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Although the clinical symptoms of psychotic disorders are dramatic and are what most clinicians focus on as their treatment targets, impairments in a wide range of cognitive function are observed in these illnesses.

Common Neural Abnormalities in Psychotic Disorders

Counter-intuitive as it may sound, happiness is a skill, and it can be practiced like a sport or musical instrument. In this Mental Health Minute, Richard J. Davidson, PhD, discusses his latest research on well-being, published in the 

Proceedings of the National Academy of Sciences

is the founder and director of the Center for Healthy Minds at the University of Wisconsin-Madison.

A meeting with the Dalai Lama sends a researcher on a new path. 

Can Happiness Be Taught? 

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

Discovery of Adult-Onset ADHD Raises Questions

Synthetic cannabinoids and cathinones are novel psychoactive substances (NPS) that have surreptitiously emerged on the market to mimic the effects of 

 These designer substances are gaining popularity due to their widespread availability and safety misperceptions. Temporal trend epidemiological data analyzed by the Centers for Disease Control indicate that acute poisonings related to synthetic cannabinoids and cathinones are increasing in the 

The rise in synthetic cathinone and cannabinoid use among patients susceptible to adverse neuropsychiatric reactions has been linked to a wide range of unpredictable effects, including 

 Emergency department (ED) psychiatrists are on the frontlines of care, and must provide the initial management and stabilization of the complex and challenging toxic effects of these drugs. Prompt recognition and management is essential to reduce morbidity and mortality.

, these designer synthetic cannabinoid receptor agonists have potent intrinsic activity at the cannabinoid (CB) 1 and 2 

 The compounds were originally developed to study the endocannabinoid system, but they emerged as 

 Initially designed to mimic the effects of delta 9-tetrahydrocannabidiol, synthetic cannabinoids are 2 to 100 times more potent than marijuana at the CB1 and CB2 receptor, resulting in a wide range of adverse neuropsychiatric symptoms.

 Furthermore, synthetic cannabinoids are often adulterated with additional ingredients to either enhance or attenuate the drug high, resulting in clinically unpredictable toxicological profiles.

 As a consequence, there is no specific toxidrome associated with synthetic cannabinoid intoxication, and patients will typically present with a constellation of sympathomimetic, anticholinergic, and marijuana toxic effects.

). The most common sympathetic nervous system cardiovascular effects are tachycardia (46%) and hypertension (21%). The anticholinergic effects closely overlap with signs and symptoms of a sympathomimetic toxidrome. Distinguishing symptoms specific to anticholinergic toxicity include: dry skin, cotton mouth, absent bowel sounds, blurred vision, and urinary retention. Moreover, patients may additionally present with marijuana intoxication symptoms (ataxia, delayed reaction time, and 

conjunctival injection). Laboratory studies are indicated in cases of severe intoxication with agitation or seizures due to the resulting life-threatening metabolic derangements.

Rates of synthetic cannabinoid use are increasing in the United States, with the lifetime prevalence estimated to be between 0.2% and 4%.

 Moreover, between January 2016 and September 2019, ED visits related to synthetic cannabinoid toxicity significantly increased in the country’s Midwestern and Northeastern regions.

 Overall, synthetic cannabinoids harms are increasing, and psychiatrists need to be cognizant about the clinical presentations and evidence based treatments. 

, these agents are synthetic psychostimulants structurally related to cathinone, a monoamine alkaloid found in the Khat plant. As substituted phenethylamines, synthetic cathinones are structurally and pharmacologically similar to amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). These agents are commonly abused for their euphoric, empathogenic, and stimulating effects. The most commonly abused synthetic cathinones are 4-methylmethcathinone (mephedrone), 3,4-methylenedioxy-N-methylcathinone (methylone), and 4-methylenedioxypyrovalerone (MDPV).

 Synthetic cathinones produce major effects on the Central Nervous System (CNS), and are linked to adverse neuropsychiatric complications (

). Synthetic cathinones stimulate the release of dopamine and inhibit the reuptake of epinephrine, norepinephrine, and serotonin inducing a broad range of sympathomimetic, serotonergic, and hallucinogenic adverse toxidrome effects (

 The most frequent sympathetic nervous system cardiovascular effects are tachycardia (46%) and hypertension (21%). The hallucinogenic effects (perceptual distortions, depersonalization, synesthesia) can be highly distressing, which often prompts emergency psychiatric care. Ancillary lab studies should be ordered in cases of severe agitation because of the increased risk for acute kidney injury, rhabdomyolysis, lactic acidosis, stroke, and intracranial hemorrhage.

Self-reported prevalence of synthetic cathinone use is an estimated 0.05%. Current estimates are imprecise, however, as established surveys and standard immunoassay testing are not sensitive for detecting cathinones.

 The most recent data from the Drug Abuse Warning Network report indicates 22,904 ED visits were related to synthetic cathinone toxicity in 2014. The frequency of ED utilization is likely increasing, as synthetic cathinones are steadily becoming more popular despite the potential harms.

The diagnosis of intoxication is based on a history of exposure and presence of characteristic signs and symptoms. Patients may unknowingly or inadvertently administer synthetic cannabinoids and cathinones, as these compounds are oftentimes adulterated with other illicit drugs such as MDMA.

 Although there is no specific toxidrome, patients will typically present with signs and symptoms of adrenergic neurohumoral activation.

 The neurotoxic symptoms (including aggression, confusion, and psychosis) may overlap with a primary mental illness, and psychiatrists must rely on the clinical history and physical exam findings to accurately diagnose toxicity. Urine immunoassay testing is the most common method to screen for substance use. In the setting of acute intoxication, however, urine immunoassay testing has a low positive predictive value for synthetic cannabinoids and cathinones.

 While gas chromatography/mass spectrometry (GC/MS) is considered the gold standard for detecting substances, the molecular geometry of synthetic cannabinoids and cathinones is everchanging, making it increasingly difficult to directly identify these compounds.

 Moreover, GC/MS is not readily available in all emergency hospitals, and the results may not return in a timely manner to aid in the diagnosis process. An atypical onset of psychosis and agitation alongside hyper-sympathetic activation and a mixed toxidrome is strongly suggestive of intoxication.

Because of the variability in clinical presentations and lack of diagnostic testing, psychiatrists should strongly consider the possibility of intoxication in any patient with no known psychiatric history, a negative urine drug screen, and no known contributing medical mimickers (presenting with a mixed toxidrome). Patients will not necessarily fit neatly into a particular toxidrome, but rather present with overlapping signs and symptoms from multiple toxidrome classes. Consequently, differentiating synthetic cannabinoid and synthetic cathinone toxicity can be challenging. Regardless, supportive care and symptom management is the mainstay of the treatment. Benzodiazepines are considered the first line of treatment to reduce the sympathomimetic neural stimulation (including hypertension, agitation, and seizures).

Agitation is the most common neuropsychiatric complication associated with synthetic cannabinoid and cathinone ingestion. Katz and colleagues reported that 40% of intoxicated patients evaluated in an ED will experience severe agitation.

 The spectrum of psychomotor agitation can be objectively measured and identified with a standardized rating scale such as the Behavioral Activity Rating Scale (BARS). For patients with mild-moderate agitation (BARS score = 5 or 6), the patient may initially be calmed with verbal de-escalation techniques, and environmental modification. For patients with moderate-severe agitation (BARS score > 6), benzodiazepines remain the first line treatment for reducing moderate to severe agitation.

 Among the benzodiazepines, midazolam and lorazepam are considered the initial drugs of choice for decreasing agitation because of their rapid onset of action, short half-life, and parenteral route of administration availability.

 Antipsychotics are commonly administered with benzodiazepines to manage the psychotomimetic effects.

 However, risks associated with administering antipsychotics in acute poisonings settings must be carefully considered. Specifically, antipsychotics: may increase the risk of seizure induction; have anticholinergic effects; impair thermoregulation mechanisms; and prolong the QTc interval.

 Serotonergic sedatives such as fentanyl should be avoided because of the increased risk of serotonin toxicity associated with synthetic cannabinoids and cathinones.

A subset of patients will develop excited delirium following ingestion of psychostimulants. A systematic review reported that 25% to 94% of patients diagnosed with excited delirium were recently exposed to synthetic cannabinoids and/or cathinones. The American College of Emergency Physicians has provided guidance on evaluating excited delirium: a minimum of 6 out of 10 clinical criteria are required to make a diagnosis. If undertreated, the case-fatality rate is estimated to be 20%, partly due to catecholaminergic cardio-respiratory failure. The cornerstone of treatment is rapid sedation to reduce the sympathomimetic outflow and facilitate lifesaving treatments.

To date, no large scale randomized controlled trials have evaluated pharmacological treatments for excited delirium. Nonetheless standard of care is to administer benzodiazepines and antipsychotics to decrease psychomotor agitation. In the emergency setting, IM ketamine (4-5 mg/kg) is increasingly used for sedation of agitated patients with excited delirium. Initial studies in the pre-hospital setting (emergency medical services) reported that intubation rates following ketamine administration were as high as 60%. Emerging literature supports that IM ketamine administration in the hospital setting (emergency department) is a safe and effective treatment for excited delirium while not significantly affecting the cardiopulmonary system.

 Mankowitz and colleagues reported that more patients required intubation after ketamine administration in the pre-hospital setting (30%) compared to the hospital setting (1.8%).

 Prospective studies conducted in the emergency department have demonstrated that there is no significant difference in incidence of complications between IM ketamine and IM haloperidol.

 The side effects of single doses of IM ketamine for agitation are generally transient and self-limiting: emesis, hypersalivation, recovery agitation (also known as emergence reaction), hypertension, and tachycardia. Moreover, ketamine has other potential benefits, including a faster onset to sedation compared with benzodiazepines and antipsychotics.

 There are observational reports of ketamine exacerbating psychosis in susceptible patients. Larger studies, however, have concluded that acute- and short-term administration of ketamine for agitation does not increase psychiatric inpatient admissions or ED psychiatric evaluations.

 Physical restraints should be used as a last resort, primarily as a bridge to pharmacologic treatment, as prolonged use of physical restraints is likely to worsen delirium and rhabdomyolysis, leading to renal failure, electrolyte abnormalities, and arrhythmias.

Synthetic cannabinoids have been linked to psychotic reactions, such as paranoia, catatonia, dissociation, auditory, and/or visual hallucinations.

 Longitudinal studies have reported that consumption of potent cannabinoids quintuples the risk of a psychotic episode.

 The psychotomimetic effects are usually transient and resolve within 5 to 8 days; however, up to one-third of patients will transition to schizophrenia.

 Although there is no established antidote, preliminary reports suggest that cannabinol, an allosteric modulator at the CB1 receptor, may reverse the neurotoxic effects.

Similarly, synthetic cathinones have pro-psychotic effects, potentially triggering a psychotic state in vulnerable groups of patients. An observational study reported that synthetic stimulants were implicated in approximately 25% of ED visits involving drug-related psychosis. Specifically, mephedrone was the most common synthetic cathinone involved in stimulant psychosis, accounting for approximately 20% of stimulant related psychotic cases.

 Synthetic cathinone induced psychosis is typically brief and resolves within days to weeks; however, 25% of patients will transition to a schizophrenia spectrum disorder.

The psychotomimetic symptoms can be controlled with first- and second-generation antipsychotic medications with careful consideration of side effect profiles. Among the first-generation antipsychotics, the butyrophenone neuroleptics IM haloperidol and IM droperidol are reasonable pharmacotherapeutic options.

 In comparison to IM haloperidol, IM droperidol has a faster onset of action, rapidly preventing and treating emergent psychotic agitation within 5 to 10 minutes of intramuscular administration.

 Some expert panels have recommended avoiding butyrophenone neuroleptics in cases of substance-induced psychosis due to the pro-convulsant properties, cardiotoxic effects, and extrapyramidal symptoms. Among the second-generation antipsychotics, p.o. olanzapine has a track record of treating NPS-induced psychosis, and pro-drug websites have touted olanzapine as the ideal medication to terminate so-called “bad trips.”

 In spite of its efficacy, olanzapine has anticholinergic and central thermoregulatory effects impairing core temperature regulation. In theory, p.o. or IM aripiprazole and ziprasidone are probably the safest antipsychotics to administer because of the relatively favorable safety profile, and negligible anticholinergic and seizurogenic effects.

 epidemiological studies do not support a correlation between ziprasidone and torsade de pointes. In many instances, detoxification with benzodiazepines and rest will often quell the substance-induced symptoms without the added need for antipsychotics. Given the risks associated with neuroleptics, especially in antipsychotic naïve patients, it may be best to consider a benzodiazepine as the first line agent to reduce the psychotic agitation. Antipsychotics can be initiated if the psychosis continues to persist after the detoxification period, or if the patient has a underlying primary psychotic illness.

Synthetic cannabinoid and cathinone harms are increasing, and psychiatrists need to be cognizant of the clinical presentations and evidence-based treatments. Synthetic cannabinoids and cathinones have pro-psychotic and agitative effects, and the toxic reactions can mimic a primary mental illness. There is no definitive diagnostic test to differentiate primary versus secondary drug induced mental illness, and ED psychiatrists must rely on the history and physical examination. In a subset of cases, the overstimulation of catecholamines may result in an excited delirium. Benzodiazepines are considered the first line treatment to reduce the sympathomimetic neural stimulation.

is anassistant professor of Medical Education and Psychiatry at California University of Sciences and Medicine, Arrowhead Regional Medical Center in San Bernardino, CA. 

is a core faculty member for the Internal Medicine Residency Program at Arrowhead Regional Medical Center, San Bernardino, CA. The authors have no relevant financial disclosures to report.

1. Dignam G, Bigham C. Novel psychoactive substances: a practical approach to dealing with toxicity from legal highs. 

2. Riederer AM, Campleman SL, Carlson RG, et al. Acute poisonings from synthetic cannabinoids - 50 U.S. toxicology investigators consortium registry sites, 2010-2015. 

3. Cohen K, Weinstein AM. Synthetic and non-synthetic cannabinoid drugs and their adverse effects-a review from public health prospective. 

4. Tai S, Fantegrossi WE. Pharmacological and toxicological effects of synthetic cannabinoids and their metabolites. 

5. Wiley JL, Marusich JA, Huffman JW, et al. Hijacking of basic research: the case of synthetic cannabinoids. 

6. Castaneto MS, Gorelick DA, Desrosiers NA, et al. Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications. 

7. Zuba D, Byrska B. Prevalence and co-existence of active components of ‘legal highs.’ 

9. Loeffler G, Delaney E, Hann M. International trends in spice use: prevalence, motivation for use, relationship to other substances, and perception of use and safety for synthetic cannabinoids. 

10. Roehler DR, Hoots BE, Vivolo-Kantor AM. Regional trends in suspected synthetic cannabinoid exposure from January 2016 to September 2019 in the United States. 

11. Weinstein AM, Rosca P, Fattore L, London ED. Synthetic cathinone and cannabinoid designer drugs pose a major risk for public health. 

12. Baumann MH, Walters HM, Niello M, Sitte HH. Neuropharmacology of synthetic cathinones. 

13. Palamar JJ, Martins SS, Su MK, Ompad DC. Self-reported use of novel psychoactive substances in a US nationally representative survey: prevalence, correlates, and a call for new survey methods to prevent underreporting. 

14. The DAWN Report. “Bath salts” were involved in over 20,000 drug-related emergency department visits in 2011. Substance Abuse and Mental Health Services Administration. 2013. Accessed November 30, 2020. https://www.samhsa.gov/data/sites/default/files/spot117-bath-salts-2013/spot117-bath-salts-2013.pdf

15. Oliver CF, Palamar JJ, Salomone A, et al. Synthetic cathinone adulteration of illegal drugs. 

16. Arntson A, Ofsa B, Lancaster D, et al. Validation of a novel immunoassay for the detection of synthetic cannabinoids and metabolites in urine specimens. 

17. Moeller KE, Kissack JC, Atayee RS, Lee KC. Clinical interpretation of urine drug tests: what clinicians need to know about urine drug screens. 

18. Bonaccorso S, Metastasio A, Ricciardi A, et al. Synthetic cannabinoid use in a case series of patients with psychosis presenting to acute psychiatric settings: clinical presentation and management issues. 

19. Katz KD, Leonetti AL, Bailey BC, et al. Case series of synthetic cannabinoid intoxication from one toxicology center. 

20. Nordstrom K, Zun LS, Wilson MP, et al. Medical evaluation and triage of the agitated patient: consensus statement of the american association for emergency psychiatry project Beta medical evaluation workgroup. 

21. Hui D. Benzodiazepines for agitation in patients with delirium: selecting the right patient, right time, and right indication. 

22. Roberto AJ, Lorenzo A, Li KJ, et al. First-episode of synthetic cannabinoid-induced psychosis in a young adult, successfully managed with hospitalization and risperidone. 

23. Gonin P, Beysard N, Yersin B, Carron PN. Excited delirium: a systematic review. 

24. Li M, Martinelli AN, Oliver WD, Wilkerson RG. Evaluation of ketamine for excited delirium syndrome in the adult emergency department. 

25. Mankowitz SL, Regenberg P, Kaldan J, Cole JB. Ketamine for rapid sedation of agitated patients in the prehospital and emergency department settings: a systematic review and proportional meta-analysis. 

26. Heydari F, Gholamian A, Zamani M, Majidinejad S. Effect of intramuscular ketamine versus haloperidol on short-term control of severe agitated patients in emergency department: a randomized clinical trial. 

27. Heydari F, Gholamian A, Zamani M, Majidinejad S. Effect of intramuscular ketamine versus haloperidol on short-term control of severe agitated patients in emergency department; a randomized clinical trial. 

28. Lebin JA, Akhavan AR, Hippe DS, et al. Psychiatric outcomes of patients with severe agitation following administration of prehospital ketamine. 

29. Annas GJ. The last resort--the use of physical restraints in medical emergencies. 

30. Hurst D, Loeffler G, McLay R. Psychosis associated with synthetic cannabinoid agonists: a case series. 

31. Di Forti M, Marconi A, Carra E, et al. Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. 

32. Murrie B, Lappin J, Large M, Sara G. Transition of substance-induced, brief, and atypical psychoses to schizophrenia: a systematic review and meta-analysis. 

33. Hudson R, Renard J, Norris C, et al. Cannabidiol counteracts the psychotropic side-effects of Delta-9-Tetrahydrocannabinol in the ventral hippocampus through bidirectional control of ERK1-2 Phosphorylation. 

34. Vallersnes OM, Dines AM, Wood DM, et al. Psychosis associated with acute recreational drug toxicity: a European case series. 

35. Calver L, Drinkwater V, Gupta R, et al. Droperidol v. haloperidol for sedation of aggressive behavior in acute mental health: randomized controlled trial. 

36. Thomas H, Schwartz E, Petrilli R. Droperidol versus haloperidol for chemical restraint of agitated and combative patients. 

37. Valeriani G, Corazza O, Bersani FS, et al. Olanzapine as the ideal “trip terminator”? Analysis of online reports relating to antipsychotics’ use and misuse following occurrence of novel psychoactive substance-related psychotic symptoms. 

 Be on the lookout for these novel psychoactive substances. 

Assessing and Addressing Synthetic Cannabinoids and Cathinones in Neuropsychiatric Toxicological Emergencies 

7 Questions that Separate ADHD from Bipolar Disorder

What are they key differences between ADHD and bipolar disorder? How can they be identified? 

In honor of the New Year, I reviewed a list of 

10 novel agents in the pharmaceutical pipeline

 that demonstrate an array of mechanisms that may eventually join our clinical pharmacopeia (see cover story). Several of these agents hold promise as treatments to improve efficacy as well as tolerability for significant subpopulations of our patients. Amidt the excitement and hope of 

, it is important to place our expectations and curative fantasies in the appropriate context. As of today, based on what we know, the human brain remains the most complex organ in the universe. The average adult brain weighs only 3 lbs and is constructed with 80 billion neurons. Each neuron connects to other neurons with up to 10,000 synapses. These synapses are in a constant state of neuroplasticity, strengthening connections here and reducing connections there based on the ever-changing demands of our environment—both internal and external.

Remarkably, each human brain has approximately 1 quadrillion synapses/connections that define our moment-to-moment changing connectome, which is the foundation of our uniqueness and identity. One quadrillion equals 1000 trillion, which is the number 1 followed by 15 zeroes: wrap your mind around that—pun intended. We continue to discover novel receptors, subreceptors, genetic polymorphisms, epigenetic modifications, enzymes, neurotransmitters, synergistic/ antagonistic interneuronal connections, and more with each passing day. This list is limited to physical elements of the brain that create our current primitive understanding of the nature of consciousness.

Additionally, we are relatively clueless as to the variables that weave together to create a personality, determine how much resilience a person has, or contribute to the opposing qualities of compassion and unapologetic violence toward others. Nonetheless it is truly remarkable how much we have learned about our brains during the past century. From sequencing the entire human genome, to mapping out neural microcircuits that cross through divergent brain structures, to the windows into brain function that MRI, 

, and single-photon emission computed tomography scans have opened, our basic science knowledge of the brain continues to explode beyond what science fiction of the past predicted.

During the last 100 years, serendipity and creative genius have produced psychiatric drugs that have truly advanced our understanding of the brain and significantly lessened the tremendous burden of suffering from major mental illnesses such as schizophrenia, major depressive disorder, bipolar disorder, anxiety disorders, and substance use disorders. In 1955, shortly after chlorpromazine was introduced in the United States as our first antipsychotic medication, 558,922 individuals were hospitalized in state and county psychiatric hospitals. By 1990, that number of hospitalized individuals dropped to 115,000 while the total US population increased.

 to the United States in 1989, our first antipsychotic FDA approved for treatment-resistant schizophrenia, led to a second wave of deinstitutionalization. In my state of New Hampshire, the number of psychiatric patients hospitalized at New Hampshire State Hospital dropped from 2700 in 1963 to 120 in 2013, according to Jay Couture, CEO of Seacoast Mental Health Center, Portsmouth, New Hampshire. Let me be clear, this dramatic decrease in national and NH state hospital admissions is not entirely based on newer or better medications, nor is it necessarily something of pride.

On October 31, 1963, President John F. Kennedy signed the Community Mental Health Act into law. He optimistically stated: “The time has come for a bold new approach … If we apply our medical knowledge and social insights fully, all but a small portion of the mentally ill can eventually achieve a wholesome and constructive social adjustment.” Although the intent was good, the ensuing deinstitutionalization of patients with psychiatric disorders across the country was rapidly enacted before the necessary outpatient and supported residential structures were in place. Additionally, the naivety in 1963 included an overinflated belief that antipsychotic medication alone would adequately treat the deinstitutionalized.

Today more individuals with schizophrenia are institutionalized in correctional facilities than in psychiatric hospitals, and the homeless population includes a large number of individuals with serious mental illnesses. An 

, Recovery After an Initial Schizophrenia Episode (RAISE),

 began in 2009, and compared the outcomes of 404 individuals with a diagnosis o first-episode psychosis who were randomized to 2 different treatment interventions and followed for 2 or more years. Remarkably, the 

 of untreated psychosis in this population was 74 weeks.

 RAISE concluded that the treatment group receiving a comprehensive intervention, in contrast with community treatment as usual, demonstrated a greater improvement in psychiatric symptoms, quality of life, and participation in work and school, and remained in treatment longer. Comprehensive intervention included aggressive antipsychotic medication, cognitive behavioral therapy, family education and support, and educational and vocational rehabilitation. The shorter the duration of untreated psychosis was predictive of a significantly greater improvement of quality of life and total score on the Positive and Negative Syndrome Scale (PANSS).

 Hence, we continue to learn the importance of a broad treatment intervention that affects many elements of day-to-day life.

Here at the beginning of 2021, 30 years after George Bush’s “decade of the brain,” we continue to struggle to achieve adequate response and less commonly full remission in all the major psychiatric disorders. As I see it, we are right where we should be. Progress is always incremental, with an occasional paradigm shift. In psychiatry we have learned that optimal treatment of our patients includes far more than medications, including the drugs in the pipeline. The same can be said about all medical disorders. Despite huge advances in medicine and surgery, illness is a familiar part of most of our lives.

We will likely never attain a complete understanding of the human mind, body, and soul. Knowledge is limited by the biases and tools of inquiry that we bring to our exploration of what is not known—which certainly greatly exceeds that which we know. Yet a fascinating quality of us humans is that we act and pretend like we know everything in contrast to the generation that preceded us. In psychiatry we sometimes speak with amusement, condescendence, or disgust when we teach students about the cutting-edge treatments of the mid-1900s. Insulin shock therapy was used routinely during the 1940s and 1950s for the treatment of schizophrenia. Frontal lobotomies were performed during this same time period for a variety of psychiatric disorders; this involved inserting an instrument into the prefrontal cortex and severing neuronal connections, which commonly resulted in a dramatic loss of the individual’s prior personality and intellect. You can be sure that we will be equally judged in 100 years for our current state-of-the-art treatments.

The good news is that this is how science and the advancement of knowledge works. In 1675, Isaac Newton wrote in a letter to Robert Hooke: “If I have seen further it is by standing on the shoulders of Giants.”

 Ultimately, no single person discovers or invents any one thing. Rather, insights organically arise when the necessary foundation has been established by the hypothesis and theories of predecessors, along with an infinite number of unknowable factors that converge to enlighten that moment in time.

Ultimately, we deserve to revel in every scientific breakthrough, no matter how large or small. However, we must remain mindful that today’s treatments will eventually become outdated and replaced by the discoveries of tomorrow, and this is what good science is all about. We must humble ourselves as modeled by one of science’s greatest minds—

I do not know what I may appear to the world, but to myself I seem to have been only like a boy playing on the seashore, and diverting myself in now and then finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lay all undiscovered before me.

It would be naïve to anticipate that one day we will understand that great ocean of truth, but we should never cease in our curiosity, exploration, and discovery of yet another pebble or seashell.

 is medical director, Brain Health, Exeter, New Hampshire; editor in chief, 

; staff psychiatrist, Seacoast Mental Health Center, Exeter; consulting psychiatrist, Exeter Hospital, Exeter; consulting psychiatrist, Insight Meditation Society, Barre, MA.

1. McKenzie JF, Pinger RR, Kotecki JE. An introduction to community health. Jones and Bartlett Publishers; 2008.

Evidence-based treatments for first episode psychosis: components of coordinated specialty care

3. Kane JM, Robinson DG, Schooler NR, et al. 

Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE early treatment program

4. Chen C. On the shoulders of giants. . Springer; 2003. 

https://doi.org/10.1007/978-1-4471-0051-5_5

5. Isaac Newton - Playing on the seashore did Newton really say it? Accessed December 6, 2020. 

https://todayinsci.com/N/Newton_Isaac/NewtonIsaac-PlayingOnTheSeashore.htm

Our basic science knowledge of the brain continues to explode beyond what science fiction of the past has predicted.

Seashells, Not an Ocean

Diagnostic and Statistical Manual of Mental Disorders

, 5th edition (DSM-5) classifies attention-deficit/hyperactivity disorder (ADHD) as a neurodevelopmental disorder characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development.

 There is growing evidence that symptoms of ADHD can persist into adulthood and can cause significant impairments in social, academic, and occupational functioning. In addition, there is emerging evidence for the existence of a different variant of adult ADHD (aADHD) where ADHD symptoms emerge for the first time in young adulthood without any symptoms being 

 In this article we review various aspects of adult ADHD (aADHD) and suggest possible treatments.

The prevalence of ADHD in childhood is between 

 Emerging evidence indicates that ADHD symptoms may persist into adulthood in approximately 

 to suggest that adult ADHD (aADHD) is not just a continuation of childhood onset ADHD (cADHD), as many individuals do not have a history of this 

 It is postulated that there may be 2 distinct subtypes of aADHD: the first with childhood onset and the other with onset exclusively in adulthood. A meta-analysis evaluating the risk markers that predicted the persistence of ADHD from childhood into adulthood found that the severity of ADHD (odds ratio (OR) = 2.33, 

 < 0.001), treatment for ADHD (OR = 2.09, 

 = 0.037), comorbid conduct disorder (OR = 1.85, 

 = 0.030), and comorbid major depressive disorder (OR = 1.8, 

 = 0.019) emerged as predictors for childhood ADHD persisting into adulthood.

A meta-analysis by Simon et al, found the conservative pooled prevalence rate for adult ADHD (aADHD) to be 

 This study also found that the proportion of individuals with ADHD decreases with age, and the prevalence rates were equal among men and women. This data is in contrast to cADHD, where boys had 3 to 10 times greater prevalence rates when compared to girls. The authors also opined that the true prevalence rate of adult ADHD may be an underestimate, as some children with ADHD do not outgrow the disorder but outgrow the current diagnostic criteria (

Adult ADHD results in significant impairments in the individual’s personal, social, and professional life.

 Individuals with aADHD tend to have poor self-esteem and reduced quality of interpersonal and professional relationships. These individuals are twice as likely to be divorced, when compared to age-matched controls. They also have significant educational difficulties with lower grades, greater rates of academic suspension and dropout rates, and are less likely to graduate than students without ADHD. Individuals with aADHD have greater rates of traffic violations and motor vehicle accidents, and higher rates of emergency room visits and hospital admissions. They also have lower life expectancies and higher risk for death, including accidental deaths. Individuals with aADHD are more likely to be unemployed and have a greater likelihood of being involved in criminal behaviors. The overall national annual incremental costs of ADHD ranges from $143 to $266 billion.

 Most of these costs were incurred by adults ($105 billion to $194 billion) compared to children ($38 to $72 billion), and the largest cost category in this group was productivity and income losses of $87 billion to $138 billion. 

Approximately 80% of aADHD cases present with at least 1 lifetime psychiatric comorbidity.

 The National Comorbidity Survey found that aADHD was significantly comorbid with mood disorders (OR = 2.7 to 7.5), anxiety disorders (OR = 1.5 to 5.5), substance use disorders (SUDs, OR = 1.5 to 7.9), and intermittent explosive disorder (OR = 3.7).

 aADHD was also associated with greater disability in both basic functioning (self-care, mobility, and cognition) and instrumental functioning (days out of role), productive role functioning and also on social role functioning). Only 10.9% of these individuals with aADHD received treatment for ADHD in the preceding 12 months.

Available evidence from family, twin, and adoption studies indicates that ADHD tends to run in families, with a high heritability rate of 74%.

 In addition, a third of ADHD’s heritability is due to a polygenic component, indicating many common variants with each having small effects. The heritability of aADHD and cADHD appear to be very similar, although family studies indicate that there may be an increased familial liability for aADHD when compared with cADHD.

 Twin studies that are based on self-rated symptoms among a sample of adult population show a moderate heritability rate at 30% to 40%.

Current evidence indicates that some of the same genes that may be involved in cADHD may also be involved in aADHD.

 Linkage studies have identified LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In a systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed among individuals with aADHD found an association between aADHD and the gene brain-specific angiogenesis inhibitor 1-associated protein 2.

 They also found lower serum docosahexaenoic acid (DHA) levels among aADHD individuals.

There is evidence from neuroimaging studies that among individuals with ADHD there is a dysfunction of dopamine pathways that are involved in attention, executive function, and motivation and reward.

 Additionally, dysfunctions are also noted in noradrenergic pathways, especially those projecting into the prefrontal cortex, the central region for executive function.

A simultaneous electroencephalography and functional magnetic resonance imaging (fMRI) study found that aADHD individuals had increased medial/lateral frontal and parietal activity during the voluntary selection task on fMRI.

 A meta-analysis found that right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in cADHD.

 Additionally, these changes and alterations in limbic regions like anterior cingulate cortex and amygdala were more pronounced among non-treated individuals and these appeared to diminish over time from childhood to adulthood.

In a study that sought to delineate the neural correlates of component-specific inhibitory deficits in aADHD using fMRI, brain activation was assessed during 3 stages of behavioral inhibition, ie interference inhibition (Simon task), action withholding (Go/no-go task), and action cancelation (Stop-signal task).

 Individuals with ADHD were impaired in all tasks. It was noted that impaired interference inhibition was associated with hypoactivation in parietal and medial frontal regions. During action withholding and cancelation, individuals with ADHD displayed hypoactivation in a fronto-striatal network. These findings indicate that at least 2 disturbed neural circuits in aADHD differentially associated with deficits in separate inhibitory subcomponents. Frontal brain responses were reduced among individuals with aADHD when compared to controls during free responses, whereas parietal brain functions seemed to be unaffected. These results appear to indicate that selection processes are related to dysfunctions, predominantly in frontal brain regions among individuals with ADHD. 

A study that investigated neural and behavioral correlates of visual encoding during a working memory (WM) task among young adults with aADHD found that there was ineffective allocation of attentional resources involved in encoding of information in WM.

 It has been noted that individuals with aADHD have significantly lower sensory gating than controls, suggesting an impaired ability to filter incoming information.

 Additionally, increased connectivity between the default mode network and a region within left lateral prefrontal cortex (PFC) has been noted. Furthermore, greater levels of resting state activity within that area of PFC was noted to be associated with reduced performance on attentional tasks.

 A common reason for this under-diagnosis is the nature of the illness, as it shares many clinical characteristics with common psychiatric disorders. These disorders include major depression, bipolar disorder, anxiety disorders, SUDs, and personality disorders. Given this overlap in symptomatology, it is recommended that aADHD should be evaluated using a dimensional rather than a categorical approach.

 Katzman et al recommend asking about long-standing and consistent problems with attention and distractibility. Additionally, inquire about complaints from the last 10 to 20 years, conceptualizing how the individual would have been as a child in a classroom. Early diagnosis and treatment of comorbid disorders appear to improve the outcomes among individuals with aADHD. 

It is also recommended that the focus of the evaluation in an adult presenting with symptoms of ADHD should be on the individual’s mental state, as it adds immediate and greater clinical value than the use of cognitive or neuroimaging information.

 Additionally, certain symptoms like physically restless, emotional dysregulation, excessive mental wandering, and sleep-onset insomnia may suggest a diagnosis of aADHD. It is also prudent to exercise caution when evaluating individuals with aADHD, as some individuals may feign ADHD symptoms in order to obtain stimulant medications for diversion to non-medical use.

To meet the DSM-5 diagnostic criteria for ADHD among adults, the individual needs to have 5 or more of the 9 symptoms of inattention and/or of hyperactivity and impulsivity.

 These symptoms need to also have persisted for at least 6 months. In addition, several inattentive or hyperactive–impulsive symptoms should have been present prior to the age of 12 years. These symptoms should be present in 2 or more settings, including home, school, or work; with friends or relatives; in other activities. Furthermore, there should be clear impairment with/or reduced quality of social, academic, or occupational functioning. These symptoms should not occur due to another psychiatric disorder, especially due to psychotic, mood, or anxiety disorders; or due to substance intoxication or withdrawal. The DSM-5 also defines 3 clinical presentations of ADHD based on symptom profile: predominantly inattentive, predominantly hyperactive/impulsive, and a combined (inattentive and hyperactive and impulsive) presentation. The DSM-5 recommends that collateral information should be obtained, as adult recall of childhood symptoms tend to be unreliable.

As there is significant co-occurrence of many common psychiatric disorders with aADHD, these disorders should ideally be diagnosed and treated first.

 This will ensure that the best treatment can be chosen for the core aADHD symptoms. If that is not possible, co-treating these disorders may also be beneficial among individuals with aADHD.

Pharmacological agents are considered first line interventions for the treatment of aADHD.

 The medications that are approved for the treatment of adult ADHD include stimulants, such as amphetamines (amphetamine, dextroamphetamine, and lisdexamfetamine) and methylphenidate (methylphenidate and dexmethylphenidate); and non-stimulants (atomoxetine).

 Other medications that are used off-label include modafinil, guanfacine, venlafaxine, bupropion, and desipramine.

Both amphetamines and methylphenidate are available as immediate release preparations requiring multiple dosing each day and sustained release preparations for once or twice daily dosing.

 The amphetamines and methylphenidate have been found equally efficacious in the treatment of aADHD, with approximately 70% of individuals reporting immediate improvement in core symptoms within 1 hour after administration of the drug. The common adverse effects of these drugs include insomnia, dry mouth, decreased appetite, weight loss, headaches, depression, and anxiety. They are contraindicated among individuals with hypertension, psychosis, or tics, as the medications may worsen these conditions. These medications need to be used with caution among individuals with serious heart disease. Stimulant medications are classified by the Drug Enforcement Agency as Schedule II substances, as they have a potential for abuse especially among individuals with SUDs.

The only non-stimulant medication that is approved for the treatment of aADHD is atomoxetine.

 It appears to have lower potential for abuse than stimulant medications. It is also preferred for use among individuals with ADHD and comorbid substance use disorders, tics, anxiety, or psychosis. However, atomoxetine appears to be less effective than stimulant drugs in reducing core ADHD symptoms and requires 1 to 2 weeks of treatment to achieve full benefit.

Additionally, there is no convincing evidence that atomoxetineis safer than stimulants, and it needs to be used cautiously among individuals with cardiovascular and cerebrovascular disease. The common side effects of atomoxetine include dry mouth, insomnia, nausea, decreased appetite, constipation, decreased libido, dizziness, and sweating.

 Other non-stimulant medications that can be used off-label among individuals with aADHD include modafinil, guanfacine, venlafaxine, bupropion, and desipramine, but the evidence for their use is limited to a few small controlled studies of short duration.

In a meta-analysis that included data from 19 trials and studied 13 different drugs, the investigators found that although both stimulant and non-stimulant medications are effective treatments for aADHD, stimulant medications show greater efficacy for the short durations of treatment when compared to placebo.

 However, there were no significant differences noted between short- and long-acting stimulant medications.

A systematic review of 18 published studies found that that cognitive behavioral therapy (CBT) was the most effective psychological treatment for aADHD and the comorbid symptoms of anxiety and depression.

The National Institute for Health and Care Excellence recommends prescribing medications to adults with ADHD if their ADHD symptoms are causing a significant impairment in at least 1 

, after environmental modifications have been implemented.

Although normally associated with children, attention-deficit/hyperactivity disorder can also persist in adulthood, presenting challenges to both patients and clinicians. 

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