of medicine.

Dr Dantz received his medical degree from Stanford University School of Medicine in Stanford, CA, and completed residencies in both internal medicine and psychiatry at the New York Presbyterian Hospital-Cornell Medical Center in New York City, NY.

Jaye Hefner, MD

Assistant Professor of Medicine

University of Pittsburgh Medical Center

Pittsburgh, PA

Dr Hefner is an assistant professor of medicine in the section of general internal medicine, division of medicine at the University of Pittsburgh Medical Center (UPMC). She serves as director of Women's Health at UMPC Shadyside Hospital and is the medical director of the UMPC Weight Management Center and the UMPC Magee-Women's Hospital Comprehensive Healthcare Center for Women with Physical Disabilities. She is the site director for the 2nd-, 3rd-, and 4th-year medical school clerkships in internal medicine. Dr Hefner has published and lectured in the areas of women's health, medical education, and physical medicine and rehabilitation. Dr Hefner has received funding for research in the areas of hypertension, depression, weight management, disability medicine, and migraine headaches.

Dr Hefner received her medical degree at Northeastern Ohio Universities College of Medicine. She completed an internal medicine residency and a fellowship in general internal medicine/women's health at the University of Pittsburgh Medical Center. She is board certified in internal medicine and has a dual appointment with the departments of internal medicine and physical medicine and rehabilitation.

F. George Leon, MD

Medical Director

Leon Medical Center

Waldorf, MD

Dr Leon is medical director of the Leon Medical Center, a family practice group, combined with a multispecialty group practice. He is a member and diplomat of the American Academy of Family Practice and the American Board of Family Medicine. Dr Leon has special interest in chronic pain management psychopharmacology, fibromyalgia, Lyme disease, and nutritional medicine.

Dr Leon received his medical degree from the University of Zaragoza in Zaragoza, Spain. He completed his pediatric internship at Thomas Jefferson University Hospital in Philadelphia, PA, and his family practice residency at Polyclinic Medical Center in Harrisburg, PA.

Gary A. Matson, MD

Primary Care Practice

Fresno, CA

Dr Matson is board-certified in family practice. In addition to a private primary care practice, he is medical director of a weight management program for Sante Community Physicians. His educational video on the obese teenager is now used throughout the school systems.

Dr Matson received a medical degree from Georgetown University School of Medicine and completed a residency through University of California, San Francisco, UCSF-San Joaquin Valley. Dr Matson also has an undergraduate degree in psychology and a master of science degree in physiology.

C. Brendan Montano, MD

Assistant Clinical Instructor

Department of Family Practice

University of Connecticut Medical School

Private Practice

Cromwell, CT

Dr Montano is an assistant clinical instructor at the University of Connecticut School of Medicine in the Department of Family Practice in Farmington, CT. He practices internal and preventative medicine in Cromwell, CT, with a special interest in treating depression and anxiety disorders. He also serves as the director of Connecticut Clinical Research.

Dr Montano earned his bachelor's degree from the College of The Holy Cross in Worcester, MA, and his medical degree from Albany Medical College in Albany, NY. In 1972, Dr Montano served as chief medical resident at St. Francis Hospital in Hartford, CT, where he completed his residency training in internal medicine.

Dr Montano is recognized internationally as an expert in the recognition and treatment of mood disorders in the primary care setting. In 1998, he presented his interview techniques at a tutorial for the World Health Organization at the AEP congress in Copenhagen. Dr Montano presents CME conferences and lectures through a variety of media. He has authored several articles in the Journal of Clinical Psychiatry.

James F. Pradko, MSc, MD

Family Practice

Director Bay Pointe Depression Clinic

New Baltimore, Michigan

Dr Pradko is in private family practice in New Baltimore, MI, on staff at Mount Clemens General Hospital, and is a part-time instructor in the department of family practice at St. John Hospital in Detroit, MI. In addition, he is the director of Bay Pointe Depression Clinic, which specializes in treating the side effects caused by antidepressants. Dr Pradko lectures nationally on the topic of neurotransmitters and antidepressants. He conducts research in the areas of antidepressant-induced sexual dysfunction and serotonin fatigue. His most recent research appeared in the May 2002 issue of the Journal of Clinical Psychiatry.

Dr Pradko received his master of science (theoretical physics) and medical degree from the University of Alberta, Canada. He completed his internship at the University of Toronto and his residency in family medicine at St. John Hospital in Detroit, MI.

Norman Sussman, MD

Professor of Psychiatry

New York University School of Medicine

New York, New York

Dr Sussman is a professor of psychiatry at the New York University School of Medicine. He is a graduate of New York Medical College and completed his internship and residency at Metropolitan Hospital in New York City and the Westchester County Medical Center in Valhalla, NY.

He has served as director of residency training at the NYU Medical Center for 4 years and is currently co-director of the Center for Study of Depression in Parkinson's Disease at the NYU Medical Center. He is editor of the journal Primary Psychiatry, and has been a contributor to The Comprehensive Textbook of Psychiatry for the past 6 editions. He is consulting editor for the next edition of The Comprehensive Textbook of Psychiatry and the current edition of The Handbook of Psychiatric Drug Therapy.

Dr Sussman's research activities have included studies of various psychotropic drugs. He is also a frequent contributor to medical literature. Dr Sussman is a Fellow of the American Psychiatric Association and a member of the American Medical Association. He also serves on the Board of Governors of the NYU/Bellevue Psychiatric Society.

Bertrand Winsberg, MS, MD

Research Professor

Department of Psychiatry

New York University School of Medicine

New York City, New York

Dr Winsberg is a research professor in psychiatry at NYU Medical School and an attending physician in child psychiatry and pediatrics at Brookdale University Hospital and Medical Center in Brooklyn, NY. He has conducted research in developmental and pediatric neuropsychiatry with a special interest in pediatric psychopharmacology. Recent work includes molecular genetic mechanisms of drug response to stimulant medication. He is a reviewer for the American Journal of Psychiatry and the recipient of research grants from the NIH. His work on the dopamine transporter received a National Research Award from the American Academy of Child and Adolescent Psychiatry.

Dr Winsberg received his medical degree from the University of Michigan, where he also completed his training in adult psychiatry. He completed his training in child psychiatry at the University of Michigan and developmental pediatrics at Mount Sinai Hospital in New York. Current research interests include the neurohormonal basis of weight gain with atypical antipsychotic drugs in children.
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Author:Leon, F. George; Ashton, Adam Keller; D'Mello, Dale A.; Dantz, Bezalel; Hefner, Jaye; Matson, Gary A
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Dec 1, 2003
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