Generalized anxiety disorder (GAD) is a common psychiatric condition recognized in modern classification systems. Both the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the International Classification of Diseases (ICD-11) include this diagnosis, describing a similar range of symptoms. The DSM-5 emphasizes the presence of excessive anxiety and worry that is difficult to control. Additional symptoms include restlessness, muscle tension, difficulty concentrating, a feeling of blankness, irritability, and sleep disturbances.
The ICD-11 highlights the presence of general apprehension (or "floating anxiety") or excessive worry about negative events that occur in everyday life. Associated symptoms include restlessness, tension, sympathetic autonomic hyperactivity, difficulty concentrating, irritability, and sleep disorders. Both systems require that symptoms be present on most days for at least 6 months (DSM-5) or several months (ICD-11), and result in some degree of functional impairment.
Cohort studies have identified certain etiological factors associated with the development of GAD, such as a family history of anxiety, depression or any psychiatric disorder, female sex, personality dimension of "neuroticism", stressful events in childhood and low economic resources. Compared to other psychiatric disorders, its onset is relatively late, in early or middle adulthood. The longitudinal persistence of GAD is substantial and is associated with younger age of onset, low educational and economic level, and lack of employment.
Several studies have investigated the neurobiological basis of GAD, including the role of certain neurotransmitters and their metabolites. GAD is associated with increased serum levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol and α2-adrenocopter sensitivity.
Urinary concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid, are positively correlated with somatic anxiety symptoms in patients with GAD. Neuroimaging studies have identified structural and functional differences relative to healthy controls. Common findings include increased amygdala and decreased hippocampal gray matter volume, increased connectivity between amygdala and prefrontal cortex, and increased amygdala activation in response to threatening stimuli.
Most patients with GAD have additional psychiatric comorbidities , most commonly major depressive disorder (MDD), specific phobias, and substance abuse disorder. Among all physical and psychiatric illnesses, anxiety disorders are the sixth leading cause of disability worldwide.
| Current pharmacological treatment options in generalized anxiety disorder |
A recent systematic review and network meta-analysis identified randomized controlled trials (RCTs) in adult patients with GAD treated in an outpatient setting, with the primary outcomes of interest being change in Hamilton Anxiety Scale (HAM-A) score. ) and tolerability (measured by trial dropout rate). The available evidence provides good support for the particular efficacy and tolerability of duloxetine, escitalopram, pregabalin and venlafaxine in GAD. Although quetiapine shows the greatest efficacy, it is also associated with the worst tolerability.
> Selective serotonin reuptake inhibitors (SSRIs).
Evidence supports the effectiveness of citalopram, escitalopram, fluoxetine, paroxetine, and sertraline.
SSRIs are prescribed as first-line treatment for major depressive disorder (MDD), panic disorder, social anxiety disorder (SAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). They are relatively safe in overdose. Its adverse effects include gastrointestinal effects (nausea, vomiting, changes in bowel habit), sedation, sexual dysfunction, and risk of bleeding.
Anxiety symptoms may increase in the first 2 weeks of treatment. Citalopram and escitalopram are also associated with a dose-dependent effect on QT interval prolongation. Paroxetine has an additional anticholinergic action with associated adverse effects, which explains the higher discontinuation rate. SSRIs are associated with discontinuation/withdrawal symptoms when treatment is discontinued. This is more common and serious with antidepressants with a shorter half-life, such as paroxetine.
> Serotonin and norepinephrine reuptake inhibitors (SNRIs).
Venlafaxine and duloxetine are widely used in psychiatric practice, with good efficacy and tolerability. The adverse effect profile is very similar to that of SSRIs. Additional adverse effects are related to increased noradrenergic stimulation: dry mouth, increased sweating, urinary retention, blurred vision and constipation. Both are also associated with a dose-dependent increase in blood pressure. Venlafaxine has a relatively short half-life, and is associated with a more marked discontinuation/withdrawal syndrome.
> Tricyclic antidepressants (TCA) and related drugs.
There is little evidence to support its use in GAD. TCAs act mainly through the inhibition of serotonin (TSER) and norepinephrine (TNA) transporters to different degrees. RCTs generally did not demonstrate efficacy.
> Additional serotonin modulating antidepressants.
There is evidence supporting the effectiveness of agomelatine and mirtazapine in the treatment of GAD. Agomelatine exerts agonist effects at melatonin 1 and 2 receptors and antagonist effects at 5-HT 2C receptors . It is relatively well tolerated, but is associated with adverse reactions including nausea, dizziness, sedation, gastrointestinal upset, and, rarely, abnormal liver function tests and hepatotoxicity. Mirtazapine exerts antagonistic effects on multiple types of receptors (α2-adrenergic, 5-HT 2 , 5-HT 3 and H 1 ). Its main adverse effects are weight gain and sedation. Similar evidence was not found for the newer modulators vilazodone and vortioxetine.
> Norepinephrine-dopamine reuptake inhibitors (NDRI).
The only IRND widely used in psychiatric practice is bupropion, which inhibits both TNA and the dopamine transporter (TDA), increasing the extracellular concentrations of both neurotransmitters. Its adverse effects include dry mouth, insomnia, increased anxiety, gastrointestinal discomfort, sweating, and hypertension. Higher doses are associated with reduced seizure threshold and appetite suppression.
> Azapirones
They act as anxiolytics through partial 5-HT 1A agonism . RCTs support the efficacy of buspirone in the short-term treatment of GAD. It has a short half-life, requiring multiple daily doses. Its adverse effects include nausea, dizziness, headache and akathisia.
> Gabapentinoids
Gabapentinoids, such as gabapentin and pregabalin, are derivatives of gamma-aminobutyric acid (GABA) and show a high affinity for the α2δ subunit of voltage-gated calcium channels, disrupting their function. They are widely used due to their analgesic, anticonvulsant and anxiolytic effect. Several RCTs support the efficacy of pregabalin in the treatment of GAD. It is generally well tolerated, with adverse effects including drowsiness, dizziness, vertigo, weight gain, and discontinuation effects with abrupt discontinuation. In recent years, gabapentinoids have been recognized as having addictive potential with misuse. Therefore, these drugs have been classified as controlled drugs in several countries.
> Antihistamines
Hydroxyzine has demonstrated efficacy vs. placebo in TAG. Its mechanism of action is inverse agonism of the H 1 receptor ; however, it shows weak antagonism at the 5-HT 2A receptor , which is not seen with other antihistamines. The main adverse effect observed is daytime drowsiness, which usually resolves by day 10 of treatment.
> Anticonvulsants
Tiagabine acts through selective inhibition of the GABA transporter (GAT-1). There is no evidence to support its effectiveness in GAD over placebo.
> Antipsychotics
Quetiapine showed the greatest efficacy in the treatment of GAD at doses of 50 to 300 mg/day. However, it was also associated with significant treatment dropout rates. This drug is widely used in the treatment of patients with schizophrenia, bipolar disorder or unipolar depression. Its common adverse effects include sedation, dizziness, and weight gain. Unlike other antipsychotics, it is rarely associated with extrapyramidal side effects or hyperprolactinemia. No other antipsychotic has been considered as monotherapy for GAD.
> Benzodiazepines and non-benzodiazepines
Benzodiazepines (BDZ) act through positive allosteric modulation of GABA A receptors , increasing their affinity to endogenous GABA. RCTs of BDZ in GAD show efficacy, although with high dropout rates. BDZs with relatively long half-lives are preferred, to prevent the need for multiple daily doses. Adverse effects include cognitive effects (sedation, drowsiness, and mental slowing), psychomotor impairment, and development of tolerance and dependence.
Non-BDZ hypnotics (or "Z drugs") are positive allosteric modulators of the GABA A receptor but of different chemical classes. They are widely used as hypnotics, but have not yet been incorporated into clinical practice for the treatment of anxiety disorders.
| Current guidelines on the treatment of generalized anxiety disorder |
Current consensus guidelines summarize current evidence and suggested treatments for GAD. Guidelines from the World Federation of Societies for Biological Psychiatry 2022 (WFSBP) and the British Association for Psychopharmacology (BAP) 2014 are included.
> Initial pharmacological treatment
The WFSBP guidelines advise offering an SSRI or SNRI as first-line pharmacological treatment. Because of its potential for abuse, pregabalin is suggested as a second-line treatment. BDZs are only recommended if SSRIs or SNRIs are not tolerated. The BAP guidelines recommend SSRIs as first-line treatment, and SNRIs and pregabalin as alternative options. A trial of at least 12 weeks is recommended for first-line treatment; lack of response within the first 4 weeks is predictive of failure. There is no strong evidence that dose increases of SSRIs or SNRIs improve response, although pregabalin may have greater efficacy at higher doses.
> Resistance to initial pharmacological treatment
Failure of response or remission to initial drug treatment is common and is estimated at 40-50%.
Treatment resistance in anxiety disorders usually refers to the failure of a first-line pharmacological treatment. The possible causes can be divided into pseudo or true resistance. "Pseudo-resistance" includes the use of ineffective drugs, treatments at inappropriate doses or durations, and, most commonly, poor medication adherence. “True resistance” may result from substance use, sleep deprivation, initial misdiagnosis of GAD and/or undiagnosed comorbid psychiatric conditions or, rarely, an underdiagnosed medical condition (such as hyperthyroidism).
Resistance to initial treatment should prompt further evaluation of the patient and consideration of possible resolvable causes. Suggested pharmacologic options after lack of response to initial treatment include switching to a different SSRI or SNRI, pregabalin, agomelatine, vilazodone, buspirone, imipramine, hydroxyzine, quetiapine, and trazodone. Specific BDZs may be used, as long as the patient has no history of substance use disorder. Combined pharmacological treatment is also suggested, considering the addition of olanzapine to fluoxetine treatment, or the addition of pregabalin to an SSRI or SNRI.
> Psychological therapies
Various forms of psychotherapy have been investigated for GAD, including cognitive behavioral therapy (CBT), applied relaxation (AR), psychodynamic psychotherapy, and mindfulness-based psychotherapy. CBT has been widely studied with evidence of effectiveness in GAD and guidelines support its use as a first-line treatment, although effectiveness is usually greater with pharmacological treatments.
> Management of psychiatric comorbidities
As most patients with GAD have psychiatric comorbidities, management of these comorbidities should occur along with treatment of GAD. Specific treatment will depend on the nature and severity of the comorbid condition and may include pharmacological treatment. Many pharmacological treatments in GAD, such as SSRIs or SNRIs, are effective in MDD and other anxiety disorders, and choosing a single effective pharmacological treatment for GAD and psychiatric comorbidity is a sensible strategy. In patients with a diagnosis or suspicion of bipolar affective disorder (BAD), the risk that a pharmacological treatment induces mania or hypomania should be considered. Finally, in patients with comorbid substance abuse, the potential for interactions between such substances and pharmacological agents (particularly BDZ and pregabalin) should be considered.
> Treatment of GAD in pregnancy and postpartum
Although studies of GAD during pregnancy and postpartum are limited, evidence suggests a higher postpartum prevalence. The decision to initiate or continue drug treatment during this period must consider the risks of potential harm to the fetus or infant balanced with the risk of untreated GAD. For the recommended first-line treatment (SSRIs), its use in pregnancy is associated with a small reduction in gestational age and birth weight and an increased risk of postpartum hemorrhage. There may be an increased risk of heart defects and persistent pulmonary hypertension in the newborn particularly with paroxetine, although this association may result from confounding factors.
SSRI use is associated with short-term neonatal syndrome characterized by irritability, nervousness, vomiting, and difficulty eating and sleeping. SSRIs are present in breast milk, with lower levels of exposure with sertraline and paroxetine. Due to the increased risk of discontinuation symptoms with paroxetine, sertraline is the SSRI of choice in nursing mothers. Psychological therapies may be the preferred initial treatment option in these circumstances, to avoid potential risks to the fetus or infant.
> Treatment of GAD in older adults
Epidemiological studies have estimated a prevalence of GAD of 1.3% to 3.7% in older adults, in line with the general population. Most trials of drug therapy for GAD have excluded this population; however, individual RCTs have demonstrated the efficacy of citalopram, pregabalin, and quetiapine.
Current treatment guidelines recommend similar drug use, although the greater sensitivity to adverse effects of this group of patients is recognized, such as increased risk of syndrome of inappropriate antidiuretic hormone secretion, sensitivity to extrapyramidal symptoms, prolongation of the QT C , and orthostatic hypotension (with resulting dizziness and falls). The use of TTC in the treatment of older adults is supported.
> Treatment of GAD in children/adolescents
The age of onset of GAD is relatively late with a median of 32 years. In children aged 5 to 16 years in the UK, 0.7% were found to have GAD. The presence of comorbid anxiety disorders seems particularly common in this group of patients. Psychological treatments are preferred, although guidelines recommend the use of SSRIs as first-line pharmacological treatment.
> Maintenance treatment
The efficacy and need for long-term drug treatment can be evaluated with placebo-controlled relapse prevention trials. Current guidelines advise continuing drug treatment after a relapse for at least several (or 6) months.
| Future developments in the pharmacological treatment of GAD |
Effective pharmacological treatments in GAD suggest modulation of the serotonin or GABA neurotransmitter systems as the basis for most effective treatments. However, several additional neurotransmitter systems have been implicated in the neurobiology of GAD and other anxiety disorders. These include glutamate and several neuropeptides, such as neuropeptide Y (NPY), tachykinins, corticotropin-releasing factor (CRF), oxytocin, orexin, and endocannabinoids.
The influence of the immune system and pro-inflammatory mechanisms is also considered, recent and ongoing developments of new anxiolytics based on serotonergic or alternative GABAergic modulation, through glutamate or neuropeptide modulation, and through of the immune system.
> New serotonergic agents
Several additional 5-HT 1A partial agonists are currently under development for the treatment of anxiety disorders. Azapirone gepirone has been shown to improve symptoms in patients with comorbid GAD and panic disorder with agoraphobia. In patients with MDD and anxiety symptoms, boosting SSRI treatment with azapirone tandospirone improved depressive symptoms and anxiety. A 5-HT 1A partial agonist with 5-HT 2 antagonist actions (FKW00GA) is under development with efficacy in phase 2 trials in GAD.
In recent years there has been a resurgence of interest in psychedelics, pharmacological compounds that alter consciousness in a variety of ways. These are produced naturally by plants, fungi and animals, and have been used by different cultures throughout history. The current consensus is that psychedelics act through agonism or partial agonism of 5-HT 2A receptors . There is some evidence for the use of psilocybin in the treatment of depression, and limited evidence to support the potential anxiolytic effect of these agents.
> New GABAergic agents
Different subtypes of GABA A receptors are selectively expressed throughout the brain and appear to have different functions. The α subunit of the GABA A receptor is of particular importance, with the α1 subunit mediating the sedative effects of BZDs, and the α2/3 subunits mediating the anxiolytic effects. Several positive allosteric modulators for α2/α3-GABA A receptors have been developed , with some progress in studies of patients with anxiety disorders, but without conclusive results to date.
> Glutamatergic agents
The dissociative anesthetic ketamine has been used in recent years for the treatment of depression, either intravenously (IV) or intranasally as esketamine.
Ketamine/esketamine is a strong glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, with actions on monoamine, opioid and cholinergic neurotransmitter systems. Many trials demonstrated the short-term effectiveness of ketamine in the treatment of depression. No RCTs have been conducted to date for the use of ketamine in GAD, although combined analysis of two RCTs conducted for SAD supported the efficacy of ketamine vs. placebo. Metabotropic glutamate receptors, particularly mGluR2 and mGluR3 have been identified as a potential anxiolytic target.
> Neuropeptides
Neuropeptide Y (NPY) is expressed throughout the brain, and has been implicated in the stress response. To date, NPY modulating treatment has not been investigated in clinical populations with GAD.
The tachykinin system is a neuropeptide system involved in a variety of physiological functions. It consists of several neuropeptides and three neurokinin receptors. Substance P (SP) is widely expressed throughout the brain and preferentially binds to the neurokinin 1 receptor (NK1R). SP and NK1R have been implicated in the stress and anxiety response in animal studies. NK1R antagonists showed promise in animal models and were translated into clinical populations, but without success to date.
Corticotropin-releasing factor/hormone (CRF/CRH) is a peptide hormone secreted by the hypothalamus in response to stress. It stimulates ACTH secretion and is a component of the hypothalamic-pituitary-adrenal (HPA) axis. CRF binds to two different receptors (CRF1 and CRF2) that are expressed in the hypothalamus and other brain regions. An anxiogenic (and pro-depressive) function of CRF1 receptors was identified in animal studies, leading to the development of several receptor antagonists. But the studies are not promising yet.
The neuropeptide oxytocin (OT) is a hormone secreted by the posterior pituitary with physiological functions (milk ejection, uterine contraction during labor) and behavioral roles (maternal behavior, pair bonding). It exerts these actions through binding to its receptor OXTR, which is widely expressed throughout the brain. An anxiolytic effect of OT has been identified in rodent models and several translational studies have been performed in humans with SAD, using exogenous OT intranasally.
The orexin neurotransmitter system comprises two neuropeptides (orexin-A and orexin-B) and two G protein-coupled receptors (types 1 and 2). The orexin system plays an important regulatory role in the sleep-wake cycle, stress response, motivation, reward processing, and arousal.
Studies with orexin receptor antagonists (ORAs) in healthy volunteers have shown a potential anxiolytic effect. Multiple ORAs are used in clinical practice for the treatment of insomnia, and there is evidence of a reduction in anxiety symptoms when used for this purpose. To date, no study has investigated the effect of an orexin modulating agent in an anxiety disorder population.
The endocannabinoid system is a neurotransmitter system consisting of endogenous ligands (anandamide and 2-AG) and two cannabinoid receptors (CB 1 and CB 2 ). Exogenous ligands for cannabinoid receptors are produced by the cannabis plant (Cannabis sativa). Identified phytocannabinoids include Δ9 - tetrahydrocannabinol (Δ9 - THC) and cannabidiol (CBD). CBD lacks the psychotomimetic effects of Δ9 - THC and animal studies indicate a potential anxiolytic effect. However, to date, there are limited clinical studies on the effect of cannabinoids on anxiety disorders.
> Immunological treatments
Interactions between the immune system and the central nervous system have been implicated in several psychiatric diseases, including anxiety disorders. Multiple studies have measured peripheral inflammatory markers in GAD, with elevated serum levels of C-reactive protein, interferon-γ, and tumor necrosis factor-α.
Patients treated for a “first episode” of GAD with SSRIs show a reduction in serum levels of pro-inflammatory cytokines, suggesting an anti-inflammatory effect of anxiolytic treatments. To date, only one RCT has investigated the effect of anti-inflammatory treatment on GAD. This study compared adjuvant treatment with simvastatin vs. placebo for 8 weeks. However, no significant differences in HAM-A score were observed between the groups.
| Conclusion |
GAD is a common psychiatric illness associated with considerable disability and much comorbidity. Current treatment guidelines support the use of SSRIs as first-line pharmacological treatment, with SNRIs and pregabalin suggested if SSRIs are not effective or well tolerated.
A wide range of neurotransmitter and hormone systems are under investigation as potential targets for new anxiolytic treatments. Most trials have not demonstrated efficacy; however, trials with psilocybin, ketamine, and oxytocin showed promise. Larger scale clinical trials are necessary to determine efficacy.
| Expert opinion |
Epidemiological data consistently demonstrate that GAD is frequent, persistent, disabling, and in most cases, comorbid with other psychiatric diseases. Despite the large number of effective anxiolytic treatments, a substantial minority of patients obtain limited benefit from current pharmacological treatment.
Most RCTs in GAD have been relatively short and focused on the efficacy of first-line pharmacological treatment. Current guidelines recommend continuing drug treatments for ≥6 months, but it is unclear how much longer treatment benefits could extend. Furthermore, the epidemiology and management of treatment resistance in GAD have not been explored in detail. Developing a clear definition of treatment-resistant GAD will allow for additional studies in this area.
