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Summary: Slide 1. Co-Occurring Mania and ADHD in Youths***Slide 2. Evidence suggests that co-occurrence with ADHD is a marker of preadolescent-onset mania. This article provides some of this evidence so that you may be able to decide whether this form of very early-onset mania represents a developmental subtype of the disorder.Source: The Clinical and Treatment Implications of Co-Occurring Mania and ADHD in Youths.***Slide 3. Among children with bipolar disorder, rates of co-occurring ADHD range from 57% to 98%, with higher, almost universal rates among prepubertal children.Source: Faraone SV, Biederman J, Wozniak J, et al. Is comorbidity with ADHD a marker for juvenile onset mania? J Am Acad Child Adolesc Psychiatry. 1997;36: 1046-1055.***Slide 4. Higher rates of ADHD were found in persons with childhood-onset bipolar disorder compared with persons with adolescent-onset bipolar disorder.Source: Faraone SV, Biederman J, Wozniak J, et al. Is comorbidity with ADHD a marker for juvenile onset mania? J Am Acad Child Adolesc Psychiatry. 1997;36: 1046-1055.***Slide 5. In a longitudinal study of boys with ADHD, 17% were found to have co-occurring bipolar disorder at baseline.Source: Biederman J, Mick E, Faraone SV, et al. A prospective follow-up study of pediatric bipolar disorder in boys with attention-deficit/hyperactivity disorder. J Affect Disord. 2004;82(suppl 1):S17-23.***Â Â Â Â Â Â Â  Slide 6. Children who meet the criteria for ADHD show high rates of conduct and oppositional defiant disorders and of learning disorders and need for academic support. Depression and psychosis as well as poor functioning-all common correlates of bipolar disorder-are also usually present.Source: Wozniak J, Biederman J, Faraone SV, et al. Heterogeneity of childhood conduct disorder: further evidence of a subtype of conduct disorder linked to bipolar disorder. J Affect Disord. 2001;64:121-131.***Slide 7. In a longitudinal study of boys with ADHD, 17% were found to have co-occurring bipolar disorder at baseline.Source: Biederman J, Mick E, Faraone SV, et al. A prospective follow-up study of pediatric bipolar disorder in boys with attention-deficit/hyperactivity disorder. J Affect Disord. 2004;82(suppl 1):S17-23.Note: This slideshow was originally published January 9, 2014 and has since been updated.

Evidence suggests that co-occurrence with ADHD is a marker of preadolescent-onset mania. This slideshow provides some evidence for you to decide whether this form of very early-onset mania represents a developmental subtype of the disorder.

Co-Occurring Mania and ADHD in Youths

CME credit for this article is now expired. It appears here for informational purposes only.

After reading this article, you will be familiar with:



• Complementary and alternative medicine (CAM) modalities available for the treatment of depressed mood
• Indications for use of CAM
• Effectiveness and safety issues associated with the different CAM modalities

Every year one-third of the adults in the United States use 1 or more 

 (CAM) modalities to treat a medical or psychiatric problem.

 It is estimated that 1 in 10 adults see CAM practitioners, and he or she does so primarily for a mental health problem.

 A large population survey found that receiving a diagnosis of a mood disorder is a strong predictor of CAM use.

 Another survey found that persons with major depressive disorder were significantly more likely to use CAM therapies than nondepressed persons.

 Almost two-thirds of psychiatrically hospitalized patients use at least 1 CAM modality before being hospitalized, and the majority self-treat depressed mood while failing to disclose CAM use to their psychiatrist or primary physician.

Most persons who use CAM modalities to self-treat a mental health problem take prescription antidepressants concurrently. Combined use can result in serious supplement-drug interactions.

Because of the high prevalence of CAM use among patients with mental illness, and especially among persons with major depressive disorder, it is important to examine the efficacy and safety evidence of CAM modalities used as either monotherapies or in combination with conventional pharmacological agents to treat depressed mood.

Select natural products used to treat depressed mood have been examined in well-designed, placebo-controlled, double-blind studies and in systematic reviews. Natural products used as stand-alone treatments of depressed mood include St John’s wort (

); S-adenosyl-L-methionine (SAMe); 5-hydroxytryptophan (5-HTP); folic acid; omega-3 essential fatty acids; and to a lesser extent, acetyl-L-carnitine (ALC) and dihydroepiandrosterone (DHEA). Some of these naturally occurring substances have also been evaluated in controlled trials for their potential role as adjuvants to conventional antidepressants. Two publications review the research evidence for natural products used to treat depressed mood.

This article is offered as a concise summary of research and clinical treatment issues pertaining to select natural products for which there is significant evidence. The 

 presents natural products commonly used to treat depressed mood as both monotherapies and adjuvants in combination with antidepressants.

Depressed mood is commonly seen in patients with folate deficiency, and refractory depressed mood is often associated with low serum levels of folate and vitamin B12.

 Low serum folate levels are associated with increased risk of relapse in patients who have successfully responded to fluoxetine or other antidepressants.

 Folate is an essential cofactor in the synthesis of SAMe, which has established antidepressant efficacy.

small randomized placebo-controlled trial

, depressed patients treated with a combination of folic acid (0.5 mg) plus fluoxetine experienced significantly greater improvements in mood than the fluoxetine-only group.

 Significantly, only women experienced a differential beneficial response to folate augmentation. The researchers theorized that this gender difference may be caused by a relatively higher male requirement for folate to efficiently convert homocysteine back to SAMe.

It has been suggested that the optimal form of folate for depressed mood is folinic acid because it more readily crosses the blood-brain barrier.

 This is consistent with cases of patients with treatment-refractory depression who responded to antidepressants when folinic acid was added to their regimen.

The authors of a systematic review of placebo-controlled studies of folate in depressed mood (N = 247) commented that folate may have a potential role as an adjuvant to pharmacological treatments of depressed mood.

 Sarris and colleagues6 have remarked that failure to take into account vitamins B12 (cobalamin) and B6 (pyridoxine) status may confound studies of folate or SAMe in patients with depressed mood in that remethylation of homocysteine to SAMe requires B12, and synthesis of all monoamine neurotransmitters requires B6.

Depressed patients with relatively higher serum vitamin B12 levels have shown a more robust response with antidepressants than matched patients with lower B12 levels.

 On this basis, B12 supplementation (800 

g/d) has been suggested as adjuvant therapy for 

Case reports suggest that some depressed patients experience consistent improvements in mood and energy with 50 mg/d of thiamine.

A daily dose of 400 to 800 IU of vitamin D noticeably improved mood in patients with seasonal affective disorder after 5 days.

Several mechanisms of action underlie the putative antidepressant effects of omega-3 essential fatty acids-including increased CNS serotonin activity, anti-inflammatory effects, suppression of phosphatidyl-inositol second messenger activity, and increased heart rate variability.

 Blood cell membrane levels as well as serum levels of the omega-3 essential fatty acid docosahexaenoic acid (DHA) may be consistently lower in persons with depression.

Preliminary findings suggest that the average dietary ratio of omega-6 to omega-3 essential fatty acids is correlated with the incidence of depressed mood. Lower dietary intake of foods rich in omega-3 fatty acids results in relatively higher ratios of arachidonic acid (AA) (an omega-6) to eicosapentaenoic acid (EPA) (an omega-3) in red blood cells, which in turn may be positively correlated with relatively greater severity of depressed mood.

Food preferences that influence fatty acid consumption may be related to varying prevalence rates of depressed mood when industrialized countries are compared with more traditional cultures. Findings of epidemiological surveys suggest that risk of depressed mood and fish consumption are inversely related; however, the results of prospective trials are inconsistent. Countries in which fish is a central part of the average diet have significantly lower rates of depressed mood and suicide.

A large prospective study showed that the incidence of depressed mood declined as dietary intake of omega-3s increased relative to omega-6 fatty acids.

 What is significant is that relatively greater intake of omega-3 fatty acids was correlated with lower C-reactive protein levels, which suggests an overall reduction in inflammation. Equivocal findings from other studies obscure the relationship between a high-fish diet and the risk of depressed mood. In a large, prospective, 6-month trial (N = 452), men with histories of cardiovascular disease were randomized to a diet high in fatty fish or a diet without fish. There were no significant differences between the 2 groups in the number of new cases of depressed mood.

Principal dietary sources of omega-3s include salmon, halibut, other deep-sea fish, certain algae products, and flaxseed oil.

Findings on purified omega-3s as stand-alone treatments of depressed mood are inconsistent. A study of 2 g of DHA daily for depressed mood found no benefit over placebo.

 However, a study that compared 3 regimens of DHA found greater antidepressant efficacy at 1 g daily than at 2 and 4 g daily.

Findings of controlled trials of omega-3s in pregnant and postpartum women with depression have been inconsistent. One small study found that in pregnant, depressed women who took a combined formula of EPA and DHA, symptoms improved more than in matched women who were given placebo.

 Nevertheless, 2 small placebo-controlled trials failed to confirm the beneficial effects of omega-3s in pregnant and postpartum depressed women.

The results from meta-analyses of placebo-controlled trials confirm the efficacy of purified omega-3 supplement as adjuvant therapy in both unipolar and bipolar depressed mood.

 A placebo-controlled study of omega-3s as adjuvants to antidepressants failed to show benefit over placebo.

In a subsequent controlled trial (N = 60), unipolar depressed patients were randomized to omega-3s (1 g of EPA), to fluoxetine (20 mg/d), or to a combination of these agents. There were equivalent improvements in mood, but the group taking the combination improved more than the other 2 groups.

Research findings suggest that EPA is probably more beneficial than DHA and that lower doses of EPA (1 to 2 g/d) are as effective as higher doses and are associated with minimal adverse effects.

Adverse effects associated with omega-3s are relatively minor. GI adverse effects have been reported.

 There has been 1 case report of increased bleeding risk when omega-3 fatty acids were used with warfarin.

In Western Europe and the United States, St John’s wort is the most widely used natural product to treat depressed mood. Discrete bioactive constituents of St John’s wort function as serotonin reuptake inhibitors; they decrease benzodiazepine receptor binding, weakly inhibit monoamine oxidase (MAO), and may have binding affinity to 

Hyperforin probably contributes more to the antidepressant effect of St John’s wort than hypericin, although many commercial preparations are standardized to 0.3% hypericin.

 Speculation about the primary antidepressant role of hyperforin has led to problems when comparing recent studies with early studies that did not control for that bioactive constituent. In response to these concerns, many St John’s wort preparations are now standardized to both hypericin and hyperforin.

More than 30 double-blind controlled trials on St John’s wort for depressed mood have been conducted. Ten placebo-controlled studies demonstrated equivalent efficacy of St John’s wort and tricyclic antidepressants, and 3 studies confirmed equivalent efficacy to SSRIs: fluoxetine, sertraline, and paroxetine.

A Cochrane review of 27 trials (N > 2200), 17 of which were placebo-controlled, concluded that St John’s wort is significantly more effective than placebo for mild to moderate symptoms of depressed mood.

However, a meta-analysis that used more stringent inclusion criteria that controlled for publication bias and small study ef-fects found a significantly smaller antidepressant effect.

Results from a large NIH-sponsored multicenter study suggest that St John’s wort and sertraline are equally ineffective against severe depressed mood, and neither treatment is more effective than placebo.

 The validity of the NIH study findings has been criticized because of serious design flaws, including the use of subtherapeutic doses of both St John’s wort and sertraline, short duration, lack of statistical power, and selective recruitment of severely depressed patients who had previously been refractory to multiple antidepressants.

In a follow-up study to the NIH study, most nonresponders (n = 95) to a standardized St John’s wort preparation responded to conventional antidepressants with significant improvements in depressed mood.

 This suggests that antidepressants are more effective than St John’s wort in refractory depressed mood, and it reopens the question of a possibly significant placebo effect of St John’s wort.

Uncommon adverse effects of St John’s wort include upset stomach, feelings of restlessness, and mild sedation. There are no published cases of serotonin syndrome or other serious adverse effects when St John’s wort is used at recommended doses, but there are several case reports of possible serotonin syndrome when St John’s wort and a conventional antidepressant are used together.

 Caution pregnant women against using St John’s wort. Although no case reports have definitively linked St John’s wort to serious interactions with MAO inhibitors (MAOIs), their combined use should be avoided. Significant safety concerns exist when St John’s wort is used concurrently with protease inhibitors, immunosuppressive agents, warfarin, digoxin, and oral contraceptives.

Michael is a fit 42-year-old insurance salesman with no medical problems who has experienced depressed mood of moderate severity since his mid-30s. Although his symptoms have responded to conventional antidepressants, he has gained 20 lb and he has had relationship problems because of diminished libido. On the advice of a naturopathic physician, Michael tapered and discontinued his SSRI over 2 weeks and then started a trial of a reputable brand of St John’s wort. After 2 weeks, he is taking 300 mg of St John’s wort 3 times a day without adverse effects. One month later his mood is stable, he has lost 10 lb, and his libido has improved.

SAMe functions as a methyl donor and is required for synthesis of several important neurotransmitters. Antidepressant effects of SAMe are probably achieved through increased CNS levels of serotonin, dopamine, and norepinephrine. The synthesis of all 3 neurotransmitters by SAMe requires vitamin B12, folate, and vitamin B6. A meta-analysis of placebo-controlled trials on SAMe in depressed mood (N = 1015) confirmed antidepressant efficacy equivalent or superior to synthetic antidepressants.

 It should be noted that most studies were based on parenteral or intramuscular administration of SAMe, which are accepted forms of treatment in Europe. An effective dose is significantly smaller when SAMe is administered parenterally, and few adverse effects have been reported.

A large multicenter, double-blind, randomized, placebo-controlled trial showed that oral SAMe 1600 mg daily (in divided doses) and imipramine 150 mg daily had equivalent efficacy while SAMe was associated with significantly fewer adverse effects.

 Two multicenter studies demonstrated equivalent efficacy between 400 mg of SAMe administered by intramuscular injection and 150 mg of oral imipramine.

Findings of a small open trial suggest that 800 to 1600 mg of SAMe daily in combination with an antidepressant improves overall response, is effective in patients who had previously been treatment-refractory to antidepressants, and accelerates the response rate.

 There is evidence that SAMe is an effective adjuvant when taken with conventional antidepressants in the absence of serious safety issues (SAMe should be avoided in bipolar depressed patients because of a small but significant risk of mania induction).

 Case reports of patients using this protocol suggest that antidepressant doses can be reduced by as much as 30%, with fewer adverse effects and improvements in medication adherence. Two large, placebo-controlled, NIMH-sponsored trials of SAMe as monotherapy and as an adjuvant to antidepressants in treatment nonresponders are ongoing.

The advantages of SAMe over synthetic antidepressants include relatively rapid onset of action-usually within 1 week of starting treatment-the absence of clinically significant interactions with drugs, and relatively few adverse effects compared with conventional antidepressants. The standard maintenance regimen for depressed mood is between 800 and 1600 mg in 2 to 4 divided doses. Absorption is improved when SAMe is taken before meals. The butane-disulfonate form of SAMe has significantly greater bioavailability than the tosylate form, and it is available as an enteric-coated tablet for longer shelf life.

SAMe is generally well tolerated; however, transient anxiety, insomnia, GI adverse effects, dry mouth, and dizziness have been reported. Cases of hypomania have been reported in patients with bipolar disorder; therefore, patients with bipolar depression who take SAMe should be carefully monitored.

5-HTP and L-tryptophan are amino acid precursors required for serotonin synthesis. Both have been extensively evaluated for their antidepressant efficacy. 5-HTP is generally preferred because it crosses the blood-brain barrier at a higher rate, is converted into serotonin more efficiently than l-tryptophan, and has more marked antidepressant effects.

The use of L-tryptophan to treat depressed mood originated in response to findings that serum L-tryptophan levels are often low in depressed patients and tend to normalize following successful response to treatment.

 Two early, double-blind, placebo-controlled studies reported that 6 to 9 g of l-tryptophan and 150 mg of imipramine daily have equivalent antidepressant efficacy.

 However research findings of controlled trials on L-tryptophan as monotherapy in depressed mood are inconsistent and limited by small study sizes and methodological problems.

Combining 2 g of L-tryptophan with 20 mg of fluoxetine resulted in a more rapid antidepressant response and improved sleep quality in depressed patients with chronic insomnia.

L-tryptophan is typically used at night because of its sedating properties and is dosed between 1500 and 5000 mg depending on therapeutic response.

Uncommon adverse effects of L-tryptophan include drowsiness, dry mouth, and blurred vision. In the late 1980s and early 1990s, 1500 cases of eosinophilia-myalgia syndrome and 37 deaths of patients taking L-tryptophan were reported. All cases of eosinophilia-myalgia syndrome were traced to contaminants in a single batch of an over-the-counter L-tryptophan preparation.

 The manufacturing problem that resulted in the contaminated batch was identified and rapidly corrected. There have been no subsequent reports of eosinophilia-myalgia syndrome associated with L-tryptophan.

5-HTP begins to have antidepressant effects at dosages between 100 and 300 mg/d. Early case reports suggest that treatment-refractory patients sometimes improve when 300 mg of 5-HTP is used as an adjuvant to carbidopa, tricyclic antidepressants, MAOIs, or SSRIs,

 but no placebo-controlled trials have confirmed this. A Cochrane review of studies of 5-HTP or L-tryptophan in depressed mood identified 108 controlled trials, but analysis of findings was limited to only 2 studies (N = 64) because of small study size, heterogeneity of study designs, and methodological flaws.

 The reviewers remarked that 5-HTP is probably more effective than placebo for depressed mood but were unable to offer more definitive conclusions. Like L-tryptophan, 5-HTP is moderately sedating, and doses greater than 100 mg are typically taken at bedtime.

ALC has general neuroprotective effects and is believed to improve mood and reduce the severity of cognitive impairments in normal aging, dementia, or traumatic brain injury. ALC enhances mitochondrial energy production and partially compensates for deficits in CNS cholinergic activity. ALC has been studied in placebo-controlled, double-blind trials in severely depressed patients, elderly depressed patients, and depressed patients with dementia.

 Most studies have evaluated ALC in elderly depressed patients and have demonstrated antidepressant effects after about 1 month of treatment at dosages between 1 and 3 g daily.

In a 2-month, placebo-controlled trial, depressed patients with dementia who were randomized to 3 g of ALC daily, in divided doses, experienced significantly greater improvements in mood and global functioning than those who were given placebo.

 In a small, double-blind, cross-over study of hospitalized elderly patients who were depressed, ALC was shown to have superior antidepressant efficacy over placebo.

 In a small, double-blind, placebo-controlled study (N = 28) half of the elderly patients with severe depression who were treated with ALC, 500 mg 4 times a day, experienced full remission, and their previously elevated serum cortisol levels normalized.

Fewer studies have been done of ALC than of other natural products used to treat depressed mood, and no studies have been undertaken to compare ALC with antidepressants. A recent review of controlled studies of ALC in depressed mood found preliminary evidence for therapeutic benefits in elderly patients with depression, including possibly cognitive-enhancing effects.

Most studies of ALC in depressed mood report few or no adverse effects. ALC may be safely used in combination with antidepressants, but studies have not been done to evaluate possible adjuvant benefits. In depressed patients who are elderly or have dementia, up to 2 g of ALC daily is a reasonable alternative in cases where antidepressants have been partially effective or have been discontinued because of adverse effects.

Mr Jones is an 82-year-old retired stockbroker with chronic moderate depressed mood who has been taking therapeutic doses of several SSRIs for 10 years. He has not experienced significant adverse effects to conventional antidepressants and his symptoms have partially responded to conventional treatment. Recently, he has noticed short-term memory problems and is concerned that he may be in the early stages of Alzheimer disease. After reading an article on ALC, he consulted his family doctor who reviewed the evidence for ALC and advised Mr Jones that it was safe to take ALC in combination with his current antidepressant medication. After 8 weeks of taking 500 mg of ALC 3 times daily, Mr Jones has noticed improvements in both his mood and short-term memory problems in the absence of adverse effects. In consultation with his family physician, Mr Jones continues to take both the antidepressant and ALC.

The amino acid L-tyrosine plays many important roles in human physiology. It is obtained through diet or synthesized from phenylalanine and is a necessary precursor for synthesis of epinephrine, norepinephrine, and dopamine as well as nerve growth factor and thyroxin. Tyrosine deficiency is frequently associated with depressed mood.

 Beneficial dosages of L-tyrosine in depressed mood range from 500 to 1500 mg daily. Large doses of tyrosine may promote growth of malignant melanoma or other cancers.

Inositol is a member of the vitamin B family that is synthesized into phosphatidyl inositol, a second messenger required for normal nerve cell function. Therapeutic effects of lithium in depressed mood and mania are believed to be mediated by the inhibition of the enzyme required for synthesis of phosphatidyl inositol in the hippocampus.

In a small, 4-week, double-blind, placebo-controlled study (N = 28), depressed patients randomized to 12 g of inositol reported significantly greater improvements in mood than did placebo recipients.

 However, more recent placebo-controlled studies failed to show an adjuvant effect of inositol when combined with SSRIs in patients with major depressive disorder.

A Cochrane review concluded that the basis for recommending inositol as a primary or adjuvant treatment of depressed mood is insufficient.

 In contrast to its probable lack of efficacy in unipolar depressed mood, preliminary findings suggest that inositol has robust adjuvant effects when combined with mood stabilizers in the treatment of bipolar depressed mood.

In a small, 6-week, double-blind trial, depressed patients with bipolar disorder (N = 24) were randomized to mood stabilizers plus 12 g of inositol daily and compared with those who were given placebo.

 By the end of the study half, 6 of the patients in the combined inositol–mood stabilizer group reported at least a 50% reduction in depressed mood symptoms, compared with only 3 patients in the placebo group.

Large prospective studies are needed to evaluate possible adjuvant effects of inositol when used with antidepressants or mood stabilizers and to determine optimal dosing strategies. GI adverse effects associated with high doses used to treat depressed mood have resulted in limited use of inositol in spite of its therapeutic potential as an adjuvant.

Antidepressant effects of DHEA are believed to be mediated by multiple endocrine systems, including both androgen and estrogen receptors, and indirect effects on neurotransmission involving serotonin, Î³-aminobutyric acid, NMDA, and possibly norepinephrine. In a small, 6-week study (N = 22), DHEA administered in an escalating dose (30 mg daily for 2 weeks, followed by 30 mg twice a day for 2 weeks, and then 30 mg 3 times a day for 2 weeks) resulted in significant improvements in mood compared with placebo.

 Two-thirds of patients in both groups continued their antidepressants throughout the study. Mood scores in half of the patients in the DHEA group improved by 50% or more.

In a 6-week, double-blind, randomized, placebo-controlled, cross-over study (N = 46), moderately depressed adults were randomized to 90 mg of DHEA daily for 3 weeks followed by 150 mg of DHEA 3 times a day for 3 weeks or to placebo.85 A 50% or more reduction in symptom severity was observed in the DHEA group, which also reported improvements in baseline sexual functioning. Most patients who responded to DHEA remained asymptomatic at 12 months’ follow-up. HIV-positive patients with depression who took 200 to 500 mg of DHEA daily experienced significant improvements in mood and fatigue.

 Serum testosterone levels and CD4 T-cell counts were not affected.

Research findings suggest that DHEA improves negative psychotic symptoms in schizophrenic patients. In a small, double-blind, placebo-controlled study (N = 30), inpatients with schizophrenia who were treated with 100 mg of DHEA daily in addition to their antipsychotic medications experienced significant improvements in depressed mood, anxiety, and negative psychotic symptoms.

Women improved more than men, and serum cortisol levels did not change during treatment.

Large prospective studies are needed to evaluate DHEA in severe depressed mood, clarify the mechanism underlying DHEA when used as an adjuvant or as monotherapy, and determine optimal dosing strategies. DHEA may promote cancer in women who have a history of estrogen receptor–positive breast cancer and should be avoided in this population.

 DHEA supplementation may increase the risk of prostate cancer in men with early or undetected prostate cancer.

 A metabolite of DHEA called 7-Keto DHEA is not converted into androgens or estrogens and can probably be safely used in this at-risk population.

 (Golden root) is a traditionally used Siberian herb that has been demonstrated to increase brain levels of 5-hydroxytryptophan and reportedly has antidepressant and cognitive enhancing effects.

 In vitro studies suggest that observed antidepressant effects of 

 are mediated by potent MAO-B inhibition.

 can be safely taken with antidepressants and there is preliminary evidence of an augmentation effect. Typical dosages of standardized extracts range from 200 to 400 mg daily. Serious adverse effects have not been reported.

In the United States, Canada, the European Community, and other developed world regions, increasing numbers of patients are using nonconventional approaches to treat psychiatric disorders. Anyone in whom a psychiatric disorder has been diagnosed is significantly more likely to use a nonconventional treatment than the general population.

 Before prescribing an antidepressant, clinicians should ask the patient about any CAM use. Conventional medications used in conjunction with CAMs can result in potentially serious safety issues.

[Note: This article was originally published in the December 2009 issue of 

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Natural Products Used to Treat Depressed Mood as Monotherapies and Adjuvants to Antidepressants

May has been a dispiriting month for psychiatry and a sad and worrying time for our patients. Three of the leading mental health organizations have squabbled among themselves-- promoting silly and competing "paradigm shifts" while ignoring the unmet needs of our patients.

The mischief started with DSM-5 and its rogues' gallery of untested diagnoses that turn everyday life problems into mental disorders. Per DSM-5, people who don't need help will often get it (to their detriment), while those desperately in need of help will continue to be shamefully neglected. And to crown the irony, APA gets to collect fat publishing profits for producing a manual that is both unnecessary and unsafe. 

Then, to compound the mess, the National Institute of Mental Health issued an inflammatory press release criticizing all of current psychiatry-- for being brainless and invalid. NIMH made it sound like psychiatric diagnosis without biological testing is worthless.

This was mindless. DSM-5 certainly deserves to be roasted, but the NIMH sneak attack was a unfair and inaccurate broadside against all of psychiatric practice. NIMH was trumpeting its new research agenda to support its  request to Congress for an expanded brain research budget (the only thing it really cares about). The statement failed to admit that NIMH won't possibly be able to deliver any real progress in clinical care in this decade (and perhaps for many more). NIMH was taking down current psychiatric diagnosis, but offering nothing in its place.
 
Then the British Psychological Society joined the silly season by also suggesting that we suddenly discard our current system of psychiatric diagnosis-- this time in favor of a psychosocial paradigm that would make obsolete the valuable (if limited) old timers like schizophrenia and bipolar disorder. Of course, no details were offered and indeed no new model of psychosocial diagnosis actually exists. A mirror image of NIMH wishful thinking about the future with no relevance to pressing present needs.     

To bring some wisdom and perspective to this whirlwind of silliness, I turned to Barney Carroll-- one of the great pioneers of biological psychiatry and perhaps the world's leading expert on the role of biological testing in psychiatry.

Dr Carroll writes: "

 from the Director of NIMH: 'The weakness (of DSM-5) is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure'.”
 

"After a few awkward days, the chair of DSM-5 

: 'In the future, we hope to be able to identify disorders using biological and genetic markers that provide precise diagnoses that can be delivered with complete reliability and validity'.”


"Patients receiving services are left to wonder whether (currently unavailable) laboratory tests are essential to the validity of their psychiatric diagnoses and the value of their treatments? Is psychiatry lost now in the wilderness without them?"

"Having biological tests is not a precondition for recognizing clinical disorders. It would be great to have them, but much good diagnostic work can be done without tests and their lack is not unique to psychiatry. The availability of biological tests is neither necessary nor sufficient for good patient care."

"So many conditions in medicine are diagnosed without any conclusive diagnostic tests. Think migraine. Think multiple sclerosis. Think chronic pain. Indeed, clinical science correctly recognized many diseases long before laboratory tests came along for confirmatory diagnostic application. Think Parkinson’s disease, Huntington’s disease, epilepsy… it’s a long list."

"We need also to be clear that laboratory tests are not an automatic gold standard of evidence for validity. Indeed, in many medical specialties, indiscriminate screening with laboratory tests has caused more harm than good."

"Laboratory measures are the servants of clinical science, not the other way around. Most laboratory tests will helpfully revise diagnostic probabilities, rather than conclusively rule in or rule out a diagnosis. Clinical judgment must always be used in their interpretation."

"Disease constructs take form through iterative attention to signs, symptoms, course of illness, response to treatments, family history, and laboratory data. This process of convergent validation has given us an A-list of psychiatric diagnoses that are candidates for future biological tests: psychosis, mania, melancholia, obsessive-compulsive disorder, vascular depression, crippling anxiety, panic disorder, dementia, autism, delirium, catatonia, and more."

"The fact that we have not nailed the pathophysiology of these conditions does not invalidate the diagnoses. We knew about Huntington’s disease and correctly diagnosed it for 110 years before its genetic basis was discovered."

"Psychiatric diagnosis is certainly imperfect -- but so is much of diagnosis throughout medicine. And whatever the current limitations, psychiatric diagnosis is useful and essential. There are no 'paradigm shifts possible til we learn a lot more. To imply otherwise is misleading and confusing to patients."  

Thanks Barney for clearing the fog with your common sense and deep experience. I would have said just the same things, but no one would have any reason to believe them. Your words carry unique authority given your lifelong commitment to establishing biological tests in psychiatry.

The biological reductionism espoused by NIMH and DSM-5 is not only nave and wrong-- it is bad for patients. As Hippocrates said: 'It is more important to know the patient who has the disease than the disease the patient has." Knowing  a person will always go well beyond knowing the lab test result. A Bio-Psycho-Social model is essential in all of medicine, but especially in psychiatry.

The NIMH and DSM 5 are eagerly chasing the holy grail of biological reductionism. But the brain will reveal its elusive secrets only in very small packets and only with the passage of many decades. Don't look for home runs or walks- be satisfied with singles and be prepared for many strikeouts.

Using a polio analogy, the NIMH director once said that he wants his institute to develop vaccines, not iron lungs. His ambition is to understand the biological roots of mental illness and to root them out. I fear that focusing on an over promised golden age in the future takes our eye off the obvious needs of patients in the present.

The delivery of mental health services in the US trails far behind most of the rest of the developed world. We have one million psychiatric patients in prison, most of them for nuisance crimes committed because they did not receive adequate care or housing in the community.

The NIMH seems to be totally indifferent to their needs and does nothing to promote its cause. It silently allows our country to engage in a barbaric mismanagement of the mentally ill that was abandoned elsewhere two centuries ago. NIMH would do well to promise less for the future and instead deliver more in the present. And DSM-5 should not have added new and questionable disorders at the fuzzy boundary with normal that distract attention and pull resources away from the unmet needs of the really sick.

We need biological research to improve the care of patients in the future, but we shouldn't be so dazzled by the (over)promise of neuroscience that we callously neglect our patients who are suffering now.

 

"Psychiatric diagnosis is certainly imperfect -- but so is much of diagnosis throughout medicine. And whatever the current limitations, psychiatric diagnosis is useful and essential. There are no 'paradigm shifts possible til we learn a lot more. To imply otherwise is misleading and confusing to patients."

The Role of Biological Tests in Psychiatric Diagnosis

You've just heard that one of your patients was involved in a criminal act (eg, a shooting, hit and run, etc) and is blaming the psychopharmacological treatment you provided for his actions. 

Charles Scott, MD, Professor of Clinical Psychiatry at the University of California, Davis, posed this question to attendees of the symposium “Psychiatric Prescribing: Medicine, Malpractice, and Mayhem” at the 

It’s not a far-fetched scenario. In 2001, Chris Pittman shot and killed his grandparents, set their house on fire, and attempted to drive off in the family SUV. The police caught up to Pittman after the SUV got stuck in mud; Pittman at first claimed a black man had killed his grandparents and kidnapped him, but then later admitted to the crime. His defense attorney argued that he should not be held responsible for his actions, as they were a direct result of the antidepressant sertraline (Zoloft). The jury was not convinced, and Pittman was sentenced to 30 years for the crime.

The best defense is an offense, and Scott said a clinician’s notes and clinical records should document and defend treatment decisions. With this in mind, Scott shared 3 key things every patient record should include to support treatment strategies and defend a clinician, if needed.

First and foremost, clinicians should review 

, and record and document such. Does the patient have a history of impulsivity, agitation/movements, psychosis, or mood swings? If this is properly documented, then lawyers cannot claim these behaviors are associated with the newly prescribed treatment. Similarly, it is important to note if the patient had failed to respond to other treatments, whether he/she is currently taking any other medications, and if there is a history of substance use.

before treatment initiation, Scott explained. Include 

. Is the patient fidgety? Squirmy? Administer and record results of AIMS as well. 

exam results also should be included in this section. What is the patient’s affect, mood? Is the patient organized/disorganized? The patient’s 

, including past attempts, should also be evaluated and documented. Scott recommended the Columbia-Suicide Severity Scale (available at: 

Finally, Scott said it is important to document 

. Risks should be explained to patients when treatment is initiated and anytime treatment is changed or adjusted. As necessary, addiction risk of off-label use should be discussed. Scott said it can be useful to share the package insert with patients and suggested using treatment guidelines for monitoring. All of these steps should be appropriately documented in the record.

Finally, Scott said the record should include 

. Assess for possible side effects, and so note. If the patient has experienced a reaction of any kind, Scott said it is important to note what was done and why. Similarly, he said it is important to monitor for depression, suicidality, psychosis, and mania (including sleep quality and quantity, energy levels, and motor activity).

So, in the previously posed hypothetical scenario, all that is needed is to gather your records. If your notes are subpoenaed, make sure it is legally appropriate to release the notes, Scott advised. And when it comes time to testify, keep in mind that whatever you say becomes part of the court record and can be used in future civil cases. Be thoughtful and honest in responding to questions, but keep to the facts that are supported by your clinical notes, Scott noted.

A clinician’s notes and clinical records should document and defend treatment decisions, and are the best defense in court. Here: 3 key things every patient record should include.

Will Your Clinical Records Support You in Court?

-acetylcysteine and bipolar-specific psychotherapies is on the horizon for this bipolar series. But with DSM-5 about to arrive, one more examination of bipolar diagnosis is warranted. After all, if a diagnosis is inaccurate, treatment efforts, however well-intentioned, may misfire.

The formal changes in DSM-5 will not be official or public until this month. But the bipolar disorder workgroup proposed 4 changes on the 

 (since removed in anticipation of publication).

 Two of the proposed changes will tighten bipolar diagnostic requirements, and two will loosen them.

The tightening criteria are (1) diagnosis of hypomania or mania will now require a finding of increased energy along with the rest of the unchanged criteria and (2) bipolar not otherwise specified (BP NOS) becomes bipolar not elsewhere classified (BP NEC), with tighter definitions of subthreshold bipolar variations. The loosening criteria are (1) mixed states will encompass a spectrum of admixtures of manic and depressive symptoms, down to specific minimums and (2) antidepressant-induced hypomania or mania will now qualify a patient for a diagnosis of bipolar disorder.

Will the tighter criteria help address the reported overdiagnosis problem?

 Take the fictional case of 31-year-old Ms Alvarez, who, since age 18, has had many clearly recognizable episodes of depression that last a week or more. When asked, she endorses phases of increased activity and remarkable productivity; increased social interaction; and a confident, positive outlook that is otherwise unusual for her-all on about 4 to 5 hours of sleep. She does not endorse increased energy during these phases, however.

Does she have bipolar II? According to DSM-IV, she might qualify (barring other diagnoses that trump bipolar disorder, such as a mood disorder due to a general medical condition). But because she does not endorse increased energy phases, she does not quite reach a diagnosis of bipolar II according to DSM-5. Will this tighter requirement increase diagnostic accuracy?

Intuitively, the answer seems obvious: surely the harder it is for a patient to meet all the diagnostic requirements, the harder it should be to award a diagnosis of bipolar disorder. Yet surprisingly, if we look at the statistical determinants of diagnostic accuracy, tighter criteria will have little impact. The reward for working through the following review of these statistical determinants is the understanding that the greatest impact of diagnostic accuracy comes from clinicians, not from tightening criteria.

Diagnostic accuracy: positive predictive value

When a clinician tells a patient “you have bipolar disorder,” how likely is it that the diagnosis is correct? In a widely cited study of overdiagnosis, Zimmerman and colleagues

 found that the answer is “less than 50% of the time.” My essay “

Overdiagnosis: Examine the Assumptions, Anticipate New Bipolar Criteria

 questions the broad assumptions that underlie that conclusion. Zimmerman and colleagues derived the 50% diagnostic accuracy figure by calculating a positive predictive value (PPV): in patients said to have bipolar disorder by local clinicians, how many will be found positive by the gold standard (in this case, a structured clinical interview)? In their study, a structured interview did not support the diagnosis in 56% of patients who had been told they had bipolar disorder.

Two key factors determine PPV, and thus determine why in this study the PPV was so low (only 46%). First is the specificity of the test in question, which in this case is the DSM criteria set as applied by the local clinicians. The other determinant of PPV is prevalence-how likely is the illness before the clinician starts trying to diagnose it?

Another related concept needs to be introduced to show that clinicians have more impact on accuracy than the DSM criteria, namely: prevalence is but one form of prior probability. Clinicians can increase prior probability, ie, the likelihood that the patient has bipolar disorder, by assessing other markers of bipolar disorder that are not in DSM.

Compare tightening diagnostic criteria (eg, adding an increased-energy criterion to the required symptoms of hypomania to increase specificity) with increasing prior probability (eg, by asking the patient for additional information not in the DSM criteria: family history, age of onset, course of illness, and response to treatment). As a starting point for this comparison, 

 (first row) presents the results from the Zimmerman study, with the very low PPV of 46%.

In the second row, using the same starting point, prevalence is held constant while specificity is increased. This reflects the intent of tightening changes in DSM-5 to make it harder to confirm the diagnosis. Although the increase in specificity is small, from 86% to 90%, this is likely in the range of what tightening criteria could produce. Note that with this change in specificity, PPV increases from 46% to 55%. (Greater increases in specificity are clinically very difficult to achieve, but even if specificity were somehow to be increased to 95%, the conclusions presented here still hold.


Increasing positive predictive value (PPV) increases diagnostic accuracy of bipolar disorder

In the third row, specificity is held constant at the same 86% value found in the Zimmerman study, while prior probability is increased to 30%. This is what happens when a clinician has a hunch (eg, by inquiring about family history and response to prior treatment attempts) that the likelihood of bipolar disorder underlying Ms Alvarez’s depression is higher than population prevalence (eg, about 1 chance in 3). Note that now PPV increases to 68%: a better than two-thirds chance of accuracy, up from less than 50% as found by Zimmerman and colleagues, and well above the increase associated with a moderate improvement in specificity shown in the second row.


Markers of bipolar disorder not found in DSM-5

Finally, the fourth row shows what happens when a clinician narrows the possibility that the patient has bipolar disorder to a 50/50 chance, before applying DSM criteria. For example, imagine that Ms Alvarez, presenting with depression, had multiple features of bipolar disorder: a first-degree relative with a firm diagnosis; onset of her first depression at age 18; postpartum depression; multiple, brief episodes; a strong adverse reaction to an antidepressant; and no sustained benefit in 4 well-conducted antidepressant trials. With all this, the likelihood that her depression is a bipolar depression is at least 50% (a conservative estimate

). With a 50/50 prior probability, use of DSM criteria with a specificity of 86% achieves a PPV of 83%. This is much higher than can be achieved by tightening DSM criteria to a specificity of 90%, or even 95%.

The analysis above suggests that the tightening of DSM criteria will have only a small effect on diagnostic accuracy. A far greater effect can be achieved if clinicians adopt a practice of routinely assessing the non-DSM markers of bipolar disorder shown in 

 Their presence does not make the diagnosis. Rather, their presence increases the probability that a depression is a bipolar depression.



This is not a novel approach. Routine assessment of these bipolar markers has been part of the assessment of patients at the Harvard-associated mood disorder clinic for 10 years, as part of a 

With DSM-5, one more examination of bipolar diagnosis is warranted. After all, if a diagnosis is inaccurate, treatment efforts, however well-intentioned, may misfire.

Mania

Co-Occurring Mania and ADHD in Youths

Natural Products Used to Treat Depressed Mood as Monotherapies and Adjuvants to Antidepressants

The Role of Biological Tests in Psychiatric Diagnosis

Will Your Clinical Records Support You in Court?

DSM-5 Won’t Solve the Overdiagnosis Problem-But Clinicians Can

Lamotrigine for Major Depressive Disorder Is Inappropriate

Update on Adolescent Mood Disorders

Context Does Not Determine “Disorderness” or Normality

Treatment Issues for Bipolar Disorder in Women

Update on the Treatment of Bipolar Depression