Anxiety 2
Anxiety 2
Anxiety 2
Department of Psy-
chiatry and Psycho- Summary
therapy, Campus
Charité Mitte (CCM), Background: Anxiety disorders are the most common type of mental illness in Europe, with a 12-month prevalence of 14%
Charité—Universi- among persons aged 14 to 65. Their onset is usually in adolescence or early adulthood. The affected patients often develop
tätsmedizin Berlin:
Prof. Dr. med. further mental or somatic illnesses (sequential comorbidity).
Andreas Ströhle
Methods: This review is based on pertinent publications retrieved by a selective search in PubMed.
Institute of General
Practice, Faculty of
Medicine, Ludwig- Results: The group of anxiety disorders includes generalized anxiety disorder (GAD), phobic disorders, panic disorders, and two
Maximilians-Universi- disorders that are often restricted to childhood—separation anxiety and selective mutism. A comprehensive differential diag-
tät München: nostic evaluation is essential, because anxiety can be a principal manifestation of other types of mental or somatic illness as
Prof. Dr. med.
Dipl.-Päd. Jochen well. Psychotherapy and treatment with psychoactive drugs are the therapeutic strategies of first choice. Of all types of psycho-
Gensichen, MPH therapy, cognitive behavioral therapy has the best documented efficacy. Modern antidepressants are the drugs of first choice for
Department of Psy- the treatment of panic disorders, agoraphobia, social phobia, and GAS; pregabalin is a further drug of first choice for GAS.
chiatry and Psycho-
therapy, University Conclusion: In general, anxiety disorders can now be effectively treated. Patients should be informed of the therapeutic options
Hospital of Freiburg:
Prof. Dr. Dr. med.
and should be involved in treatment planning. Current research efforts are centered on individualized and therefore, it is hoped,
Katharina Domschke even more effective treatment approaches than are available at present.
A
nxiety is a a normal and necessary basic emotion absence of any threat, or in disproportionate relation to a
without which individual survival would be im- threat, and keeps the affected individual from leading a
possible. Pathologically increased anxiety can arise normal life.
not only in anxiety disorders per se, but also in most other
types of mental illness. Anxiety can also be a warning sig- Learning objectives
nal of potential harm in somatic illnesses, such as myo- After reading this article, the reader should
cardial infarction or hypoglycemia in a diabetic patient; it ● know that anxiety disorders are common mental
naturally requires an entirely different therapeutic ap- illnesses of early onset that elevate the risk of
proach in such situations. For any patient presenting with developing further mental illnesses;
pathologically increased anxiety, a thorough psychiatric ● understand the clinical manifestations of anxiety
and somatic evaluation is needed so that an underlying disorders;
pulmonary (e1), cardiovascular (e2), neurological (e3), or ● be aware of the current treatments of first choice.
endocrine disease (e.g., of the thyroid gland) (e4) can be
ruled out. Anxiety reactions as such are important indi- Methods
cators of a possible threat to homeostasis; anxiety is con- This review is based on pertinent publications retrieved
sidered a disease requiring treatment when it arises in the by a selective search in PubMed.
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anxiety disorders, i.e., the degree of participation of terminalis, which has recently been ascribed a central
genetic factors in their development, lies in the range of role in what is called “sustained anxiety”—a typical
30–67%, with the remainder of the variation accounted feature of generalized anxiety disorder, panic dis-
for by individual negative environmental factors, such order, and social anxiety disorder (19).
as life events (13). These include, for example (14): Learning plays a major role in the development and
● Abuse and neglect (emotional and/or physical) maintenance of anxiety disorders, as well as in their
● Sexual violence treatment. Classical and operant conditioning exert
● Chronic illness their effects, and avoidant behavior contributes to the
● Traumatic injuries maintenance of the disorder. There also seems to be
● Deaths of significant others an evolutionarily determined capacity to mount an ex-
● Separation and divorce cessive anxiety reaction to the objects of the specific
● Financial difficulties. phobias, encouraging the development of these pho-
On the other hand, positive environmental factors, bias; Seligman introduced the term “preparedness”
effective coping strategies, secure bonding styles, for this capacity (e8). Personality traits, too, es-
supportive learning experiences, and a good social pecially neuroticism, are related to the development
support network can increase resilience, even in the of anxiety disorders (e9). Extinction learning via
presence of a genetic risk-factor constellation. Mean- in-vivo exposure is now considered to be a form of
while, the role of epigenetic mechanisms in the cau- relearning, rather than the erasure (unlearning) of
sation of anxiety disorders is gaining increased previously acquired content.
attention. Epigenetic mechanisms are biochemical
processes, such as, for example, DNA methylation or Treatment
histone acetylation, that act on DNA or its spatial As recommended in the S3 guideline on the treatment
structure without changing the DNA sequence per se. of anxiety disorders issued in May 2014 (20), psycho-
They play an important role in the regulation of gene therapy and pharmacotherapy should both be offered,
activity and display marked temporal plasticity, being and the two are considered comparably effective.
alterable by life events or even by psychotherapeutic Decisions about treatment should be made in the light
intervention. Epigenetic processes may, therefore, play of the severity of the disorder, the preference of the in-
a key role in tipping the balance between risk factors formed patient, the expected latency and durability of
and resilience, leading to an adaptive or maladaptive the treatment effect, the expected side effects, and the
outcome: it is perhaps the integration of the genetic risk availability of the treatment in question. If one form
together with the environmentally determined risk by of treatment proves to be ineffective, the other (or a
way of epigenetic processes that ultimately determines combination of both) should be tried. Only for the spe-
whether an anxiety disorder will arise. Individual epi- cific phobias is there very good evidence, and there-
genetic effects, like individual genetic effects, are fore a very strong recommendation, for psychotherapy
small (15). Initial epigenetic pilot studies on small alone; drugs are not indicated in the treatment of the spe-
groups of patients with anxiety disorders have re- cific phobias.
vealed altered patterns of DNA methylation in risk For all types of anxiety disorder, cognitive beha-
genes for these disorders, and it seems that successful vioral therapy is the type of psychotherapy for which
psychotherapy or pharmacotherapy leads to the there is the strongest evidence and which receives the
normalization of these altered epigenetic patterns highest-level recommendation (Ia; A). Initial ran-
(16). domized controlled trials have confirmed the clinical
The neuronal structures that participate in the efficacy of psychodynamic therapies, e.g., in social
anxiety network include the amygdala, whose efferent phobia (21). Nonetheless, psychodynamic therapy
fibers to the hypothalamus, the locus ceruleus, and the receives evidence level IIa in the current German
periaqueductal gray play a role in the regulation of the guidelines because of the incomplete state of the data
central and peripheral manifestations of the anxiety from clinical trials, along with the recommendation
response, and areas of prefrontal cortex and the ante- that this type of psychotherapy should be offered if
rior cingulate gyrus that exert an inhibitory effect on cognitive behavioral therapy has been ineffective or is
the amygdala (17, 18). Further brain areas belonging unavailable, or if an informed patient expresses a
to the anxiety network are the insula, which integrates preference for it (20). The specifics of cognitive
interoceptive signals, and the bed nucleus of the stria behavioral therapy vary depending on the particular
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FIGURE
Neurobiological/cognitive-behavioral changes/sensitization
Early-childhood inhibition,
internalizing symptoms
5 10 15 20 25 30 35 +
Age
Anxiety disorders presenting early in life increase the risk of developing other mental illnesses later on in life (sequential comorbidity) (modified from [e7] and
reprinted with the kind permission of John Wiley, publishers)
anxiety disorder being treated, with the common el- ing pharmacotherapy with psychotherapy is usually
ement that the patient must make the experience that not superior to monotherapy with either one of the
his or her situationally induced anxiety is unfounded two options alone (20). In a meta-analysis of the few
and the situation actually harmless. This is best available studies with long follow-up periods, Ban-
achieved through exposure under the supervision of a delow et al. (25) concluded that further symptomatic
therapist (22), in the course of which the patient must improvement took place 26–104 weeks after the end
experience habituation of the anxiety response, so that of cognitive behavioral therapy. After pharmacother-
the central fear underlying it is refuted. Exposure in apy, there was no worsening in the follow-up period,
virtual reality is now increasingly a part of cognitive- but this difference compared to cognitive behavioral
behavioral therapeutic interventions (23). therapy did not reach statistical significance.
Cognitive behavioral therapy has been found to The drugs with the highest level of supporting evi-
have a moderately strong beneficial effect against all dence are the selective serotonin reuptake inhibitors
types of anxiety disorder compared to a placebo drug (SSRI) and SNRI, as well as the calcium-channel
(Cohen’s d = 0.57); the same is true of pharmacother- modulator pregabalin for generalized anxiety disorder
apy (e.g., sertraline, d = 0.54; venlafaxine, d = 0.50) (Table 2).
(24). If only the before vs after changes are studied, In the informed-consent discussion, the patient
remarkably strong effects are found for pharmaco- should not only be informed of the specific side ef-
therapy (selective serotonin and norepinephrine fects of the drug class(es) to be prescribed, but should
reuptake inhibitors [SNRI], d = 2.25) compared to also be told that the effect of antidepressant drugs
cognitive behavioral therapy (d = 1.30) (24). Combin- may be delayed by a latency of approximately two
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weeks (range: 1–6 weeks), and that these drugs may, ● Noninvasive stimulation techniques, such as re-
in fact, initially worsen nervousness, agitation, and petitive transcranial magnetic stimulation (rTMS)
anxiety. They should therefore be given at a low dose or transcranial direct-current stimulation (tDCS)
at first, with gradual upward titration (Box). (32)
A common question in clinical practice is how ● Physical activity and exercise (33).
long drug therapy should be continued in order to A systematic review of the literature is needed so
prevent a relapse. The response rates are generally that the relevance of new studies for the guideline rec-
high (ca. 80%), but too early discontinuation of ommendations can be appropriately assessed.
medication is associated with non-negligible relapse We find the use of physical activity and exercise as
rates. Among patients with panic disorder, for a treatment of anxiety disorders to be particularly
example, a relapse is seen in 15–50% within 6–12 interesting. This mode of treatment is inexpensive and
months of the discontinuation of tricyclic antidepres- has few undesired effects; it should be applied in
sants, SSRI, or venlafaxine. It is therefore recom- combination with the first-line therapies (not as the
mended that maintenance therapy with SSRI or SNRI sole intervention) and is used much too rarely in rou-
be continued for at least 6–12 months after the end of tine clinical practice (33). Very strong pre/post effect
the acute phase, at the effective final dose that was strengths of g = −1.23 (24) seem impressive but have
attained. Any attempt to discontinue medication not been reproduced in studies with active control
should be gradual, e.g., over the course of 12 weeks groups (34). Even single units of endurance training
if the duration of treatment until now has been 40 can have an anxiolytic effect (e13–e15) or perhaps re-
weeks (27). inforce the effect of exposure therapy (35).
Benzodiazepines are approved in Germany for the Aside from drug therapy of the types discussed,
acute treatment of “states of tension, excitation, and clinical practice guidelines also contain recommen-
anxiety.” Nonetheless, the German guidelines on the dations for psychological treatments of anxiety dis-
treatment of anxiety disorders discuss the use of ben- orders in the primary medical care setting. The essen-
zodiazepines for this purpose in decidedly critical tial building-blocks of treatment are (20):
terms: “Benzodiazepines are effective against panic ● counseling,
disorder/agoraphobia/generalized anxiety disorder/ ● psycho-education about anxiety and anxiety dis-
social phobia (Ia; guideline adaptation). They should orders,
nonetheless not be offered to patients with panic ● instructions for anxiety-confronting exercises in
disorder/agoraphobia/generalized anxiety disorder/ real-life situations, and
social phobia because of their serious side effects (de- ● the use of self-help manuals (20).
velopment of dependence, etc.). They can be used for The primary care physician and the patient work
a limited time after careful evaluation of the risks and jointly to develop a gradually intensifying treatment
benefits in exceptional cases, e.g., patients with se- plan (participative decision-making). With the pri-
vere cardiac disease, contraindications for standard mary care physician’s attentive personal support and
drugs, suicidality, and other conditions.“ The discon- counseling, the patient carries out specific anxiety-
tinuation of benzodiazepines after they have been reducing exercises (36). Anxiety-confronting exer-
taken for months or years, as is often the case, is a cises are performed in controlled fashion according to
special challenge in the treatment of patients with the principles of cognitive behavioral therapy (CBT).
anxiety disorders (28). Drug discontinuation must Patients with panic disorder, in particular, are con-
often take place in an inpatient setting, and only a few fronted with so-called interoceptive stimuli (as an
of the pertinent treatment recommendations are sup- exercise, including, for instance, 60 seconds of hyper-
ported by adequate evidence. ventilation under supervision); patients with agora-
While cognitive behavioral therapy and psycho- phobia are confronted with so-called situational
pharmacotherapy are considered first-line treatments stimuli (e.g., taking a train ride by oneself). It is im-
for anxiety disorders, further treatment strategies portant for the patient to discuss the exercise after-
have been studied and applied in routine clinical prac- ward with the physician in order to reinforce the new
tice in recent years, such as the following: experience and solidify the associated learning
● Metacognitive therapy (29) achievement. The stimuli that were originally felt to
● Acceptance and commitment therapy (ACT) (30) be anxiety-producing are now judged more appropri-
● Mindfulness-based techniques (31) ately. Trained medical practice assistants can serve as
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TABLE 2
case managers to help the patient carry out these exer- fail to improve rapidly under the care of the primary
cises: they telephone the patient regularly to record care physician, a psychiatrist or psychotherapist
the patient’s current disease manifestations with the should be consulted without delay. It has been shown
aid of a brief symptom checklist. This list is at the that the ambulatory treatment of patients with panic
center of communication between the physician, the disorder and agoraphobia with exposure therapy is
patient, and the practice assistant (37); it permits rapid more effective when carried out under direct super-
assessment of the patient’s situation and reliable vision than when carried out by the patient alone
transmission of this information to the physician, who according to directions (22). Supervision of the ex-
can then respond in timely fashion. If the symptoms posure places a heavy psychological demand on the
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BOX
Little Kids program was significantly superior to con-
trol (no treatment) in a population of 3- to 5-year-old
The off-label use of drugs that have not been approved for preschool children: the preventive intervention signifi-
the treatment of anxiety disorders cantly lowered the incidence of anxiety disorders at 12
(p = 0.03), 24 (p = 0.03), and 36 (p = 0.01) months, and
The atypical antipsychotic drug quetiapine has not been approved for the treat- even after a further follow-up period of 11 years—but
ment of anxiety disorders. Still, a meta-analysis of three randomized, double- then only among the girls, who were about 15 years old
blind, placebo-controlled trials of this drug for the treatment of generalized by that time (Cohen’s d = 0.55, p = 0.04) (e16, e17).
anxiety disorder (GAD), given for a period of 10 weeks in each trial, showed Targeted prevention in persons who already display
that it is significantly more effective than placebo in the 50 to 300 mg/day dose subclinical symptoms has been shown to significantly
range, albeit with an unfavorable profile of metabolic side effects (e10). lessen the rate of development of clinically relevant
Agomelatine acts as an agonist at melatonin MT1- and MT2-receptors and anxiety disorders and is thus probably the most cost-
as an antagonist at the serotonin 2C receptor. Multiple studies published from effective primary measure. Meta-analyses have re-
2008 onward have shown it to be well tolerated and highly effective against vealed low effect strengths for the prevention of
GAD in the 25–50 mg/day dose range (e11), yet this drug has not been anxiety; targeted measures were found to be somewhat
approved for the treatment of anxiety disorders either. more effective than universal ones right after the inter-
Silexan, a patented active substance derived from lavender oil, has been vention (Cohen’s d = 0.26 versus 0.17 [e18, e19]). The
approved since 2009 in Germany for the treatment of subsyndromal anxiety prevention manuals now available in the German-
and tension states at a daily dose of 80 mg, but not for the treatment of anxiety speaking countries include, for example, the Friends
disorders. Nonetheless, randomized controlled trials (RCTs) have shown its program; the Separation Anxiety Program for
effectiveness against GAS and so-called mixed anxiety and depression (e12). Families (Trennungsangstprogramm für Familien,
TAFF); the Being Brave with Til Tiger program
(Mutig werden mit Til Tiger); and the Health and Op-
timism Program (Gesundheits- und Optimismus-Pro-
gramm). The encouraging initial data imply that pre-
therapist as well (38); this can be observed in the ventive measures against mental illnesses, and in
activation of the stress hormone system, particularly particular against anxiety disorders, which are very
with massive exposure (flooding) (39). common and socioeconomically relevant, urgently
need to be studied further, systematically, and in de-
Prevention tail. If their effects can be confirmed, these measures
The development and assessment of preventive should be implemented in timely fashion in the
measures against anxiety disorders should have a high healthcare system.
priority in view of these disorders’ high prevalence and
chronicity, the severity of the suffering that they cause,
Conflict of interest statement
their high socioeconomic costs, and their role as precur- The authors declare that no conflict of interest exists.
sors of depression and substance-abuse disorders and as
complicating factors in somatic disease (40). Universal Manuscript submitted on 30 April 2018, revised version accepted on
31 July 2018.
preventive measures, applied regardless of the risk
status of the individual, might prevent many cases of Translated from the original German by Ethan Taub, M.D.
clinically manifest anxiety disorders, even if their indi- References
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2016; 18: 23. Internet: cme.aerzteblatt.de. This unit can be accessed until 9 Decem-
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Only one answer is possible per question. Please choose the most appropriate answer.
Question 1 Question 6
What is the approximate 12-month prevalence of anxiety Which of the following substances is effective against
disorders among 14- to 65-year-olds in Europe? generalized anxiety disorder, according to clinical
a) 5% trials, but not approved for this purpose in Germany?
b) 14% a) Lavender oil extract
c) 24% b) Oil of St. John’s wort
d) 34% c) Ginger extract
e) 44% d) Thyme extract
e) Sage extract
Question 2
What is the most common type of anxiety disorder? Question 7
a) Selective mutism What is a typical feature of a panic disorder?
b) Panic disorder a) Panic attacks arise exclusively in certain situations.
c) Specific phobia b) Panic attacks begin unexpectedly.
d) Social phobia c) The patient has a constant feeling of panic.
e) Generalized anxiety disorder d) The patient complains of persistent worry.
e) Hypochondriac fears are expressed.
Question 3
What percentage of the development of anxiety disorders Question 8
is accounted for by genetic factors? What type of complementary treatment can be used
a) 1–27% beneficially in patients with anxiety disorders?
b) 30–67% a) Bioresonance tomography
c) 40–77% b) Aggression training
d) 50–87% c) Hypnosis
e) 60–97% d) Physical activity and exercise
e) Bach blossom therapy
Question 4
What type of psychotherapy is the treatment of first choice Question 9
for anxiety disorders? How long after the end of the acute phase of success-
a) Psychoanalysis ful drug treatment for panic disorder should the drug
b) Cognitive behavioral therapy be continued for maintenance therapy?
c) Psychodynamic psychotherapy a) 1 to 3 months
d) Talk psychotherapy b) 3 to 6 months
e) Eye movement desensitization and reprocessing (EMDR) c) 6 to 12 months
d) 12 to 18 months
e) 18 to 24 months
Question 5
What psychoactive drug(s) is/are the first line of drug
therapy for anxiety disorders? Question 10
a) Benzodiazepines What is a typical feature of selective mutism?
b) Selective serotonin a) It is a disease of old age.
(and norepinephrine) reuptake inhibitors b) The patient has a marked fear of bodily contact.
c) Lithium c) Girls of pubertal age are often affected.
d) Neuroleptic drugs d) The patient cannot speak in certain situations.
e) T tricyclic antidepressants e) The patient cannot make eye contact.
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Deutsches Ärzteblatt International | Dtsch Arztebl Int 2018; 115: 611–20 | Supplementary material I