Depression can lead to ADHD

Often underestimated in adults

Today everyone has a rough idea of ​​what ADHD is. Attention deficit / hyperactivity disorder is a very recent psychiatric illness. The symptom complex has been discussed among academics since 1775, but with a constantly changing focus: sometimes as a defect in the brain, sometimes as a defect in morality, sometimes as a defect in upbringing.

It was not until the 20th century that it was described as a disease. The four letters were finally included in the "Diagnostic and Statistical Manual of Mental Disorders" in 1987 and thus became an internationally defined diagnosis. Hardly three years later, media reports of a "diagnostic boom" and the "fashion diagnosis" increased. The old controversies about the clinical picture have been rewarmed, often expanded to include criticism of the modern environment, the mass media and the consumer or performance society.

What should not be forgotten in the lively media debates: It is people who suffer from ADHD. Their way to competent and empathic help must not be made more difficult by such discussions. This is also indicated in the current S3 guideline "ADHD in children, adolescents and adults" (as of May 2017).

ADHD is undisputedly a disease that begins in childhood. The prevalence in Germany is around 5 percent of children. The disease is usually diagnosed around school entry - significantly more often in boys than in girls.

Until the early 2000s, it was believed that the symptoms "grew together" and that the disease subsided over the course of adolescence. Today we know that 35 to 50 percent of the sick children take annoying symptoms with them into adulthood and about 30 percent of them are impaired in their everyday life. It can be assumed that 3 percent of adults suffer from ADHD, with the gender ratio being balanced in adulthood.

These figures mean that some experts now suspect that there is an undersupply of adult - especially female - patients with ADHD. What makes the assessment of the situation more difficult is that a drug for the treatment of ADHD was only approved for adults in Germany in 2011. There are now two available. So it is a very young therapy.

It is also unclear how things stand with ADHD in advanced age. Initial studies indicate a prevalence among seniors of around 2.8 percent.

Symptoms of young and old

The term “fidgety philipp” can be used as a first idea of ​​ADHD symptoms in children. They are inattentive, cannot sit still and burst into every situation with words and deeds. These are all behaviors that every child experiences from time to time.

As with any psychiatric illness, it is important that symptoms are seen in the context of the rest of life. In the case of ADHD, the symptoms must have persisted for at least six months and the child must suffer from them every day. Of course, this doesn't just mean bad school grades. Due to the different behavior, children with ADHD often find themselves in an outsider role. They also need to be observed in more than one environment, not just at school, but also at home or with friends.

Often it is only the demands of the environment that lead to symptoms becoming noticeable. In preschool age it is often only the hyperactivity that becomes noticeable, while the lack of concentration becomes a problem during and after school entry. The symptoms can vary from person to person. Often three types are formed:

  • the impulsive-hyperkinetic type,
  • the inattentive,
  • the combined or mixed type.

People with and without ADHD learn to come to terms with society as they grow up. For ADHD sufferers, this means that the restlessness is often internalized: the fidgeting and other external signs become less, but the inner restlessness increases. Other symptoms, such as impulsiveness or poor concentration, may also improve, but remain more pronounced compared to their peers without ADHD.

Dopamine and adrenaline play an important role in drug symptom control. But you can also get a dopamine / adrenaline surge without medication. Many ADHD patients learn in the course of their lives how they can give themselves the "kick" to alleviate their symptoms: through risky professional maneuvers, an aggressive driving style, (extreme) sport or gambling, to name just a few.

There is hardly any meaningful data on ADHD in advanced age. It is observed that the symptoms of adulthood persist: missed appointments, lack of order, poor financial planning. The elimination of behavior chosen to control symptoms, for example sport, can increase the level of suffering. Diagnosis in the elderly is made more difficult by the overlap of symptoms with dementia processes or other psychiatric illnesses.

Serious consequences in adulthood

Psychiatric comorbidities are very common in ADHD (Table 1).

Psychiatric illness Frequency (in percent)
depression 93
Nicotine abuse 51
Partial performance disorder 46
anxious personality disorder, emotionally unstable personality disorder 31 to 32 each
Anxiety Disorder, Post Traumatic Stress Disorder, Restless Legs Syndrome, Combined Personality Disorder, Obesity 25 to 29 each
dependent personality disorder, eating disorder, obsessive-compulsive disorder 10 to 18 each time
Abuse of illegal substances, bipolar disorder, alcohol abuse Under 10
Table 1: Psychiatric comorbidities in ADHD in adulthood; Twelve-month prevalence of comorbidities in in-patient psychiatric patients. Modified from Miesch, M, Deister, A, Forsch Neurol Psychatr 201

Follow-up studies suggest that ADHD patients, on average, have a lower level of education, lower income and lower socio-economic status than those who are not sick. Risk behavior is increased; As a result, sick people are more often involved in traffic accidents or come into conflict with the law. It is difficult for those affected to make sensible plans for dealing with money and time and to implement them. To the outside world they appear chaotic, forgetful and fluctuating between inexplicable disinterest and equally inexplicable overzealousness - depending on whether a topic interests them or not. Adults with ADHD often live in socially strained circumstances, have problems working in teams or maintaining relationships.

The symptoms are just as incomprehensible to the sick as to their fellow human beings. Self-doubt, feelings of inferiority and stress are often the result. Since chronic stress is a powerful factor in the development of psychiatric illnesses, it is not surprising that ADHD and other psychiatric illnesses often coexist.

In 2018, a study in Schleswig-Holstein found an ADHD prevalence of 59 percent in 116 patients in a fully inpatient general psychiatry; up to 33 percent of the patients had severe symptoms. Above all, depression was the most common comorbid disorder in 93 percent of patients, followed by nicotine abuse and weaknesses in learnable areas such as reading, spelling or arithmetic (partial performance disorder). Personality and anxiety disorders are also very prevalent (Table 1). Based on these results, the authors suggest that an examination for ADHD should be carried out upon admission to psychiatry.

A study from England that was a few years older also found in 124 adult outpatients receiving psychiatric care that one in four could be diagnosed with ADHD. Based on the studies, it can be assumed that there is a large population of undiagnosed adult ADHD sufferers.

The therapy of psychiatric illnesses should never only be medication. An important component, also in ADHD, is psychoeducation, i.e. the teaching of and education about the functions of the psyche and its diseases.

In the case of ADHD, self-organization and self-control are the main focus. Often those affected have already developed their own methods, such as keeping calendars or creating personal to-do lists. If it is difficult to integrate these methods into everyday life or if new ways have to be found, professional therapists can help. Cognitive behavioral therapy in adults has been researched best.

If a non-drug therapy is unsuccessful or if it is not possible due to external circumstances, drugs can be used. This also applies to severe symptoms or acute deterioration. It has been shown that substances that increase the concentration of noradrenaline and dopamine in the synaptic gap are particularly suitable for treating ADHD. Various studies have also indicated that the norepinephrine or dopamine systems are involved in the development of ADHD. As is so often the case in psychopharmacotherapy, the exact mechanism of action has not been precisely clarified.

In terms of their chemical structure, neurotransmitters and drugs are clearly similar (Figure 1). Amfetamine only differs from dopamine in that it has an additional methyl group. It is usually present as a racemate, the receptor affinities of the enantiomers differing slightly. Levoamfetamine has more cardiovascular and peripheral effects, Dex (tro) - amfetamine has a stronger effect on the central nervous system (CNS).

In the case of lisdexamfetamine, the carboxy group of the amino acid lysine was linked to the amino group of amfetamine. It is pharmacologically ineffective. Only after absorption is this amide bond split and effective dexamfetamine released. So Lisdexamfetamine is a prodrug.

In Germany, only slow-release methylphenidate (MPH) and atomoxetine are currently approved for the treatment of ADHD in adulthood. The market launch of lisdexamfetamine for adults is imminent. Some MPH retard preparations are approved if therapy is to be continued from childhood and adolescence; others can also be used as an initial prescription for adults. Prescriptions for methylphenidate predominate by far, presumably also because of the relatively low price (Table 2).

Medicinal substances, commercial preparations (examples) DDD (in millions) Price / DDD
Methylphenidate: Ritalin (Adult), Medikinet (adult), Concerta, Generics 51
Lisdexamfetamine: Elvanse 8 € € €
Atomoxetine: Strattera 2 € € € € € €
Guanfacine: Intuniv 0,4 € € €
Dexamphetamine: assassin 0,3 € € € €
Amphetamine: formulations ? € € € € €
Table 2: ADHD therapeutics in Defined Daily Doses (DDD) dispensed by the GKV in 2017. Data from adults and children

The starting dose should be low for both MPH and atomoxetine. For both substances, the dose should only be increased after a week.

It is currently estimated that 25 to 78 percent of patients respond to MPH. The range is so large because the studies on this are mostly small and difficult to compare with one another. The responder rate for atomoxetine is around 26 percent during the first six months of therapy. The effects that can be achieved with both drugs are of low to moderate strength; the symptoms cannot be completely eliminated by drug therapy.

Since there is still little global experience with ADHD in adulthood, much of the data comes from studies in which other substances were used in addition to the drugs approved in Germany. In 2018, a network meta-analysis came to the conclusion that amfetamine had the best effectiveness for adults, followed by methylphenidate, atomoxetine and the norepinephrine reuptake inhibitor bupropion (whose INN was typically amfebutamone until 2000). Only the modafinil used for narcolepsy was no better than placebo. There were no meaningful data for guanfacine in adults.

Note the retardation principle with MPH

Methylphenidate is a reuptake inhibitor for norepinephrine and dopamine and is only approved for adults in a retarded form. Non-delayed preparations would have to be taken twice a day because of the short half-life of the drug. The plasma level curve of a twice daily intake is simulated by different delay technologies.

It should be noted here that different formulations release the active ingredient differently (Figure 2).

For example, Medikinet® adult releases one half of its dose immediately and the other half with a delay, which is achieved by a different coating of the pellets contained in the capsules. It is similar with Ritalin® Adult, where the course of the plasma level curve is different. Also Equasym® works with differently coated pellets; here, however, 30 percent of the dose is released immediately and 70 percent delayed.

At Concerta® the ratio is fast to delayed 22: 78 percent and is achieved through a different mechanism. The capsule is coated on the outside with the fast-release component; the retarded portion is then slowly released into the digestive tract through a semipermeable membrane under osmotic pressure. The different galenics result in different inundation speeds of MPH with a comparable mg strength.

The comparability of the preparations is also complicated by different intake recommendations. Food ingested at the same time changes the pharmacokinetics of Ritalin® LA don't. Medicinet® on the other hand, it should always be taken with breakfast, otherwise the second plasma peak will be reached much earlier and the concentration curve will be shortened.

Patients may well notice these differences; In addition, these can lead to side effects or influence the success of the treatment. Since MPH is also on the market as a generic in Germany, pharmacists should pay attention to which release kinetics are actually interchangeable. The appropriate trade name or manufacturer should be documented with the prescription.

MPH is deactivated in the body by carboxylesterases through ester cleavage and eliminated in the urine. Carboxylesterases are found in abundance in the liver, but can be present in any tissue. The CYP system does not play a role in the breakdown of methylphenidate.

Side effects and contraindications

When starting treatment with stimulants, euphoria or activation can occur, which can lead to problems, especially in the case of frequently comorbid depression. If the euphoria is misinterpreted as the success of the treatment of the "antidepressant", the feeling of a "loss of effectiveness" inevitably arises after this initial effect has subsided. If only one activation occurs, suicidal thoughts and actions caused by the depression may be encouraged. The increased availability of norepinephrine increases the sympathetic tone, which is associated with an increase in pulse rate and blood pressure.

Other side effects can also occur, which one would usually call anticholinergic - i.e. parasympathicolytic -: blurred vision, slow gastrointestinal passage and dryness of the mucous membranes of the mouth and airways. Therefore, MPH is contraindicated in glaucoma, hyperthyroidism, strokes, many heart diseases and severe hypertension. Because of the risk of hypertensive derailment, MPH must not be given at the same time as or within two weeks after the end of treatment with irreversible, unselective monoamine oxidase inhibitors (tranylcypromine).

Psychological side effects of the stimulating effect can be sleep disorders, nervousness and anxiety. In some cases, tics and aggressive behavior can occur. Often the appetite is suppressed. These side effects can worsen psychiatric comorbidities. New psychiatric illnesses were also documented in studies on MPH. Therefore, the psychiatric state is precisely recorded before therapy with stimulants.

Every time the dose is adjusted and then at least every six months or every time you visit a doctor, you must check whether psychiatric illnesses have developed or worsened.

A history or diagnosis of some psychiatric illnesses, such as major depression, major mood disorder, anorexia nervosa, suicidal tendency, mania, or schizophrenia, is a contraindication for MPH. Due to the increased dopaminergic transmission, the stimulant can weaken the effectiveness of dopamine-blocking psychotropic drugs, for example antipsychotics such as risperidone, haloperidol or higher-dose quetiapine.

MPH has not been tried in elderly patients. Due to the cardiovascular and psychiatric side effects, use should be carried out carefully and under close supervision.

Substance abuse is one of the more common comorbidities in ADHD. Longitudinal studies show an increased risk of developing substance dependence (nicotine> alcohol> other substances).

However, the data is also ambiguous and very poor overall. On the one hand, population studies see a decrease in substance abuse in AHDS patients as soon as stimulants are used for therapy. On the other hand, there is a high prevalence of MPH abuse in patients who abuse substances intravenously.

It is known from the USA that around a quarter of ADHD patients increased the dose of their medication without consulting a doctor and also a quarter sold their doses to third parties. The improper use of MPH as a »power amplifier« in schools seems to be of particular importance. About 17 percent of college students in the United States said they had used ADHD medication in this way.

Important to know: intoxication, euphoria and delusions are almost always associated with non-oral application of MPH and a significant overdose. Such effects are not to be expected with intended use and the use of retarded preparations.

Atomoxetine as an alternative

If side effects such as anxiety, tension, activation or tics occur under MPH or if there is an increased potential for abuse, atomoxetine can be prescribed. This is not a stimulant and does not appear to be suitable for abuse. The frequency of prescriptions is low compared to MPH in Germany (Figure 3, Table 2).

The active ingredient was originally developed as an antidepressant and acts mainly as a norepinephrine reuptake inhibitor. The noradrenergic load is also in the foreground with the atomoxetine side effects. The contraindications are the same as for MPH.

However, atomoxetine also brings new problems: it is broken down in the liver with the participation of CYP2D6. Detoxification can therefore be inhibited by inhibitors such as fluoxetine, paroxetine and bupropion. Liver damage has also been observed very rarely. Occasionally atomoxetine can increase the QT time; The product information advises caution when used in pre-stressed patients or in combination with other QT time-prolonging drugs.

The antidepressant bupropion, which was initially listed under the INN Amfebutamone, is sometimes used for the off-label therapy of ADHD in adults. The data situation is extremely thin, so that the current S3 guideline "ADHD in children, adolescents and adults" does not recommend it. Bupropion is primarily a reuptake inhibitor of norepinephrine and dopamine with little inhibitory effect on the reuptake of serotonin.

The active ingredient and its metabolites are potent inhibitors of CYP2D6. The potential for interaction with other 2D6 substrates (example: typical antipsychotics, other SSRIs, tricyclic antidepressants, beta blockers or low-potency opioids) is significant. Bupropion can lower the seizure threshold and is contraindicated in patients who have had a seizure.

Attention deficit / hyperactivity disorder is a common psychiatric illness. It is not just a disease of childhood and adolescence, but can persist into adulthood and even senior citizens. However, as the patient ages, motor hyperactivity tends to decrease; other psychiatric symptoms or illnesses may occur more frequently. There are often psychiatric comorbidities, particularly depressive or anxious disorders.

Since ADHD has only been known in adulthood for a few decades, diagnostic and therapeutic options are not yet fully developed. In addition to supportive measures for self-organization and cognitive behavioral therapy, drugs can be used - the stimulant methylphenidate is most common in adults. The sympathetic-mediated side effects on the cardiovascular system are just as important as the continuous monitoring of newly emerging or existing psychiatric symptoms.

The abuse potential or psychiatric side effects of MPH can limit its use in high-risk patients. Then the norepinephrine reuptake inhibitor atomoxetine is approved for the treatment of ADHD in adults. /

Sebastian P. Lenhart studied pharmacy at the Ludwig Maximilians University in Munich and received his license to practice medicine in 2012. He worked for five years as a pharmacist in the kbo-Isar-Amper-Kliniken. In mid-2016, he completed his training as a specialist pharmacist for clinical pharmacy. Since 2018 he has been running a public pharmacy and giving presentations on pharmaceutical topics. Lenhart examines pharmacology in the third part of the pharmaceutical examination and is involved in the training and further education of pharmacists.