Chris Aiken, MD

The Mighty Blueberry

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Studies suggest blueberries may have the power to treat depression...

The way to treat anxiety in bipolar disorder is to treat the bipolar disorder. Anxiety is a synonym for distress, and nearly all mental disorders cause distress, except perhaps the classic, euphoric manias that lift the patient into a carefree state of bliss.

Some mood episodes are more anxiety-provoking than others, and at the top of the list are mixed states. Although anxiety does not appear in the criteria for mixed states, it is often created when 

 The International Society for Bipolar Disorders has even calculated the exact proportions for this troubling recipe. It takes only 1 manic symptom during a depression, or 2 depressive symptoms during a mania, to spark anxiety.

Mixed states tend to respond better to anticonvulsants and atypical antipsychotics than to lithium, which may be why anxiety predicts resistance to lithium in 

 There are, however, 2 exceptions to this rule: suicide and panic disorder. Both mixed states and anxiety raise the risk of suicide in bipolar disorder, and lithium 

 This preventative effect is independent of lithium’s mood benefits, so it is worth considering lithium in patients who are suicidal, even when it has a lower chance of reducing the core symptoms.

Although the classic lithium-responsive patient tends to have pure manias and hypomanias and no anxiety disorder comorbidities, a recent study identified panic disorder as a 

 Although anxiety is low in pure mania and hypomania, these patients are on high alert for threat, which is the essence of panic disorder. One study found that they had more phobias of panic sensations than patients in 

The next step in treating mixed states is to reduce antidepressants and anything else that contributes to manic symptoms (eg, drugs of abuse, steroids, and irregular circadian rhythms). Most patients who are in a mixed state have been on an antidepressant for a long time, and it can be difficult to tell if the drug is exacerbating the mixed presentation. Given these uncertainties, it is best to taper slowly, 

 Rapid discontinuation can trigger mania and other mood symptoms. The work is much like tapering a benzodiazepine. If the symptoms worsen, raise back the dose and slow down the taper.

In bipolar disorder, anxiety is a non-specific symptom with 

, including mood episodes, stress, and comorbid anxiety disorders. With so many different causes, can any mood stabilizer truly be said to be anxiolytic? Probably not, but we do have a few trials that may point the way when selecting a mood stabilizer for a patient with significant anxiety.

Among the anticonvulsants, valproate and lamotrigine improved anxiety in small controlled trials of 

 Valproate’s evidence here is more robust, and this medication also improved anxiety in patients who do not have bipolar disorder, perhaps because of its benzodiazepine-like 

 Lamotrigine may also treat obsessive compulsive disorder through glutamatergic effects, based on a small placebo controlled and several uncontrolled studies.

The atypical antipsychotics can also improve anxiety. Quetiapine and olanzapine reduced anxiety in large, randomized, placebo-controlled trials of patients with bipolar depression and non-specific anxiety (both were secondary analyses). The effect sizes were large enough to make them noticeable to the casual observer (

0.35 for olanzapine and 0.56 for quetiapine

 Quetiapine had similar anxiolytic effects in the 300 mg and 600 mg doses, and olanzapine had similar anxiolytic effects as monotherapy or when paired with fluoxetine.

These anxiolytic properties do not seem to extend to other atypical antipsychotics. Ziprasidone and risperidone both failed in placebo-controlled trials of bipolar disorder with anxiety, and risperidone actually worsened anxiety in a study of bipolar with comorbid panic disorder.

The unanswered question here is whether these medications were targeting anxiety directly or treating mild mixed states. Most of the patients had 1 to 2 manic symptoms along with their depression, judging from their average Young Mania Rating Scale of 5, and anxiety was higher as the 

 On the other hand, quetiapine has a large effect size in generalized anxiety disorder (GAD), suggesting 

 Quetiapine came close to FDA approval in GAD, but was held back because the FDA did not think this disorder was severe enough to warrant all the risks of an antipsychotic. That lesson applies to bipolar disorder as well. Quetiapine may be very effective for anxiety, but it should not be used in mild cases.

Anxiety may not offer a direct path to pharmacotherapy in bipolar disorder, but it does tell us something about the care of the patient. These patients are at greater risk for treatment dropout, adverse effects of medications, substance abuse, and suicide. Supportive psychotherapy, fast-acting treatment, and an extra phone call to make sure they are tolerating any new medication go a long way in these cases.

is the Mood Disorders Section Editor for 

 and the director of the Mood Treatment Center. He has written several books on mood disorders, most recently 

The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis.

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Panic disorder and bipolar disorder: anxiety sensitivity as a potential mediator of panic during manic states.

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Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient.

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Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial.

Valproate (depakine-chrono) in the acute treatment of outpatients with generalized anxiety disorder without psychiatric comorbidity: randomized, double-blind placebo-controlled study.

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Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study

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Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies.

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Effect of comorbid anxiety on treatment response in bipolar depression.

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Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis.

Articles

Some mood episodes are more anxiety-provoking than others, and at the top of the list are mixed states.

How to Treat Anxiety in Bipolar Disorder

Four recent studies may have turned what we know about attention-deficit/hyperactivity disorder (ADHD) on its head. By following large cohorts from early childhood to adulthood, they claim to have discovered that ADHD can start in adults who did not have the disorder before the DSM-5 cutoff of 12 years. However, before we rewrite the DSM and start prescribing stimulants to every adult who cannot concentrate, it is important to take a closer look at this 

In 3 of the 4 papers, the adult-onset ADHD actually 

 Furthermore, many of these teenaged-onset cases (29% to 75%) had symptoms of ADHD in their childhood that were either below the threshold for the full diagnosis or were classified as part of a related disorder (eg, conduct disorder or oppositional-defiant disorder).

The fourth paper claimed to identify new-onset ADHD in middle-aged adults, and it made the biggest headlines.

 The study followed a group of more than 1000 residents of New Zealand from aged 3 to 38 years as part of a larger investigation on the effects of adverse birth experiences on health. Researchers gathered symptoms of ADHD at 3 time points: ages 5 to 7; 11 to 15; and finally at age 38. What they discovered surprised them. Most of the children with ADHD no longer had the full disorder as adults, and most of the adults who met criteria for ADHD in middle age did not have the full disorder in childhood. The problem with this surprise discovery is that they did not ask the participants when their ADHD symptoms began, so these may have been teenaged-onset cases like we saw in the other 3 studies.

Comorbid Confounders and Other Confusions

The New Zealand study counted 27 adults with ADHD who did not have the full disorder in their childhood. A quick breakdown of those cases suggests that other disorders could have caused the attention problems endorsed by these patients.

 Specifically, 10 patients had conduct disorder in childhood; 15 had substance use disorders as adults; and 15 sought treatment for major psychiatric disorders as adults.

Two other studies that looked at purported cases of adult-onset ADHD 

 that the majority (93% to 95%) of the cases were better explained by sleep disorders, substance use disorders, or another psychiatric disorder.

If adult-onset ADHD does exist, it may not be the same disorder as childhood-onset ADHD. Indeed, most cases of adult-onset ADHD can be better explained as true ADHD that was partially expressed in childhood; false positives in patients whose symptoms are due to another disorder; or false positives in healthy people who overendorsed their symptoms during the 

But what if there remains a small number of individuals whose ADHD genuinely begins in adulthood? These studies point to that possibility, but they do not tell us whether these cases share common biological markers, familial patterns, and treatment response with childhood-onset ADHD. The gender distribution, for example, was different, with more males in the childhood-onset cases.

When someone goes through the effort to see a psychiatrist, there is a good chance that they have a real psychiatric problem. Or, as Groucho Marx put it, “Anyone who goes to a psychiatrist ought to have their head examined.” With community samples, the working assumption is that the participants are “normal,” which is why this kind of research is so prone to false positives. The 

 in these community studies were further elevated by the reliance on self-report.

Although these studies attempted to rule out other causes of adult-onset ADHD, those exclusions are hampered by false-negative rates. For example, it is not unusual for patients to forget past episodes of mania or psychosis, and those episodes often cause long-standing cognitive problems that could be mistaken for ADHD. Some important causes, like autism spectrum or personality disorders, were not evaluated in these studies.

If nothing else, these studies are a good reminder to look for a cause before you reach for a stimulant. In practice, the first thing to do when a patient presents with adult-onset ADHD is to screen for other psychiatric disorders that might explain the symptoms. Medical and environmental factors, including age-related cognitive decline, sleep deprivation, sleep apnea, inflammation, obesity, air pollution, chemical exposure, and excessive use of digital media, can also 

 Patients who suffer from these problems might ask their doctor for a stimulant, but none of those syndromes require a psychopharmacologic approach.

is the Mood Disorders Section Editor for 

 and the director of the Mood Treatment Center. He has written several books on mood disorders, most recently 

The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

Discovery of Adult-Onset ADHD Raises Questions

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Investigating late-onset ADHD: a population cohort investigation

2. Agnew-Blais JC, Polanczyk GV, Danese A, et al. Evaluation of the persistence, remission, and emergence of attention-deficit/hyperactivity disorder in young adulthood. 

3. Caye A, Rocha TB, Anselmi L, et al. Attention-deficit/hyperactivity disorder trajectories from childhood to young adulthood: Evidence from a birth cohort supporting a late-onset syndrome. 

4. Moffitt TE, Houts R, Asherson P, et al. Is adult ADHD a childhood-onset neurodevelopmental disorder? Evidence from a four-decade longitudinal cohort study. 

5. Sibley MH, Rohde LA, Swanson JM, et al. 

Late-onset ADHD reconsidered with comprehensive repeated assessments between ages 10 and 25

6. Lopez R, Micoulaud-Franchi JA, Galera C, Dauvilliers Y. Is adult-onset attention deficit/hyperactivity disorder frequent in clinical practice? 

Can attention-deficit/hyperactivity disorder onset occur in adulthood? 

8. Ra CK, Cho J, Stone MD, et al. Association of digital media use with subsequent symptoms of attention-deficit/hyperactivity disorder among adolescents. 

9. Park J, Sohn JH, Cho SJ, et al. Association between short-term air pollution exposure and attention-deficit/hyperactivity disorder-related hospital admissions among adolescents: A nationwide time-series study. 

Association of exposure to endocrine-disrupting chemicals during adolescence with attention-deficit/hyperactivity disorder-related behaviors

2020;3(8):e2015041. Published 2020 Aug 3.

11. Dunn GA, Nigg JT, Sullivan EL. Neuroinflammation as a risk factor for attention deficit hyperactivity disorder. 

12. Cook RL, O’Dwyer NJ, Donges CE, et al. Relationship between obesity and cognitive function in young women: the food, mood and mind study. 

12. Hartanto A, Yong JC, Toh WX. Bidirectional associations between obesity and cognitive function in midlife adults: a longitudinal study. 

Before starting to prescribe stimulants to every adult who cannot concentrate, it is important to take a closer look at the research.

Adult-Onset ADHD Raises Questions

How To Switch Stimulants: A Dosing Guide for ADHD

Getting the dose just right can be tough...

How to Switch Stimulants: A Dosing Guide for ADHD

In what 5 ways can anxiety present in bipolar disorder? 

5 Types of Anxious Bipolar Disorder 

A randomised controlled trial of dietary improvement for adults with major depression (the 'SMILES' trial).

2. Faraone SV, Biederman J, Spencer TJ, et al. 

Comparing the efficacy of medications for ADHD using meta-analysis.

4. Opie RS, O’Neil A, Jacka FN, et al. 

A modified Mediterranean dietary intervention for adults with major depression: dietary protocol and feasibility data from the SMILES trial.

5. Chang SC, Cassidy A, Willett WC, et al. 

Dietary flavonoid intake and risk of incident depression in midlife and older women.

Tea consumption and the risk of depression: a meta-analysis of observational studies.

7. Grassi D, Socci V, Tempesta D, et al. 

Flavanol-rich chocolate acutely improves arterial function and working memory performance counteracting the effects of sleep deprivation in healthy individuals.

8. Bowtell JL, Aboo-Bakkar Z, Conway ME, et al. 

Enhanced task-related brain activation and resting perfusion in healthy older adults after chronic blueberry supplementation.

9. Conner TS, Brookie KL, Carr AC, et al. 

Let them eat fruit! The effect of fruit and vegetable consumption on psychological well-being in young adults: a randomized controlled trial.

10. Morris MC, Tangney CC, Wang Y, et al. 

MIND diet associated with reduced incidence of Alzheimer's disease.

The effects of probiotics on depressive symptoms in humans: a systematic review.

12. Morris MC, Tangney CC, Wang Y, et al. 

MIND diet slows cognitive decline with aging

13. Topiwala A, Allan CL, Valkanova V, et al. 

Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study.

This article was originally posted on September 15, 2017, and has since been updated. -Ed.

Although supported by basic science, it’s still a sea change to think that diet can treat depression. Some research puts that idea to the test.

Can Food Treat Depression?

 of alcohol use disorders (AUD) with depression, one medication stood out as the most effective but is not widely used. The meta-analysis, which included 66 randomized controlled trials that tested 18 categories of medications in 5890 patients who had an AUD and either 

 or depressive symptoms, found that disulfiram was the most effective at reducing alcohol use across all comparisons.

Only 3 medications reached statistical significance for remission: disulfiram, anticonvulsants (carbamazepine, topiramate, tiagabine), and a naltrexone with a selective serotonin reuptake inhibitor (

). The odds ratio for remission was much higher with disulfiram, although the spread of the data was also wider as indicated by the standard deviations in the graph. This difference held up to sensitivity analysis, in which studies that might have skewed the results were removed.

For abstinence, only disulfiram and baclofen reached statistical significance. (Baclofen is a muscle relaxant with mixed results in AUD when studied independent of 

. It has no measurable reinforcing properties; there have been rare reports of baclofen abuse.) The odds ratio for days abstinent was higher for disulfiram compared with baclofen; this finding held up to sensitivity analysis (

, there were no clear winners. The noradrenergic medications appeared effective as a group, but this group included only venlafaxine and the non-US medication viloxazine. Nearly all efficacy was attributable to viloxazine, a norepinephrine reuptake inhibitor. Mirtazapine showed promise, but only in a secondary analysis of studies looking at full episodes of depression, rather than subsyndromal cases.

Although these studies cannot explain why disulfiram works well in depression, I will venture a guess from clinical experience. Patients with depression are often unable to take action on the things that are good for them, ie, bathing, eating healthy, and achieving sobriety. Although they want to stop drinking, they struggle with ruminative thoughts and never arrive at an executable plan. Disulfiram halts indecision, relieving them of the struggle. Patients are unlikely to drink on disulfiram because their actions are driven more by 

Disulfiram’s efficacy may not be unique to depression. The drug worked well in general AUD in prior analyses. In the 1930s, workers who were exposed to it at a rubber factory became sick after drinking alcohol. This led to the first clinical use in the 1940s and its FDA approval for alcohol cessation in 1951. However, only 200,000 individuals— about 1% of patients with AUD — take disulfiram in the US.

The reason for disulfiram’s decline may be due to its unique mechanism. Disulfiram induces an immediate hangover reaction when combined with alcohol. It blocks the enzyme that metabolizes acetaldehyde, the toxin responsible for alcohol’s hangover effect. With heavy drinking or high doses of disulfiram, this effect can be fatal. When disulfiram was first released, that effect was thought to be necessary, so patients were advised to drink. That practice ended when a few patients died, but it also left a stain on disulfiram’s reputation.

Oncologists do not withhold lifesaving medications because they are potentially toxic. Yet disulfiram appears underutilized, despite the fact that alcohol-related fatalities have soared to the No. 1 cause of death in middle-aged adults. Although fatalities are extremely rare with disulfiram, physicians may feel a greater weight of responsibility for those deaths than they do when patients die from 

. An oncologist, however, would not feel this way when a patient dies from 

 of disulfiram’s safety noted, “Deaths from the disulfiram-alcohol (ethanol) interaction have not been reported in recent years, possibly because the dosages used are lower than those used 40 years ago and patients with cardiac disease are now excluded from treatment.”

Today, most physicians prefer the lower dose of 250 mg/day. This produces a less toxic interaction with alcohol and works just as well as 500 mg/day. Actually, placebo worked just as well as disulfiram in the blinded studies because simply warning a patient that the interaction is toxic will help them achieve sobriety even when the pill is a placebo.

Patients must be alcohol free for 12 hours before starting disulfiram; the disulfiram-alcohol interaction persists for up to 2 weeks after stopping disulfiram. Disulfiram is contraindicated in severe 

 or heart failure, as there have been cases of sudden death after drug initiation. Relative contraindications include liver disease (disulfiram can elevate liver function tests, as can naltrexone), psychotic disorder (there are rare cases of psychosis or confusional states), and active alcohol use (in the past 12 hours). When used in absence of alcohol, common adverse effects include fatigue and headache. Check for drug interactions in the 

The bottom line seems pretty straightforward: Don’t overlook disulfiram, but know how to use it safely in 

is an instructor in clinical psychiatry at the Wake Forest School of Medicine and the director of the Mood Treatment Center in Winston-Salem, North Carolina. He is editor in chief of The Carlat Psychiatry Report and coeditor of the bipolar disorder section for

Efficacy of pharmacotherapeutics for patients comorbid with alcohol use disorders and depressive symptoms-a bayesian network meta-analysis

Safety issues concerning the use of disulfiram in treating alcohol dependence

Despite alcohol-related fatalities soaring to the No. 1 cause of death in middle-aged adults, this medication is often overlooked.

Underused Medication May Be Best Bet for Comorbid AUD and Depression

Food is an ideal drug delivery system, and an intriguing trio of studies suggest antidepressant potential for 1 food in particular: the blueberry.

All 3 studies hail from a single group lead by Claire Williams at the University of Reading, England.

 the effect of a powdered blueberry drink—equivalent to 1 cup of fresh blueberries—on mood in 144 children, adolescents, and young adults through 3 randomized, placebo-controlled trials. The placebo drink had the same sugar and vitamin C content as the 

 juice, and both drinks were made to look the same by mixing them with concentrated orange juice. The 

 outlines the key points from these studies.

The first 2 studies (which were published in a single paper) examined mood 2 hours after a single drink, and the third looked at longer term effects of a daily drink over 4 weeks.

 All 3 studies were positive, with effect sizes that ranged from small (0.27) to medium (0.65).

Table. Three Trials of Blueberries and Mood

The main limitation is the fact that the studies were small and came from a single research group. Also, they all enrolled healthy participants, so we don’t know if blueberries actually treat clinical depression. No risks were identified, though one might wonder if blueberries can trigger mania. Reassuringly, 3 animal studies found anti-manic effects with blueberries, 1 of which compared them with lithium.

These findings are supported in part by a 

 where blueberry juice prevented postpartum blues (ie, the brief lability seen after delivery known as the “baby blues”) in healthy pregnant women, but the juice in that small controlled trial also contained tryptophan (2 g) and tyrosine (10 g).

 In contrast, 2 other independent groups that 

 blueberries in healthy older patients did not find any mood benefits.

This does not mean blueberries are only helpful in the young. Although the berries did not improve mood in the geriatric studies, they did improve cognition, which was the primary outcome. There are 13 controlled trials of the cognitive effects of blueberries and their extracts all age groups, and 85% of those 

What is the medication inside this efficient drug delivery system? Blueberries have several positive effects on the brain. They are neuroprotective, increasing brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1); anti-inflammatory; and raise production of 

 Most of these effects are because of anthocyanins, a group of 

 that give the fruit its purplish-blue hue.

Anthocyanins are found in other purple-tinted foods, like blackberries, blackcurrants, acai, black “forbidden” rice, eggplant, and the exotic purple varieties of cauliflower, asparagus, and sweet potatoes. Anthocyanins are also featured in red produce like cranberries, cherries, pomegranate, and red cabbage.

, but super-foods are not what nutritional psychiatry is all about. When working with medications, we shy away from polypharmacy, and aim instead to bring about the miracle of remission with a single pill. In nutritional psychiatry, polypharmacy is the ideal. The brain and body do best with a healthy mix of nutrients, and while 1 cup a day of blueberries is unlikely to cause harm, too much of a good thing is not the intent of this research.

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 He has written several books on mood disorders, most recently 

 with his co-host Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

. Effects of acute blueberry flavonoids on mood in children and young adults.

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Effect of 4 weeks daily wild blueberry supplementation on symptoms of depression in adolescents.

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Combined actions of blueberry extract and lithium on neurochemical changes observed in an experimental model of mania: exploiting possible synergistic effects.

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Selective dietary supplementation in early postpartum is associated with high resilience against depressed mood.

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Enhanced neural activation with blueberry supplementation in mild cognitive impairment.

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Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial.

7. Travica N, D'Cunha NM, Naumovski N, et al. 

The effect of blueberry interventions on cognitive performance and mood: A systematic review of randomized controlled trials.

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Blueberry phenolics are associated with cognitive enhancement in supplemented healthy older adults.

Improved metabolic function and cognitive performance in middle-aged adults following a single dose of wild blueberry

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Polyphenols from grape and blueberry improve episodic memory in healthy elderly with lower level of memory performance: a bicentric double-blind, randomized, placebo-controlled clinical study.

Three new trials suggest a novel antidepressant hides inside the blue-skinned fruit.

Blueberries Treat Depression, With a Catch

A new test screens for bipolar disorder with respectable accuracy

How to Screen for Bipolar Disorder in 2 Minutes

A recent finding that ADHD can begin in adulthood has surprised researchers. Here are reasons why it may be wrong.