What is Trifluoperazine?

Introduction

Trifluoperazine, sold under a number of brand names, is a typical antipsychotic primarily used to treat schizophrenia.

It may also be used short term in those with generalised anxiety disorder but is less preferred to benzodiazepines. It is of the phenothiazine chemical class.

Medical Uses

Schizophrenia

Trifluoperazine is an effective antipsychotic for people with schizophrenia. There is low-quality evidence that trifluoperazine increases the chance of being improved when compared to placebo when people are followed up for 19 weeks. There is low-quality evidence that trifluoperazine reduces the risk of relapse when compared with placebo when people are followed for 5 months. As of 2014 there was no good evidence for a difference between trifluoperazine and placebo with respect to the risk of experiencing intensified symptoms over a 16-week period nor in reducing significant agitation or distress.

There is no good evidence that trifluoperazine is more effective for schizophrenia than lower-potency antipsychotics like chlorpromazine, chlorprothixene, thioridazine and levomepromazine, but trifluoperazine appears to cause more adverse effects than these drugs.

Other

It appears to be effective for people with generalised anxiety disorder but the benefit-risk ratio was unclear as of 2005.

It has been experimentally used as a drug to kill eukaryotic pathogens in humans.

Side Effects

Its use in many parts of the world has declined because of highly frequent and severe early and late tardive dyskinesia, a type of extrapyramidal symptom. The annual development rate of tardive dyskinesia may be as high as 4%.

A 2004 meta-analysis of the studies on trifluoperazine found that it is more likely than placebo to cause extrapyramidal side effects such as akathisia, dystonia, and Parkinsonism. It is also more likely to cause somnolence and anticholinergic side effects such as red eye and xerostomia (dry mouth). All antipsychotics can cause the rare and sometimes fatal neuroleptic malignant syndrome. Trifluoperazine can lower the seizure threshold. The antimuscarinic action of trifluoperazine can cause excessive dilation of the pupils (mydriasis), which increases the chances of patients with hyperopia developing glaucoma.

Contraindications

Trifluoperazine is contraindicated in CNS depression, coma, and blood dyscrasias. Trifluoperazine should be used with caution in patients suffering from renal or hepatic impairment.

Mechanism of Action

Trifluoperazine has central antiadrenergic, antidopaminergic, and minimal anticholinergic effects. It is believed to work by blockading dopamine D1 and D2 receptors in the mesocortical and mesolimbic pathways, relieving or minimising such symptoms of schizophrenia as hallucinations, delusions, and disorganised thought and speech.

Names

Brand names include Eskazinyl, Eskazine, Jatroneural, Modalina, Stelazine, Stilizan, Terfluzine, Trifluoperaz, Triftazin.

In the United Kingdom and some other countries, trifluoperazine is sold and marketed under the brand ‘Stelazine’.

The drug is sold as tablet, liquid and ‘Trifluoperazine-injectable USP’ for deep intramuscular short-term use. GP studying pharmacological data has indicated cases of neck vertebrae irreversible fusing leading to NHS preparations being predominantly of the liquid form trifluoperazine as opposed to the tablet form as in Stela zine etc.

In the past, trifluoperazine was used in fixed combinations with the MAO inhibitor (antidepressant) tranylcypromine (tranylcypromine/trifluoperazine) to attenuate the strong stimulating effects of this antidepressant. This combination was sold under the brand name Jatrosom N. Likewise a combination with amobarbital (potent sedative/hypnotic agent) for the amelioration of psychoneurosis and insomnia existed under the brand name Jalonac. In Italy the first combination is still available, sold under the brand name Parmodalin (10 mg of tranylcypromine and 1 mg of trifluoperazine).

What is Venlafaxine?

Introduction

Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.

It is used to treat major depressive disorder (MDD), generalised anxiety disorder (GAD), panic disorder, and social phobia. It may also be used for chronic pain. It is taken by mouth.

Common side effects include loss of appetite, constipation, dry mouth, dizziness, sweating, and sexual problems. Severe side effects include an increased risk of suicide, mania, and serotonin syndrome. Antidepressant withdrawal syndrome may occur if stopped. There are concerns that use during the later part of pregnancy can harm the baby. How it works is not entirely clear, but it seems to be related to the potentiation of the activity of some neurotransmitters in the brain.

Venlafaxine was approved for medical use in the United States in 1993. It is available as a generic medication. In 2018, it was the 50th most commonly prescribed medication in the United States with more than 16 million prescriptions.

Medical Uses

Venlafaxine is used primarily for the treatment of depression, general anxiety disorder, social phobia, panic disorder, and vasomotor symptoms.

Venlafaxine has been used off label for the treatment of diabetic neuropathy and migraine prevention (in some people, however, venlafaxine can exacerbate or cause migraines). It may work on pain via effects on the opioid receptor. It has also been found to reduce the severity of ‘hot flashes’ in menopausal women and men on hormonal therapy for the treatment of prostate cancer.

Due to its action on both the serotoninergic and adrenergic systems, venlafaxine is also used as a treatment to reduce episodes of cataplexy, a form of muscle weakness, in patients with the sleep disorder narcolepsy. Some open-label and three double-blind studies have suggested the efficacy of venlafaxine in the treatment of attention deficit-hyperactivity disorder (ADHD). Clinical trials have found possible efficacy in those with post-traumatic stress disorder (PTSD). Case reports, open trials and blinded comparisons with established medications have suggested the efficacy of venlafaxine in the treatment of obsessive-compulsive disorder (OCD).

Depression

A comparative meta-analysis of 21 major antidepressants found that venlafaxine, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, and vortioxetine were more effective than other antidepressants, although the quality of many comparisons was assessed as low or very low.

Venlafaxine was similar in efficacy to the atypical antidepressant bupropion; however, the remission rate was lower for venlafaxine. In a double-blind study, patients who did not respond to an SSRI were switched to either venlafaxine or another SSRI (citalopram); similar improvement was observed in both groups.

Studies of venlafaxine in children have not established its efficacy.

Studies have shown that the extended release is superior to the immediate release form of venlafaxine.

A meta-analysis shown that efficacity of venlafaxine is not correlated with baseline severity of depression.

Dosage

Venlafaxine has been shown to have an optimal efficacity and tolerability towards the lower end of their licensed dose range.

Contraindications

Venlafaxine is not recommended in patients hypersensitive to it, nor should it be taken by anyone who is allergic to the inactive ingredients, which include gelatin, cellulose, ethylcellulose, iron oxide, titanium dioxide and hypromellose. It should not be used in conjunction with a monoamine oxidase inhibitor (MAOI), as it can cause potentially fatal serotonin syndrome.

Adverse Effects

Refer to Adverse Effects of Venlafaxine.

Venlafaxine can increase eye pressure, so those with glaucoma may require more frequent eye checks.

A 2017 meta-analysis estimated venlafaxine discontinuation rate to 9.4%.

Suicide

The US Food and Drug Administration (FDA) requires all antidepressants, including venlafaxine, to carry a black box warning with a generic warning about a possible suicide risk.

A 2014 meta analysis of 21 clinical trials of venlafaxine for the treatment of depression in adults found that compared to placebo, venlafaxine reduced the risk of suicidal thoughts and behaviour.

A study conducted in Finland followed more than 15,000 patients for 3.4 years. Venlafaxine increased suicide risk by 60% (statistically significant), as compared to no treatment. At the same time, fluoxetine (Prozac) halved the suicide risk.

In another study, the data on more than 200,000 cases were obtained from the UK general practice research database. At baseline, patients prescribed venlafaxine had a greater number of risk factors for suicide (such as prior suicide attempts) than patients treated with other anti-depressants. The patients taking venlafaxine had significantly higher risk of completed suicide than the ones on fluoxetine or citalopram (Celexa). After adjusting for known risk factors, venlafaxine was associated with an increased risk of suicide relative to fluoxetine and dothiepin that was not statistically significant. A statistically significant greater risk for attempted suicide remained after adjustment, but the authors concluded that it could be due to residual confounding.[28]

An analysis of clinical trials by the FDA statisticians showed the incidence of suicidal behaviour among the adults on venlafaxine to be not significantly different from fluoxetine or placebo.

Venlafaxine is contraindicated in children, adolescents and young adults. According to the FDA analysis of clinical trials venlafaxine caused a statistically significant 5-fold increase in suicidal ideation and behaviour in persons younger than 25. In another analysis, venlafaxine was no better than placebo among children (7-11 years old), but improved depression in adolescents (12-17 years old). However, in both groups, hostility and suicidal behaviour increased in comparison to those receiving a placebo. In a study involving antidepressants that had failed to produce results in depressed teenagers, teens whose SSRI treatment had failed who were randomly switched to either another SSRI or to venlafaxine showed an increased rate of suicide on venlafaxine. Among teenagers who were suicidal at the beginning of the study, the rate of suicidal attempts and self-harm was significantly higher, by about 60%, after the switch to venlafaxine than after the switch to an SSRI.

Discontinuation Syndrome

Refer to Antidepressant Discontinuation Syndrome.

People stopping venlafaxine commonly experience discontinuation symptoms such as dysphoria, headaches, nausea, irritability, emotional lability, sensation of electric shocks, and sleep disturbance. Venlafaxine has a higher rate of moderate to severe discontinuation symptoms relative to other antidepressants (similar to the SSRI paroxetine).

The higher risk and increased severity of discontinuation syndrome symptoms relative to other antidepressants may be related to the short half-life of venlafaxine and its active metabolite. After discontinuing venlafaxine, the levels of both serotonin and norepinephrine decrease, leading to the hypothesis that the discontinuation symptoms could result from an overly rapid reduction of neurotransmitter levels.

Serotonin Syndrome

Refer to Serotonin Syndrome.

The development of a potentially life-threatening serotonin syndrome (also more recently classified as “serotonin toxicity”) may occur with venlafaxine treatment, particularly with concomitant use of serotonergic drugs, including but not limited to SSRIs and SNRIs, many hallucinogens such as tryptamines and phenethylamines (e.g. LSD/LSA, DMT, MDMA, mescaline), dextromethorphan (DXM), tramadol, tapentadol, pethidine (meperidine) and triptans and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Venlafaxine-induced serotonin syndrome has also been reported when venlafaxine has been taken in isolation in overdose. An abortive serotonin syndrome state, in which some but not all of the symptoms of the full serotonin syndrome are present, has been reported with venlafaxine at mid-range dosages (150 mg per day). A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5 mg per day) has also been reported.

Pregnancy

There are few well-controlled studies of venlafaxine in pregnant women. A study released in May 2010 by the Canadian Medical Association Journal suggests use of venlafaxine doubles the risk of miscarriage. Consequently, venlafaxine should only be used during pregnancy if clearly needed. A large case-control study done as part of the National Birth Defects Prevention Study and published in 2012 found a significant association of venlafaxine use during pregnancy and several birth defects including anencephaly, cleft palate, septal heart defects and coarctation of the aorta. Prospective studies have not shown any statistically significant congenital malformations. There have, however, been some reports of self-limiting effects on newborn infants. As with other serotonin reuptake inhibitors (SRIs), these effects are generally short-lived, lasting only 3 to 5 days, and rarely resulting in severe complications.

Drug Interactions

Venlafaxine should be taken with caution when using St John’s wort. Venlafaxine may lower the seizure threshold, and co-administration with other drugs that lower the seizure threshold such as bupropion and tramadol should be done with caution and at low doses.

Bipolar Disorder

Venlafaxine is neither recommended nor approved for the treatment of major depressive episodes in bipolar disorder, as it can induce mania or mixed episodes. Venlafaxine appears to be more likely than the SSRIs and bupropion to induce mania and mixed episodes in bipolar patients.

Liver Injury

A rare but serious side effect of venlafaxine is liver injury. It reaches man and female patients with a median age of 44 years. Cessation of venlafaxine is one of the appropriate measure of management. The mechanism of venlafaxine related-liver injury is unclear but may be related to a CYP2D6 polymorphism.

Other

In rare cases, drug-induced akathisia (movement disorder) can occur after use in some people.

Venlafaxine should be used with caution in hypertensive patients. Venlafaxine must be discontinued if significant hypertension persists. It can also have undesirable cardiovascular effects.

Overdose

Most patients overdosing with venlafaxine develop only mild symptoms. Plasma venlafaxine concentrations in overdose survivors have ranged from 6 to 24 mg/l, while postmortem blood levels in fatalities are often in the 10-90 mg/l range. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose. It is usually reserved as a second-line treatment for depression due to a combination of its superior efficacy to the first-line treatments like fluoxetine, paroxetine and citalopram and greater frequency of side effects like nausea, headache, insomnia, drowsiness, dry mouth, constipation, sexual dysfunction, sweating and nervousness.

There is no specific antidote for venlafaxine, and management is generally supportive, providing treatment for the immediate symptoms. Administration of activated charcoal can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed with benzodiazepines or other anticonvulsants. Forced diuresis, hzemodialysis, exchange transfusion, or hemoperfusion are unlikely to be of benefit in hastening the removal of venlafaxine, due to the drug’s high volume of distribution.

Mechanism of Action

Pharmacology

Venlafaxine is usually categorised as a serotonin-norepinephrine reuptake inhibitor (SNRI), but it has also been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It works by blocking the transporter “reuptake” proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin and norepinephrine. Additionally, in high doses it weakly inhibits the reuptake of dopamine, since dopamine is inactivated by norepinephrine reuptake in the frontal cortex. The frontal cortex largely lacks dopamine transporters; therefore venlafaxine can increase dopamine neurotransmission in this part of the brain.

Venlafaxine indirectly affects opioid receptors as well as the alpha2-adrenergic receptor, and was shown to increase pain threshold in mice. These benefits with respect to pain were reversed with naloxone, an opioid antagonist, thus supporting an opioid mechanism.

Pharmacokinetics

Venlafaxine is well absorbed, with at least 92% of an oral dose being absorbed into systemic circulation. It is extensively metabolized in the liver via the CYP2D6 isoenzyme to desvenlafaxine (O-desmethylvenlafaxine, now marketed as a separate medication named Pristiq), which is just as potent an SNRI as the parent compound, meaning that the differences in metabolism between extensive and poor metabolisers are not clinically important in terms of efficacy. Side effects, however, are reported to be more severe in CYP2D6 poor metabolisers. Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the kidneys. The half-life of venlafaxine is relatively short, so patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed dose can result in withdrawal symptoms.

Venlafaxine is a substrate of P-glycoprotein (P-gp), which pumps it out of the brain. The gene encoding P-gp, ABCB1, has the SNP rs2032583, with alleles C and T. The majority of people (about 70% of Europeans and 90% of East Asians) have the TT variant. A 2007 study found that carriers of at least one C allele (variant CC or CT) are 7.72 times more likely than non-carriers to achieve remission after 4 weeks of treatment with amitriptyline, citalopram, paroxetine or venlafaxine (all P-gp substrates). The study included patients with mood disorders other than major depression, such as bipolar II; the ratio is 9.4 if these other disorders are excluded. At the 6-week mark, 75% of C-carriers had remitted, compared to only 38% of non-carriers.

Chemistry

The IUPAC name of venlafaxine is 1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl]cyclohexanol, though it is sometimes referred to as (±)-1-[a-[a-(dimethylamino)methyl]-p-methoxybenzyl]cyclohexanol. It consists of two enantiomers present in equal quantities (termed a racemic mixture), both of which have the empirical formula of C17H27NO2. It is usually sold as a mixture of the respective hydrochloride salts, (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl]cyclohexanol hydrochloride, C17H28ClNO2, which is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioid analgesic tramadol, and more distantly to the newly released opioid tapentadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or RIMAs.

Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release (controlled release) version distributes the release of the drug into the gastrointestinal tract over a longer period than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended release formula has a lower incidence of nausea as a side effect, resulting in better compliance.

Society and Culture

Venlafaxine was originally marketed as Effexor in most of the world; generic venlafaxine has been available since around 2008 and extended release venlaxafine has been available since around 2010.

As of January 2020 venlafaxine is marketed under many brand names worldwide, many with alternative extended release forms (not shown): Adefaxin, Alenthus, Altven, Alventa, Amfax, Anapresin, Ansifix, Arafaxina, Argofan, Arrow Venlafaxine, Axone, Axyven, Benolaxe, Blossom, Calmdown, Dalium, Defaxine, Depefex, Depretaxer, Deprevix, Deprexor, Deprixol, Depurol, Desinax, Dislaven, Dobupal, Duofaxin, Easyfor, Ectien, Eduxon, Efastad, Efaxin, Efaxine, Efectin, Efegen, Efevelon, Efevelone, Efexiva, Efexor, Effegad, Effexine, Effexor, Elafax, Elaxine, Elify, Enpress, Enlafax, Envelaf, Falven, Faxigen, Faxine, Faxiprol, Faxiven, Faxolet, Flavix, Flaxen, Fobiless, Ganavax, Idixor, Idoxen, Intefred, Illovex, Lafactin, Lafaxin, Lanvexin, Laroxin, Levest, Limbic, Linexel, Maxibral, Mazda, Melocin, Memomax, Mezine, Neoxacina, Neoxacina, Nervix, Norafexine, Norezor, Norpilen, Noviser, Nulev, Odiven, Olwexya, Oriven, Paxifar, Politid, Pracet, Prefaxine, Psiseven, Quilarex, Rafax, Senexon, Sentidol, Sentosa, Serosmine, Seroxine, Sesaren, Subelan, Sulinex, Sunveniz, Sunvex, Symfaxin, Tedema, Tifaxin, Tonpular, Trevilor, Tudor, Vafexin, Valosine, Vandral, Velaf, Velafax, Velahibin, Velaxin, Velept, Velpine, Venax, Venaxin, Venaxx, Vencarm, Vencontrol, Vendep, Venegis, Venex, Venexor, Venfalex, Venfax, Ven-Fax, Venfaxine, Venforin, Venforspine, Veniba, Veniz, Venjoy, Venla, Venlabax, Venlablue, Venlabrain, Venladep, Venladex, Venladoz, Venlaf, Venlafab, Venlafaxin, Venlafaxina, Venlafaxine, Venlagamma, Venlalic, Venlamax, Venlamylan, Venlaneo, Venlapine, Venla-Q, Venlasand, Venlatrin, Venlavitae, Venlax, Venlaxin, Venlaxine, Venlaxor, Venlazid, Venlectine, Venlifax, Venlift, Venlix, Venlobax, Venlofex, Venlor, Venorion, Venozap, Vensate, Ventab, Venxin, Venxor, Venzip, Vexamode, Vfax, Viepax, ViePax, Voxafen, Zacalen, Zanfexa, Zaredrop, Zarelis, Zarelix, and Zenexor.

What is Escitalopram?

Introduction

Escitalopram, sold under the brand names Cipralex and Lexapro, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder (MDD) or generalised anxiety disorder (GAD). It is taken by mouth.

Common side effects include trouble sleeping, nausea, sexual problems, and feeling tired. More serious side effects may include suicide in people under the age of 25. It is unclear if use during pregnancy or breastfeeding is safe. Escitalopram is the (S)-stereoisomer (left-handed version) of citalopram (which exists as a racemate), hence the name escitalopram. In other words, escitalopram is a chiral switch of citalopram.

Escitalopram was approved for medical use in the United States in 2002. Escitalopram is sometimes replaced by twice the dose of citalopram. In 2018, it was the 22nd most commonly prescribed medication in the United States with more than 25 million prescriptions.

Brief History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.

The FDA issued the approval of escitalopram for major depression in August 2002 and for GAD in December 2003. On 23 May 2006, the FDA approved a generic version of escitalopram by Teva. On 14 July of that year, however, the US District Court of Delaware decided in favour of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.

In 2006, Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram. This pushed the patent expiration date from 07 December 2009, to 14 September 2011. Together with the 6-month paediatric exclusivity, the final expiration date was 14 March 2012.

Medical Uses

Escitalopram has FDA approval for the treatment of major depressive disorder in adolescents and adults, and generalized anxiety disorder in adults. In European countries and the United Kingdom, it is approved for depression (MDD) and anxiety disorders, these include: GAD, social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder with or without agoraphobia. In Australia it is approved for major depressive disorder.

Depression

Escitalopram was approved by regulatory authorities for the treatment of major depressive disorder on the basis of four placebo-controlled, double-blind trials, three of which demonstrated a statistical superiority over placebo.

Controversy existed regarding the effectiveness of escitalopram compared with its predecessor, citalopram. The importance of this issue followed from the greater cost of escitalopram relative to the generic mixture of isomers of citalopram, prior to the expiration of the escitalopram patent in 2012, which led to charges of evergreening. Accordingly, this issue has been examined in at least 10 different systematic reviews and meta analyses. As of 2012, reviews had concluded (with caveats in some cases) that escitalopram is modestly superior to citalopram in efficacy and tolerability.

A 2011 review concluded that second-generation antidepressants appear equally effective, although they may differ in onset and side effects. Treatment guidelines issued by the National Institute of Health and Clinical Excellence and by the American Psychiatric Association generally reflect this viewpoint.

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective.

Anxiety Disorder

Escitalopram appears to be effective in treating general anxiety disorder, with relapse on escitalopram at 20% rather than placebo at 50%.

Escitalopram appears effective in treating social anxiety disorder.

Other

Escitalopram is effective in reducing the symptoms of premenstrual syndrome, whether taken continuously or in the luteal phase only. There are no good data available for escitalopram as treatment for seasonal affective disorder as of 2021.

Side Effects

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, delayed ejaculation, and anorgasmia.

There is also evidence that SSRIs may cause an increase in suicidal ideation. An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications. The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients.

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in those with congenital long QT syndrome or known pre-existing QT interval prolongation, or in combination with other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. In December 2011, the UK implemented new restrictions on the maximum daily doses at 20 mg for adults and 10 mg for those older than 65 years or with liver impairment. There are concerns of higher rates of QT prolongation and torsades de pointes compared with other SSRIs. The US Food and Drug Administration (FDA) and Health Canada did not similarly order restrictions on escitalopram dosage, only on its predecessor citalopram.

Very Common Effects

Very common effects (>10% incidence) include:

  • Headache (24%).
  • Nausea (18%).
  • Ejaculation disorder (9-14%).
  • Somnolence (4-13%).
  • Insomnia (7-12%).

Common Effects

Common effects (1-10% incidence) include:

  • Insomnia.
  • Somnolence (sleepiness).
  • Dizziness.
  • Paraesthesia.
  • Tremor.
  • Decreased or increased appetite.
  • Anxiety.
  • Restlessness.
  • Abnormal dreams.
  • Libido decreased.
  • Anorgasmia.
  • Sinusitis (nasal congestion).
  • Yawning.
  • Diarrhoea.
  • Constipation.
  • Vomiting.
  • Dry mouth.
  • Excessive sweating.
  • Arthralgia (joint pain).
  • Myalgia (muscular aches and pains).
  • Fatigue.
  • Pyrexia (fever).
  • Impotence (erectile dysfunction).

Psychomotor Effects

The most common effect is fatigue or somnolence, particularly in older adults, although patients with pre-existing daytime sleepiness and fatigue may experience paradoxical improvement of these symptoms. Escitalopram has not been shown to affect serial reaction time, logical reasoning, serial subtraction, multitask, or MacWorth clock task performance.

Discontinuation Symptoms

Refer to Antidepressant Discontinuation Syndrome.

Escitalopram discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as anhedonia (83%), “electric shock” sensations, colloquially called “brain shivers” or “brain zaps” by sufferers. Frequent symptoms in one study were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). Very slow tapering was recommended. There have been spontaneous reports of discontinuation of Lexapro and other SSRIs and SNRIs, especially when abrupt, leading to dysphoric mood, irritability, agitation, anxiety, headache, lethargy, emotional lability, insomnia, and hypomania. Other symptoms such as panic attacks, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), mania, worsening of depression, and suicidal ideation can emerge when the dose is adjusted down.

Sexual Dysfunction

Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as post-SSRI sexual dysfunction (PSSD). Common symptoms include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. Rates are unknown, and there is no established treatment.

Pregnancy

Antidepressant exposure (including escitalopram) is associated with shorter duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion. There is a tentative association of SSRI use during pregnancy with heart problems in the baby. The advantages of their use during pregnancy may thus outweigh the possible negative effects on the baby.

Overdose

Excessive doses of escitalopram usually cause relatively minor untoward effects, such as agitation and tachycardia. However, dyskinesia, hypertonia, and clonus may occur in some cases. Therapeutic blood levels of escitalopram are usually in the range of 20-80 μg/L but may reach 80-200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolisers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.

Pharmacology

Mechanism of Action

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently available, escitalopram has the highest selectivity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), making the side-effect profile relatively mild in comparison to less-selective SSRIs.

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood brain barrier penetrability. In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor, its antidepressant-like effects were enhanced.

Interactions

Escitalopram, similarly to other SSRIs, inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazole, risperidone, tramadol, codeine, etc. As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected. Escitalopram should be taken with caution when using St. John’s wort. Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole. The authors of this study suggested that this increase is unlikely to be of clinical concern. Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome has been reported.

Bupropion has been found to significantly increase citalopram plasma concentration and systemic exposure; as of April 2018 the interaction with escitalopram had not been studied, but some monographs warned of the potential interaction.

Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that also have the ability to prolong the QT interval. These drugs include antiarrhythmics, antipsychotics, tricyclic antidepressants, some antihistamines (astemizole, mizolastine) and some antiretrovirals (ritonavir, saquinavir, lopinavir). As an SSRI, escitalopram should generally not be given concurrently with MAOIs.

Chemistry

Escitalopram is the (S)-stereoisomer (left-handed version) of the racemate citalopram, which is responsible for its name: escitalopram. The (R)-stereoisomer (R-citalopram, the right-handed version) is not thought to have useful effects for treating depression.

Society and Culture

Allegations of Illegal Marketing

In 2004, separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers: a physician named Joseph Piacentile and a Forest salesman named Christopher Gobble. In February 2009, the suits were joined. Eleven states and the District of Columbia filed notices of intent to intervene as plaintiffs in the action.

The suits alleged that Forest illegally engaged in off-label promotion of Lexapro for use in children; hid the results of a study showing lack of effectiveness in children; paid kickbacks to physicians to induce them to prescribe Lexapro to children; and conducted so-called “seeding studies” that were, in reality, marketing efforts to promote the drug’s use by doctors. Forest denied the allegations but ultimately agreed to settle with the plaintiffs for over $313 million.

Brand Names

Escitalopram is sold under many brand names worldwide such as Cipralex, Lexapro, Mozarin, Aciprex, Depralin, Ecytara, Elicea, Nexpram, Pramatis, and Betesda.

Can the MHS: A Serve as a Clinically Useful Screening Tool for GAD?

Research Paper Title

A Brief Online and Offline (Paper-and-Pencil) Screening Tool for Generalized Anxiety Disorder: The Final Phase in the Development and Validation of the Mental Health Screening Tool for Anxiety Disorders (MHS: A).

Background

Generalised anxiety disorder (GAD) can cause significant socioeconomic burden and daily life dysfunction; hence, therapeutic intervention through early detection is important.

Methods

This study was the final stage of a 3-year anxiety screening tool development project that evaluated the psychometric properties and diagnostic screening utility of the Mental Health Screening Tool for Anxiety Disorders (MHS: A), which measures GAD.

Results

A total of 527 Koreans completed online and offline (i.e., paper-and pencil) versions of the MHS: A, Beck Anxiety Inventory (BAI), Generalised Anxiety Disorder-7 (GAD-7), and Penn State Worry Questionnaire (PSWQ). The participants had an average age of 38.6 years and included 340 (64.5%) females. Participants were also administered the Mini-International Neuropsychiatric Interview (MINI).

Internal consistency, convergent/criterion validity, item characteristics, and test information were assessed based on the item response theory (IRT), and a factor analysis and cut-off score analyses were conducted. The MHS: A had good internal consistency and good convergent validity with other anxiety scales.

The two versions (online/offline) of the MHS: A were nearly identical (r = 0.908). It had a one-factor structure and showed better diagnostic accuracy (online/offline: sensitivity = 0.98/0.90, specificity = 0.80/0.83) for GAD detection than the GAD-7 and BAI. The IRT analysis indicated that the MHS: A was most informative as a screening tool for GAD.

Conclusions

The MHS: A can serve as a clinically useful screening tool for GAD in Korea. Furthermore, it can be administered both online and offline and can be flexibly used as a brief mental health screener, especially with the current rise in telehealth.

Reference

Kim, S-H., Park, K., Yoon, S., Choi, Y., Lee, S-H. & Choi, K-H. (2021) A Brief Online and Offline (Paper-and-Pencil) Screening Tool for Generalized Anxiety Disorder: The Final Phase in the Development and Validation of the Mental Health Screening Tool for Anxiety Disorders (MHS: A). Frontiers in Psychology. doi: 10.3389/fpsyg.2021.639366. eCollection 2021.

What is Avoidant Personality Disorder?

Introduction

Avoidant personality disorder (AvPD) is a Cluster C personality disorder in which the main coping mechanism of those affected is avoidance of feared stimuli.

Those affected display a pattern of severe social anxiety, social inhibition, feelings of inadequacy and inferiority, extreme sensitivity to negative evaluation and rejection, and avoidance of social interaction despite a strong desire for intimacy.

People with AvPD often consider themselves to be socially inept or personally unappealing and avoid social interaction for fear of being ridiculed, humiliated, rejected, or disliked. They often avoid becoming involved with others unless they are certain they will be liked.

Childhood emotional neglect (in particular, the rejection of a child by one or both parents) and peer group rejection are associated with an increased risk for its development; however, it is possible for AvPD to occur without any notable history of abuse or neglect.

Brief History

The avoidant personality has been described in several sources as far back as the early 1900s, although it was not so named for some time. Swiss psychiatrist Eugen Bleuler described patients who exhibited signs of avoidant personality disorder in his 1911 work Dementia Praecox: Or the Group of Schizophrenias. Avoidant and schizoid patterns were frequently confused or referred to synonymously until Kretschmer (1921), in providing the first relatively complete description, developed a distinction.

Signs and Symptoms

Avoidant individuals are preoccupied with their own shortcomings and form relationships with others only if they believe they will not be rejected. They often view themselves with contempt, while showing a decreased ability to identify traits within themselves that are generally considered as positive within their societies. Loss and social rejection are so painful that these individuals will choose to be alone rather than risk trying to connect with others.

Some with this disorder fantasize about idealized, accepting and affectionate relationships because of their desire to belong. They often feel themselves unworthy of the relationships they desire, and shame themselves from ever attempting to begin them. If they do manage to form relationships, it is also common for them to pre-emptively abandon them out of fear of the relationship failing.

Individuals with the disorder tend to describe themselves as uneasy, anxious, lonely, unwanted and isolated from others. They often choose jobs of isolation in which they do not have to interact with others regularly. Avoidant individuals also avoid performing activities in public spaces for fear of embarrassing themselves in front of others.

Symptoms include:

  • Extreme shyness or anxiety in social situations, though the person feels a strong desire for close relationships;
  • Heightened attachment-related anxiety, which may include a fear of abandonment; and
  • Substance abuse and/or dependence.

Comorbidity

AvPD is reported to be especially prevalent in people with anxiety disorders, although estimates of comorbidity vary widely due to differences in (among others) diagnostic instruments. Research suggests that approximately 10-50% of people who have panic disorder with agoraphobia have avoidant personality disorder, as well as about 20-40% of people who have social anxiety disorder. In addition to this, AvPD is more prevalent in people who have comorbid social anxiety disorder and generalised anxiety disorder (GAD) than in those who have only one of the aforementioned conditions.

Some studies report prevalence rates of up to 45% among people with GAD and up to 56% of those with obsessive-compulsive disorder. Posttraumatic stress disorder is also commonly comorbid with AvPD.

Avoidants are prone to self-loathing and, in certain cases, self-harm. In particular, avoidants who have comorbid PTSD have the highest rates of engagement in self-harming behaviour, outweighing even those with borderline personality disorder (with or without PTSD). Substance use disorders are also common in individuals with AvPD – particularly in regard to alcohol, benzodiazepines and heroin – and may significantly affect a patient’s prognosis.

Earlier theorists proposed a personality disorder with a combination of features from borderline personality disorder and avoidant personality disorder, called “avoidant-borderline mixed personality” (AvPD/BPD).

Causes

Causes of AvPD are not clearly defined, but appear to be influenced by a combination of social, genetic and psychological factors. The disorder may be related to temperamental factors that are inherited.

Specifically, various anxiety disorders in childhood and adolescence have been associated with a temperament characterised by behavioural inhibition, including features of being shy, fearful and withdrawn in new situations. These inherited characteristics may give an individual a genetic predisposition towards AvPD.

Childhood emotional neglect and peer group rejection are both associated with an increased risk for the development of AvPD. Some researchers believe a combination of high-sensory-processing sensitivity coupled with adverse childhood experiences may heighten the risk of an individual developing AvPD.

Subtypes

Millon

Psychologist Theodore Millon notes that because most patients present a mixed picture of symptoms, their personality disorder tends to be a blend of a major personality disorder type with one or

more secondary personality disorder types. He identified four adult subtypes of AvPD as outlined below.

SubtypePersonality Traits/Features
Phobic Avoidant (including dependent features)General apprehensiveness displaced with avoidable tangible precipitant; qualms and disquietude symbolised by a repugnant and specific dreadful object or circumstances.
Conflicted Avoidant (including negativistic features)Internal discord and dissension; fears dependence; unsettled; unreconciled within self; hesitating, confused, tormented, paroxysmic, embittered; and unresolvable angst.
Hypersensitive Avoidant (including paranoid features)Intensely wary and suspicious; alternatively panicky, terrified, edgy, and timorous, then thin-skinned, high-strung, petulant, and prickly.
Self-Deserting Avoidant (including depressive features)Blocks or fragments self-awareness; discards painful images and memories; casts away untenable thoughts and impulses; ultimately jettisons self (suicidal).

Others

In 1993, Lynn E. Alden and Martha J. Capreol proposed two other subtypes of avoidant personality disorder, as outlined below.

SubtypePersonality Traits/Features
Cold-AvoidantCharacterised by an inability to experience and express positive emotion towards others.
Exploitable-AvoidantCharacterised by an inability to express anger towards others or to resist coercion from others. May be at risk for abuse by others.

Diagnosis

ICD

The World Health Organisation’s ICD-10 lists avoidant personality disorder as anxious (avoidant) personality disorder (F60.6).

It is characterised by the presence of at least four of the following:

  1. Persistent and pervasive feelings of tension and apprehension.
  2. Belief that one is socially inept, personally unappealing, or inferior to others.
  3. Excessive preoccupation with being criticised or rejected in social situations.
  4. Unwillingness to become involved with people unless certain of being liked.
  5. Restrictions in lifestyle because of need to have physical security.
  6. Avoidance of social or occupational activities that involve significant interpersonal contact because of fear of criticism, disapproval, or rejection.

Associated features may include hypersensitivity to rejection and criticism.

It is a requirement of ICD-10 that all personality disorder diagnoses also satisfy a set of general personality disorder criteria.

DSM

The Diagnostic and Statistical Manual of Mental Disorders (DSM) of the APA also has an avoidant personality disorder diagnosis (301.82). It refers to a widespread pattern of inhibition around people, feeling inadequate and being very sensitive to negative evaluation. Symptoms begin by early adulthood and occur in a range of situations.

Four of the following seven specific symptoms should be present:

  1. Avoids occupational activities that involve significant interpersonal contact, because of fears of criticism, disapproval, or rejection.
  2. Is unwilling to get involved with people unless certain of being liked.
  3. Shows restraint within intimate relationships because of the fear of being shamed or ridiculed.
  4. Is preoccupied with being criticised or rejected in social situations.
  5. Is inhibited in new interpersonal situations because of feelings of inadequacy.
  6. Views self as socially inept, personally unappealing, or inferior to others.
  7. Is unusually reluctant to take personal risk or to engage in any new activities because they may prove embarrassing.

Differential Diagnosis

In contrast to social anxiety disorder, a diagnosis of AvPD also requires that the general criteria for a personality disorder are met.

According to the DSM-5, avoidant personality disorder must be differentiated from similar personality disorders such as dependent, paranoid, schizoid, and schizotypal. But these can also occur together; this is particularly likely for AvPD and dependent personality disorder. Thus, if criteria for more than one personality disorder are met, all can be diagnosed.

There is also an overlap between avoidant and schizoid personality traits and AvPD may have a relationship to the schizophrenia spectrum.

Epidemiology

Data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions indicates a prevalence of 2.36% in the US general population. It appears to occur with equal frequency in males and females. In one study, it was seen in 14.7% of psychiatric outpatients.

Criticism

There is controversy as to whether avoidant personality disorder (AvPD) is distinct from generalised social anxiety disorder. Both have similar diagnostic criteria and may share a similar causation, subjective experience, course, treatment and identical underlying personality features, such as shyness.

It is contended by some that they are merely different conceptualisations of the same disorder, where avoidant personality disorder may represent the more severe form. In particular, those with AvPD experience not only more severe social phobia symptoms, but are also more depressed and more functionally impaired than patients with generalised social phobia alone. But they show no differences in social skills or performance on an impromptu speech. Another difference is that social phobia is the fear of social circumstances whereas AvPD is better described as an aversion to intimacy in relationships.

Treatment

Treatment of avoidant personality disorder can employ various techniques, such as social skills training, psychotherapy, cognitive therapy, and exposure treatment to gradually increase social contacts, group therapy for practicing social skills, and sometimes drug therapy.

A key issue in treatment is gaining and keeping the patient’s trust since people with an avoidant personality disorder will often start to avoid treatment sessions if they distrust the therapist or fear rejection. The primary purpose of both individual therapy and social skills group training is for individuals with an avoidant personality disorder to begin challenging their exaggerated negative beliefs about themselves.

Significant improvement in the symptoms of personality disorders is possible, with the help of treatment and individual effort.

Prognosis

Being a personality disorder, which is usually chronic and has long-lasting mental conditions, an avoidant personality disorder is not expected to improve with time without treatment. Given that it is a poorly studied personality disorder and in light of prevalence rates, societal costs, and the current state of research, AvPD qualifies as a neglected disorder.

PHQ-9 & GAD-7 Data in a National Survey about COVID-19 Restrictions in Australia

Research paper Title

Patient Health Questionnaire 9 (PHQ-9) and General Anxiety Disorder 7 (GAD-7) data contributed by 13,829 respondents to a national survey about COVID-19 restrictions in Australia.

Background

While the Patient Health Questionnaire 9 (PHQ-9) and General Anxiety Disorder 7 (GAD-7) are frequently used in mental health research, few studies have reported comprehensive data on these measures from population or community samples.

The aim of this study was to describe gender- and age-specific PHQ-9 and GAD-7 item and summary data contributed by those who completed this survey.

Methods

The PHQ-9 and GAD-7 were used as indicators of symptoms of depression and anxiety in a national online anonymous survey to assess the mental health of adults in Australia during the COVID-19 restrictions.

Data were analysed descriptively.

Results

Complete survey responses were contributed by 13,829 people.

For both measures, item-by-item results, summary statistics (mean, standard deviation, minimum, maximum, median and interquartile range) and prevalence of severity categories are reported for the whole sample, and disaggregated by gender and age groups.

Conclusions

These comprehensive data provide a useful point of comparison for future COVID-19-related or other research among population or community samples.

Other researchers are encouraged to report detailed PHQ-9 and GAD-7 data in the future, to enable and promote relevant between-group comparisons.

Reference

Stocker, R., Tran, T., Hammarberg, K., Nguyen, H., Rowe, H. & Fisher, J. (2021) Patient Health Questionnaire 9 (PHQ-9) and General Anxiety Disorder 7 (GAD-7) data contributed by 13,829 respondents to a national survey about COVID-19 restrictions in Australia. Psychiatry Research. doi: 10.1016/j.psychres.2021.113792. Online ahead of print.

What is Generalised Anxiety Disorder (GAD)?

Introduction

Generalised anxiety disorder (GAD) is an anxiety disorder characterised by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning, and sufferers are overly concerned about everyday matters such as health, finances, death, family, relationship concerns, or work difficulties. Symptoms may include excessive worry, restlessness, trouble sleeping, exhaustion, irritability, sweating, and trembling.

Symptoms must be consistent and ongoing, persisting at least six months, for a formal diagnosis of GAD. Individuals with GAD often suffer from other disorders including other psychiatric disorders (e.g. major depressive disorder), substance use disorder, obesity, and may have a history of trauma or family with GAD. Clinicians use screening tools such as the GAD-7 and GAD-2 questionnaires to determine if individuals may have GAD and warrant formal evaluation for the disorder. Additionally, sometimes screening tools may enable clinicians to evaluate the severity of GAD symptoms.

GAD is believed to have a hereditary or genetic basis (e.g. first-degree relatives of an individual who has GAD are themselves more likely to have GAD) but the exact nature of this relationship is not fully appreciated. Genetic studies of individuals who have anxiety disorders (including GAD) suggest that the hereditary contribution to developing anxiety disorders is only approximately 30-40%, which suggests that environmental factors may be more important to determining whether an individual develops GAD.

The pathophysiology of GAD implicates several regions of the brain that mediate the processing of stimuli associated with fear, anxiety, memory, and emotion (i.e. the amygdala, insula and the frontal cortex). It has been suggested that individuals with GAD have greater amygdala and medial prefrontal cortex (mPFC) activity in response to stimuli than individuals who do not have GAD. However, the relationship between GAD and activity levels in other parts of the frontal cortex is the subject of ongoing research with some literature suggesting greater activation in specific regions for individuals who have GAD but where other research suggests decreased activation levels in individuals who have GAD as compared to individuals who do not have GAD.

Traditional treatment modalities include variations on psychotherapy (e.g. cognitive-behavioural therapy (CBT)) and pharmacological intervention (e.g. citalopram, escitalopram, sertraline, duloxetine, and venlafaxine). CBT and selective serotonin reuptake inhibitors (SSRIs) are the respectively predominant psychological and pharmacological treatment modalities; other treatments (e.g. selective norepinephrine reuptake inhibitors (SNRIs)) are often considered depending on individual response to therapy. Areas of active investigation include the usefulness of complementary and alternative medications (CAMs), exercise, therapeutic massage and other interventions that have been proposed for study.

Estimates regarding prevalence of GAD or lifetime risk (i.e. lifetime morbid risk (LMR)) for GAD vary depending upon which criteria are used for diagnosing GAD (e.g. DSM-5 vs ICD-10) although estimates do not vary widely between diagnostic criteria. In general, ICD-10 is more inclusive than DSM-5, so estimates regarding prevalence and lifetime risk tend to be greater using ICD-10. In regard to prevalence, in a given year, about two (2%) percent of adults in the United States and Europe have been suggested to suffer GAD. However, the risk of developing GAD at any point in life has been estimated at 9.0%. Although it is possible to experience a single episode of GAD during one’s life, most people who experience GAD experience it repeatedly over the course of their lives as a chronic or ongoing condition. GAD is diagnosed twice as frequently in women as in men.

Diagnosis

DSM-5 Criteria

The diagnostic criteria for GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013), published by the American Psychiatric Association, are paraphrased as follows:

  1. “Excessive anxiety or worry” experienced most days over at least six (6) month and which involve a plurality of concerns.
  2. Inability to manage worry.
  3. At least three (3) of the following occur:
    • Restlessness.
    • Fatigability.
    • Problems concentrating.
    • Irritability.
    • Muscle tension.
    • Difficulty with sleep.
    • Note that in children, only one (1) of the above items is required.
  4. One experiences significant distress in functioning (e.g. work, school, social life).
  5. Symptoms are not due to drug abuse, prescription medication or other medical condition(s).
  6. Symptoms do not fit better with another psychiatric condition such as panic disorder.

No major changes to GAD have occurred since publication of the Diagnostic and Statistical Manual of Mental Disorders (2004); minor changes include wording of diagnostic criteria.

ICD-10 Criteria

The 10th revision of the International Statistical Classification of Disease (ICD-10) provides a different set of diagnostic criteria for GAD than the DSM-5 criteria described above. In particular, ICD-10 allows diagnosis of GAD as follows:

  • A period of at least six months with prominent tension, worry, and feelings of apprehension, about everyday events and problems.
  • At least four symptoms out of the following list of items must be present, of which at least one from items (1) to (4).
    • Autonomic arousal symptoms:
      • (1) Palpitations or pounding heart, or accelerated heart rate.
      • (2) Sweating.
      • (3) Trembling or shaking.
      • (4) Dry mouth (not due to medication or dehydration).
    • Symptoms concerning chest and abdomen:
      • (5) Difficulty breathing.
      • (6) Feeling of choking.
      • (7) Chest pain or discomfort.
      • (8) Nausea or abdominal distress (e.g. churning in the stomach).
    • Symptoms concerning brain and mind:
      • (9) Feeling dizzy, unsteady, faint or light-headed.
      • (10) Feelings that objects are unreal (derealization), or that one’s self is distant or “not really here” (depersonalization).
      • (11) Fear of losing control, going crazy, or passing out.
      • (12) Fear of dying.
    • General symptoms:
      • (13) Hot flashes or cold chills.
      • (14) Numbness or tingling sensations.
    • Symptoms of tension:
      • (15) Muscle tension or aches and pains.
      • (16) Restlessness and inability to relax.
      • (17) Feeling keyed up, or on edge, or of mental tension.
      • (18) A sensation of a lump in the throat or difficulty with swallowing.
    • Other non-specific symptoms:
      • (19) Exaggerated response to minor surprises or being startled.
      • (20) Difficulty in concentrating or mind going blank, because of worrying or anxiety.
      • (21) Persistent irritability.
      • (22) Difficulty getting to sleep because of worrying.
  • The disorder does not meet the criteria for panic disorder (F41.0), phobic anxiety disorders (F40.-), obsessive-compulsive disorder (F42.-) or hypochondriacal disorder (F45.2).
  • Most commonly used exclusion criteria: not sustained by a physical disorder, such as hyperthyroidism, an organic mental disorder (F0) or psychoactive substance-related disorder (F1), such as excess consumption of amphetamine-like substances, or withdrawal from benzodiazepines.[21]

See ICD-10 F41.1

Note: For children different ICD-10 criteria may be applied for diagnosing GAD (see F93.80).

History of Diagnostic Criteria

The American Psychiatric Association introduced GAD as a diagnosis in the DSM-III in 1980, when anxiety neurosis was split into GAD and panic disorder. The definition in the DSM-III required uncontrollable and diffuse anxiety or worry that is excessive and unrealistic and persists for 1 month or longer. High rates in comorbidity of GAD and major depression led many commentators to suggest that GAD would be better conceptualised as an aspect of major depression instead of an independent disorder. Many critics stated that the diagnostic features of this disorder were not well established until the DSM-III-R. Since comorbidity of GAD and other disorders decreased with time, the DSM-III-R changed the time requirement for a GAD diagnosis to 6 months or longer. The DSM-IV changed the definition of excessive worry and the number of associated psychophysiological symptoms required for a diagnosis. Another aspect of the diagnosis the DSM-IV clarified was what constitutes a symptom as occurring “often”. The DSM-IV also required difficulty controlling the worry to be diagnosed with GAD. The DSM-5 emphasized that excessive worrying had to occur more days than not and on a number of different topics. It has been stated that the constant changes in the diagnostic features of the disorder have made assessing epidemiological statistics such as prevalence and incidence difficult, as well as increasing the difficulty for researchers in identifying the biological and psychological underpinnings of the disorder. Consequently, making specialized medications for the disorder is more difficult as well. This has led to the continuation of GAD being medicated heavily with SSRIs.

Risk Factors

Genetics, Family and Environment

The relationship between genetics and anxiety disorders is an ongoing area of research. It is broadly understood that there exists an hereditary basis for GAD, but the exact nature of this hereditary basis is not fully appreciated. While investigators have identified several genetic loci that are regions of interest for further study, there is no singular gene or set of genes that have been identified as causing GAD. Nevertheless, genetic factors may play a role in determining whether an individual is at greater risk for developing GAD, structural changes in the brain related to GAD, or whether an individual is more or less likely to respond to a particular treatment modality. Genetic factors that may play a role in development of GAD are usually discussed in view of environmental factors (e.g. life experience or ongoing stress) that might also play a role in development of GAD. The traditional methods of investigating the possible hereditary basis of GAD include using family studies and twin studies (there are no known adoption studies of individuals who suffer anxiety disorders, including GAD). Meta-analysis of family and twin studies suggests that there is strong evidence of a hereditary basis for GAD in that GAD is more likely to occur in first-degree relatives of individuals who have GAD than in non-related individuals in the same population. Twin studies also suggest that there may be a genetic linkage between GAD and major depressive disorder (MDD), which may explain the common occurrence of MDD in individuals who suffer GAD (e.g. comorbidity of MDD in individuals with GAD has been estimated at approximately 60%). When GAD is considered among all anxiety disorders (e.g. panic disorder, social anxiety disorder), genetic studies suggest that hereditary contribution to the development of anxiety disorders amounts to only approximately 30-40%, which suggests that environmental factors are likely more important to determining whether an individual may develop GAD. In regard to environmental influences in the development of GAD, it has been suggested that parenting behaviour may be an important influence since parents potentially model anxiety-related behaviours. It has also been suggested that individuals who suffer GAD have experienced a greater number of minor stress-related events in life and that the number of stress-related events may be important in development of GAD (irrespective of other individual characteristics).

Studies of possible genetic contributions to the development of GAD have examined relationships between genes implicated in brain structures involved in identifying potential threats (e.g. in the amygdala) and also implicated in neurotransmitters and neurotransmitter receptors known to be involved in anxiety disorders. More specifically, genes studied for their relationship to development of GAD or demonstrated to have had a relationship to treatment response include:

  • PACAP (A54G polymorphism): remission after 6 month treatment with Venlafaxine suggested to have a significant relationship with the A54G polymorphism (Cooper et al. (2013)).
  • HTR2A gene (rs7997012 SNP G allele): HTR2A allele suggested to be implicated in a significant decrease in anxiety symptoms associated with response to 6 months of Venlafaxine treatment (Lohoff et al. (2013)).
  • SLC6A4 promoter region (5-HTTLPR): Serotonin transporter gene suggested to be implicated in significant reduction in anxiety symptoms in response to 6 months of Venlafaxine treatment (Lohoff et al. (2013)).

Pathophysiology

The pathophysiology of GAD is an active and ongoing area of research often involving the intersection of genetics and neurological structures. GAD has been linked to changes in functional connectivity of the amygdala and its processing of fear and anxiety. Sensory information enters the amygdala through the nuclei of the basolateral complex (consisting of lateral, basal and accessory basal nuclei). The basolateral complex processes the sensory-related fear memories and communicates information regarding threat importance to memory and sensory processing elsewhere in the brain, such as the medial prefrontal cortex and sensory cortices. Neurological structures traditionally appreciated for their roles in anxiety include the amygdala, insula and orbitofrontal cortex (OFC). It is broadly postulated that changes in one or more of these neurological structures are believed to allow greater amygdala response to emotional stimuli in individuals who have GAD as compared to individuals who do not have GAD.

Individuals who GAD have been suggested to have greater amygdala and medial prefrontal cortex (mPFC) activation in response to stimuli than individuals who do not have GAD. However, the exact relationship between the amygdala and the frontal cortex (e.g. prefrontal cortex or the orbitofrontal cortex (OFC)) is not fully understood because there are studies that suggest increased or decreased activity in the frontal cortex in individuals who have GAD. Consequently, because of the tenuous understanding of the frontal cortex as it relates to the amygdala in individuals who have GAD, it’s an open question as to whether individuals who have GAD bear an amygdala that is more sensitive than an amygdala in an individual without GAD or whether frontal cortex hyperactivity is responsible for changes in amygdala responsiveness to various stimuli. Recent studies have attempted to identify specific regions of the frontal cortex (e.g. dorsomedial prefrontal cortex (dmPFC)) that may be more or less reactive in individuals who have GAD or specific networks that may be differentially implicated in individuals who have GAD. Other lines of study investigate whether activation patterns vary in individuals who have GAD at different ages with respect to individuals who do not have GAD at the same age (e.g. amygdala activation in adolescents with GAD).

Treatment

Traditional treatment modalities broadly fall into two (2) categories:

  • Psychotherapeutic; and
  • Pharmacological intervention.

In addition to these two conventional therapeutic approaches, areas of active investigation include complementary and alternative medications (CAMs), brain stimulation, exercise, therapeutic massage and other interventions that have been proposed for further study. Treatment modalities can, and often are utilised concurrently so that an individual may pursue psychological therapy (i.e. psychotherapy) and pharmacological therapy. Both cognitive behavioural therapy (CBT) and medications (such as SSRIs) have been shown to be effective in reducing anxiety. A combination of both CBT and medication is generally seen as the most desirable approach to treatment. Use of medication to lower extreme anxiety levels can be important in enabling patients to engage effectively in CBT.

Psychotherapy

Psychotherapeutic interventions include a plurality of therapy types that vary based upon their specific methodologies for enabling individuals to gain insight into the working of the conscious and subconscious mind and which sometimes focus on the relationship between cognition and behaviour. Cognitive behavioural therapy (CBT) is widely regarded as the first-line psychological therapy for treating GAD. Additionally, many of these psychological interventions may be delivered in an individual or group therapy setting. While individual and group settings are broadly both considered effective for treating GAD, individual therapy tends to promote longer-lasting engagement in therapy (i.e. lower attrition over time).

Psychodynamic Therapy

Psychodynamic therapy is a type of therapy premised upon Freudian psychology in which a psychologist enables an individual explore various elements in their subconscious mind to resolve conflicts that may exist between the conscious and subconscious elements of the mind. In the context of GAD, the psychodynamic theory of anxiety suggests that the unconscious mind engages in worry as a defence mechanism to avoid feelings of anger or hostility because such feelings might cause social isolation or other negative attribution toward oneself. Accordingly, the various psychodynamic therapies attempt to explore the nature of worry as it functions in GAD in order to enable individuals to alter the subconscious practice of using worry as a defence mechanism and to thereby diminish GAD symptoms. Variations of psychotherapy include a near-term version of therapy, “short-term anxiety-provoking psychotherapy (STAPP).

Behavioural Therapy

Behavioural therapy is therapeutic intervention premised upon the concept that anxiety is learned through classical conditioning (e.g., in view of one or more negative experiences) and maintained through operant conditioning (e.g. one finds that by avoiding a feared experience that one avoids anxiety). Thus, behavioural therapy enables an individual to re-learn conditioned responses (behaviours) and to thereby challenge behaviours that have become conditioned responses to fear and anxiety, and which have previously given rise to further maladaptive behaviours.

Cognitive Therapy

Cognitive therapy (CT) is premised upon the idea that anxiety is the result of maladaptive beliefs and methods of thinking. Thus, CT involves assisting individuals to identify more rational ways of thinking and to replace maladaptive thinking patterns (i.e. cognitive distortions) with healthier thinking patterns (e.g. replacing the cognitive distortion of catastrophising with a more productive pattern of thinking). Individuals in CT learn how to identify objective evidence, test hypotheses, and ultimately identify maladaptive thinking patterns so that these patterns can be challenged and replaced.

Acceptance and Commitment Therapy

Acceptance and commitment therapy (ACT) is a behavioural treatment based on acceptance-based models. ACT is designed with the purpose to target three therapeutic goals:

  1. Reduce the use of avoiding strategies intended to avoid feelings, thoughts, memories, and sensations;
  2. Decreasing a person’s literal response to their thoughts (e.g., understanding that thinking “I’m hopeless” does not mean that the person’s life is truly hopeless); and
  3. Increasing the person’s ability to keep commitments to changing their behaviours.

These goals are attained by switching the person’s attempt to control events to working towards changing their behaviour and focusing on valued directions and goals in their lives as well as committing to behaviours that help the individual accomplish those personal goals. This psychological therapy teaches mindfulness (paying attention on purpose, in the present, and in a non-judgemental manner) and acceptance (openness and willingness to sustain contact) skills for responding to uncontrollable events and therefore manifesting behaviours that enact personal values. Like many other psychological therapies, ACT works best in combination with pharmacology treatments.

Intolerance of Uncertainty Therapy

Intolerance of uncertainty (IU) refers to a consistent negative reaction to uncertain and ambiguous events regardless of their likelihood of occurrence. Intolerance of uncertainty therapy (IUT) is used as a stand-alone treatment for GAD patients. Thus, IUT focuses on helping patients in developing the ability to tolerate, cope with and accept uncertainty in their life in order to reduce anxiety. IUT is based on the psychological components of psychoeducation, awareness of worry, problem-solving training, re-evaluation of the usefulness of worry, imagining virtual exposure, recognition of uncertainty, and behavioural exposure. Studies have shown support for the efficacy of this therapy with GAD patients with continued improvements in follow-up periods.

Motivational Interviewing

A promising innovative approach to improving recovery rates for the treatment of GAD is to combine CBT with motivational interviewing (MI). Motivational interviewing is a strategy centred on the patient that aims to increase intrinsic motivation and decrease ambivalence about change due to the treatment. MI contains four key elements:

  • Express empathy;
  • Heighten dissonance between behaviours that are not desired and values that are not consistent with those behaviours;
  • Move with resistance rather than direct confrontation; and
  • Encourage self-efficacy.

It is based on asking open-ended questions and listening carefully and reflectively to patients’ answers, eliciting “change talk”, and talking with patients about the pros and cons of change. Some studies have shown the combination of CBT with MI to be more effective than CBT alone.

Cognitive Behavioural Therapy

Cognitive behavioural therapy (CBT) is an evidence-based type of psychotherapy that demonstrates efficacy in treating GAD and which integrates the cognitive and behavioural therapeutic approaches. The objective of CBT is to enable individuals to identify irrational thoughts that cause anxiety and to challenge dysfunctional thinking patterns by engaging in awareness techniques such as hypothesis testing and journaling. Because CBT involves the practice of worry and anxiety management, CBT includes a plurality of intervention techniques that enable individuals to explore worry, anxiety and automatic negative thinking patterns. These interventions include anxiety management training, cognitive restructuring, progressive relaxation, situational exposure and self-controlled desensitisation.

Other forms of psychological therapy include:

  • Relaxation techniques (e.g. relaxing imagery, meditational relaxation).
  • Metacognitive Therapy (MCT):
    • The objective of MCT is to alter thinking patterns regarding worry so that worry is no longer used as a coping strategy.
  • Mindfulness based stress reduction (MBSR).
  • Mindfulness based cognitive therapy (MBCT).
  • Supportive therapy:
    • This is a Rogerian method of therapy in which subjects experience empathy and acceptance from their therapist to facilitate increasing awareness.
    • Variations of active supportive therapy include Gestalt therapy, Transactional analysis and Counselling.

Pharmacotherapy

Historically, benzodiazepines (BZs) were used prominently to treat anxiety starting in the 1970s but support for this use attenuated in view of the risk for dependence and tolerance to the medication. BZs can have a plurality of effects that made them a seemingly desirable option for treating anxiety – i.e. BZs have anxiolytic, hypnotic (induce sleep), myorelaxant (relax muscles), anticonvulsant and amnestic (impair short-term memory) properties. While BZs are well appreciated for their ability to alleviate anxiety (i.e. their anxiolytic properties) shortly after administration, they are also known for their ability to promote dependence and are frequently abused. Current recommendations for using BZs to treat anxiety in GAD allow no more than 2-4 weeks of BZ exposure. Antidepressants (e.g. SSRIs/SNRIs) have become a mainstay in treating GAD in adults. First-line mediations from any drug category often include drugs that have been approved by the US Food and Drug Administration (FDA) for treating GAD because these medications have been proven safe and effective for treating GAD.

FDA-Approved Medications for Treating GAD

FDA-approved medications for treating GAD include:

  • SSRIs:
    • Paroxetine.
    • Escitalopram.
  • SNRIs:
    • Venlafaxine.
    • Duloxetine.
  • Benzodiazepines (BZs):
    • Alprazolam: Alprazolam is the only FDA-approved BZ for treating GAD.
  • Azapirones:
    • Buspirone.

Non-FDA Approved Medications

While certain medications are not specifically FDA approved for treatment of GAD, there are a number of medications that historically have been used or studied for treating GAD. Other medications that have been used or evaluated for treating GAD include:

  • SSRIs (antidepressants):
    • Citalopram.
    • Fluoxetine.
    • Sertraline.
    • Fluvoxamine (SSRI).
  • Benzodiazepines:
    • Clonazepam.
    • Lorazepam.
    • Diazepam.
  • GABA analogs:
    • Pregabalin (atypical anxiolytic, GABA analog).
    • Tiagabine.
  • Second-generation antipsychotics (SGAs):
    • Olanzapine (evidence of effectiveness is merely a trend).
    • Ziprasidone.
    • Risperidone.
    • Aripiprazole (studied as an adjunctive measure in concert with other treatment).
    • Quetiapine (atypical antipsychotic studied as an adjunctive measure in adults and geriatric patients).
  • Antihistamines:
    • Hydroxyzine (H1 receptor antagonist).
  • Vilazodone (atypical antidepressant).
  • Agomelatine (antidepressant, MT1/2 receptor agonist, 5HT2c antagonist).
  • Clonidine (noted to cause decreased blood pressure and other AEs).
  • Guanfacine (a2A receptor agonist, studied in paediatric patients with GAD).
  • Mirtazapine (atypical antidepressant having 5HT2A and 5HT2c receptor affinity).
  • Vortioxetine (multimodal antidepressant).
  • Eszopiclone (non-benzodiazepine hypnotic).
  • Tricyclic antidepressants:
    • Amitriptyline.
    • Clomipramine.
    • Doxepin.
    • Imipramine.
    • Trimipramine.
    • Desipramine.
    • Nortriptyline.
    • Protriptyline.
  • Opipramol (atypical TCA).]
  • Trazodone.
  • Monamine oxidase inhibitors (MAOIs):
    • Tranylcypromine.
    • Phenelzine.
  • Homeopathic preparations (discussed below, see complementary and alternative medications (CAMs))

Selective Serotonin Reuptake Inhibitors

Pharmaceutical treatments for GAD include selective serotonin reuptake inhibitors (SSRIs).[50] SSRIs increase serotonin levels through inhibition of serotonin reuptake receptors.

FDA approved SSRIs used for this purpose include escitalopram and paroxetine. However, guidelines suggest using sertraline first due to its cost-effectiveness compared to other SSRIs used for GAD and a lower risk of withdrawal compared to SNRIs. If sertraline is found to be ineffective, then it is recommended to try another SSRI or SNRI.

Common side effects include nausea, sexual dysfunction, headache, diarrhoea, constipation, restlessness, increased risk of suicide in young adults and adolescents, among others. Sexual side effects, weight gain, and higher risk of withdrawal are more common in paroxetine than escitalopram and sertraline. In older populations or those taking concomitant medications that increase risk of bleeding, SSRIs may further increase the risk of bleeding. Overdose of an SSRI or concomitant use with another agent that causes increased levels of serotonin can result in serotonin syndrome, which can be life-threatening.

Serotonin Norepinephrine Reuptake Inhibitors

First line pharmaceutical treatments for GAD also include serotonin-norepinephrine reuptake inhibitors (SNRIs). These inhibit the reuptake of serotonin and noradrenaline to increase their levels in the CNS.

FDA approved SNRIs used for this purpose include duloxetine (Cymbalta) and venlafaxine (Effexor). While SNRIs have similar efficacy as SSRIs, many psychiatrists prefer to use SSRIs first in the treatment of GAD The slightly higher preference for SSRIs over SNRIs as a first choice for treatment of anxiety disorders may have been influenced by the observation of poorer tolerability of the SNRIs in comparison to SSRIs in systematic reviews of studies of depressed patients.

Side effects common to both SNRIs include anxiety, restlessness, nausea, weight loss, insomnia, dizziness, drowsiness, sweating, dry mouth, sexual dysfunction and weakness. In comparison to SSRIs, the SNRIs have a higher prevalence of the side effects of insomnia, dry mouth, nausea and high blood pressure. Both SNRIs have the potential for discontinuation syndrome after abrupt cessation, which can precipitate symptoms including motor disturbances and anxiety and may require tapering. Like other serotonergic agents, SNRIs have the potential to cause serotonin syndrome, a potentially fatal systemic response to serotonergic excess that causes symptoms including agitation, restlessness, confusion, tachycardia, hypertension, mydriasis, ataxia, myoclonus, muscle rigidity, diaphoresis, diarrhoea, headache, shivering, goose bumps, high fever, seizures, arrhythmia and unconsciousness. SNRIs like SSRIs carry a black box warning for suicidal ideation, but it is generally considered that the risk of suicide in untreated depression is far higher than the risk of suicide when depression is properly treated.

Pregabalin and Gabapentin

Pregabalin (Lyrica) acts on the voltage-dependent calcium channel to decrease the release of neurotransmitters such as glutamate, norepinephrine and substance P. Its therapeutic effect appears after 1 week of use and is similar in effectiveness to lorazepam, alprazolam and venlafaxine but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychic and somatic anxiety symptoms. Long-term trials have shown continued effectiveness without the development of tolerance and additionally, unlike benzodiazepines, it does not disrupt sleep architecture and produces less severe cognitive and psychomotor impairment. It also has a low potential for abuse and dependency and may be preferred over the benzodiazepines for these reasons. The anxiolytic effects of pregabalin appear to persist for at least six months continuous use, suggesting tolerance is less of a concern; this gives pregabalin an advantage over certain anxiolytic medications such as benzodiazepines.

Gabapentin (Neurontin), a closely related medication to pregabalin with the same mechanism of action, has also demonstrated effectiveness in the treatment of GAD, though unlike pregabalin, it has not been approved specifically for this indication. Nonetheless, it is likely to be of similar usefulness in the management of this condition, and by virtue of being off-patent, it has the advantage of being significantly less expensive in comparison. In accordance, gabapentin is frequently prescribed off-label to treat GAD.

Complementary and Alternative Medicines Studied for Potential in Treating GAD

Complementary and alternative medicines (CAMs) are widely used by individuals who suffer GAD despite having no evidence or varied evidence regarding efficacy. Efficacy trials for CAM medications often suffer from various types of bias and low quality reporting in regard to safety. In regard to efficacy, critics point out that CAM trials sometimes predicate claims of efficacy based on a comparison of a CAM against a known drug after which no difference in subjects is found by investigators and which is used to suggest an equivalence between a CAM and a drug. Because this equates a lack of evidence with the positive assertion of efficacy, a “lack of difference” assertion is not a proper claim for efficacy. Moreover, an absence of strict definitions and standards for CAM compounds further burdens the literature regarding CAM efficacy in treating GAD. CAMs academically studied for their potential in treating GAD or GAD symptoms along with a summary of academic findings are given below. What follows is a summary of academic findings. Accordingly, none of the following should be taken as offering medical guidance or an opinion as to the safety or efficacy of any of the following CAMs.

  • Kava Kava (Piper methysticum) extracts:
    • Meta analysis does not suggest efficacy of Kava Kava extracts due to few data available yielding inconclusive results or non-statistically significant results.
    • Nearly a quarter (25.8%) of subjects experienced adverse effects (AEs) from Kava Kava extracts during six (6) trials.
    • Kava Kava may cause liver toxicity.
  • Lavender (Lavandula angustifolia) extracts:
    • Small and varied studies may suggest some level of efficacy as compared to placebo or other medication; claims of efficacy are regarded as needing further evaluation.
    • Silexan is an oil derivative of Lavender studied in paediatric patients with GAD.
    • Concern exists regarding the question as to whether Silexan may cause unopposed oestrogen exposure in boys due to disruption of steroid signalling.
  • Galphimia glauca extracts:
    • While Galphima glauca extracts have been the subject of two (2) randomised controlled trials (RCTs) comparing Galphima glauca extracts to lorazepam, efficacy claims are regarded as “highly uncertain.”
  • Chamomile (Matricaria chamomilla) extracts:
    • Poor quality trials have trends that may suggest efficacy but further study is needed to establish any claim of efficacy.
  • Crataegus oxycantha and Eschscholtzia californica extracts combined with magnesium:
    • A single12-week trial of Crataegus oxycantha and Eschscholtzia californica compared to placebo has been used to suggest efficacy.
    • However, efficacy claims require confirmation studies.
    • For the minority of subjects who experienced AEs from extracts, most AEs implicated gastrointestinal tract (GIT) intolerance.
  • Echium amoneum extract:
    • A single, small trial used this extract as a supplement to fluoxetine (vs using a placebo to supplement fluoxetine); larger studies are needed to substantiate efficacy claims.
  • Gamisoyo-San:
    • Small trials of this herbal mixture compared to placebo have suggested no efficacy of the herbal mixture over placebo but further study is necessary to allow definitive conclusion of a lack of efficacy.
  • Passiflora incarnata extract:
    • Claims of efficacy or benzodiazepam equivalence are regarded as “highly uncertain.”
  • Valeriana extract:
    • A single 4-week trial suggests no effect of Valeriana extract on GAD but is regarded as “uninformative” on the topic of efficacy in view of its finding that the benzodiazepine diazepam also had no effect.
    • Further study may be warranted.

Other Possible Modalities Discussed in Literature for Potential in Treating GAD

Other modalities that have been academically studied for their potential in treating GAD or symptoms of GAD are summarised below. What follows is a summary of academic findings. Accordingly, none of the following should be taken as offering medical guidance or an opinion as to the safety or efficacy of any of the following modalities.

  • Acupuncture:
    • A single, very small trial revealed a trend toward efficacy but flaws in the trial design suggest uncertainty regarding efficacy.
  • Balneotherapy:
    • Data from a single non-blinded study suggested possible efficacy of balneotherapy as compared to paroxetine.
    • However, efficacy claims need confirmation.
  • Therapeutic massage:
    • A single, small, possibly biased study revealed inconclusive results.
  • Resistance and aerobic exercise:
    • When compared to no treatment, a single, small, potentially unrepresentative trial suggested a trend toward GAD remission and reduction of worry.
  • Chinese bloodletting:
    • When added to paroxetine, a single, small, imprecise trial that lacked a sham procedure for comparison suggested efficacy at 4-weeks.
    • However, larger trials are needed to evaluate this technique as compared to a sham procedure.
  • Floating in water:
    • When compared to no treatment, a single, imprecise, non-blinded trial suggested a trend toward efficacy (findings were statistically insignificant).
  • Swedish massage:
    • When compared to a sham procedure, a single trial showed a trend toward efficacy (i.e. findings were statistically insignificant).
  • Ayurvedic medications:
    • A single non-blinded trial was inconclusive as to whether Ayurvedic medications were effective in treating GAD.
  • Multi-faith spiritually-based intervention:
    • A single, small, non-blinded study was inconclusive regarding efficacy.

Lifestyle

Lifestyle factors including: stress management, stress reduction, relaxation, exercise, sleep hygiene, and caffeine and alcohol reduction can influence anxiety levels. Physical activity has shown to have a positive impact whereas low physical activity may be a risk factor for anxiety disorders.

Substances and Anxiety in GAD

While there are no substances that are known to cause GAD, certain substances or the withdrawal from certain substances have been implicated in promoting the experience of anxiety. For example, even while benzodiazepines may afford individuals with GAD relief from anxiety, withdrawal from benzodiazepines is associated with the experience of anxiety among other adverse events like sweating and tremor.

Tobacco withdrawal symptoms may provoke anxiety in smokers and excessive caffeine use has been linked to aggravating and maintaining anxiety.

Comorbidity

Depression

In the National Comorbidity Survey (2005), 58% of patients diagnosed with major depression were found to have an anxiety disorder; among these patients, the rate of comorbidity with GAD was 17.2%, and with panic disorder, 9.9%. Patients with a diagnosed anxiety disorder also had high rates of comorbid depression, including 22.4% of patients with social phobia, 9.4% with agoraphobia, and 2.3% with panic disorder. A longitudinal cohort study found 12% of the 972 participants had GAD comorbid with MDD. Accumulating evidence indicates that patients with comorbid depression and anxiety tend to have greater illness severity and a lower treatment response than those with either disorder alone. In addition, social function and quality of life are more greatly impaired.

For many, the symptoms of both depression and anxiety are not severe enough (i.e. are subsyndromal) to justify a primary diagnosis of either major depressive disorder (MDD) or an anxiety disorder. However, dysthymia is the most prevalent comorbid diagnosis of GAD clients. Patients can also be categorised as having mixed anxiety-depressive disorder, and they are at significantly increased risk of developing full-blown depression or anxiety.

Various explanations for the high comorbidity between GAD and depressive disorders have been suggested, including genetic pleiotropy, meaning that GAD and nonbipolar depression might represent different phenotypic expressions of a common aetiology.

Comorbidity and Treatment

Therapy has been shown to have equal efficacy in patients with GAD and patients with GAD and comorbid disorders. Patients with comorbid disorders have more severe symptoms when starting therapy but demonstrated a greater improvement than patients with simple GAD.

Pharmacological approaches i.e. the use of antidepressants must be adapted for different comorbidities. For example, serotonin reuptake inhibitors and short acting benzodiazepines (BZDs) are used for depression and anxiety. However, for patients with anxiety and substance abuse, BZDs should be avoided due to their abuse liability. CBT has been found an effective treatment since it improves symptoms of GAD and substance abuse.

Compared to the general population, patients with internalising disorders such as depression, GAD and post-traumatic stress disorder (PTSD) have higher mortality rates, but die of the same age-related diseases as the population, such as heart disease, cerebrovascular disease and cancer.

GAD often coexists with conditions associated with stress, such as muscle tension and irritable bowel syndrome.

Patients with GAD can sometimes present with symptoms such as insomnia or headaches as well as pain and interpersonal problems.

Further research suggests that about 20% to 40% of individuals with attention deficit hyperactivity disorder have comorbid anxiety disorders, with GAD being the most prevalent.

Those with GAD have a lifetime comorbidity prevalence of 30% to 35% with alcohol use disorder and 25% to 30% for another substance use disorder. People with both GAD and a substance use disorder also have a higher lifetime prevalence for other comorbidities. A study found that GAD was the primary disorder in slightly more than half of the 18 participants that were comorbid with alcohol use disorder.

Epidemiology

GAD is often estimated to affect approximately 3-6% of adults and 5% of children and adolescents. Although estimates have varied to suggest a GAD prevalence of 3% in children and 10.8% in adolescents. When GAD manifests in children and adolescents, it typically begins around 8 to 9 years of age.

Estimates regarding prevalence of GAD or lifetime risk (i.e. lifetime morbid risk (LMR)) for GAD vary depending upon which criteria are used for diagnosing GAD (e.g. DSM-5 vs ICD-10) although estimates do not vary widely between diagnostic criteria. In general, ICD-10 is more inclusive than DSM-5, so estimates regarding prevalence and lifetime risk tend to be greater using ICD-10. In regard to prevalence, in a given year, about two (2%) percent of adults in the United States and Europe have been suggested to suffer GAD. However, the risk of developing GAD at any point in life has been estimated at 9.0%. Although it is possible to experience a single episode of GAD during one’s life, most people who experience GAD experience it repeatedly over the course of their lives as a chronic or ongoing condition. GAD is diagnosed twice as frequently in women as in men and is more often diagnosed in those who are separated, divorced, unemployed, widowed or have low levels of education, and among those with low socioeconomic status. African Americans have higher odds of having GAD and the disorder often manifests itself in different patterns. It has been suggested that greater prevalence of GAD in women may be because women are more likely than men to live in poverty, are more frequently the subject of discrimination, and be sexually and physically abused more often than men. In regard to the first incidence of GAD in an individual’s life course, a first manifestation of GAD usually occurs between the late teenage years and the early twenties with the median age of onset being approximately 31 and mean age of onset being 32.7. However, GAD can begin or reoccur at any point in life. Indeed, GAD is common in the elderly population.

  • US: Approximately 3.1% of people age 18 and over in a given year (9.5 million).
  • UK: 5.9% of adults were affected by GAD in 2019.
  • Australia: 3% of adults
  • Canada: 2.5%.
  • Italy: 2.9%
  • Taiwan: 0.4%.

What is Exposure Therapy?

Introduction

Exposure therapy is a technique in behaviour therapy to treat anxiety disorders. Exposure therapy involves exposing the target patient to the anxiety source or its context without the intention to cause any danger. Doing so is thought to help them overcome their anxiety or distress. Procedurally, it is similar to the fear extinction paradigm developed studying laboratory rodents. Numerous studies have demonstrated its effectiveness in the treatment of disorders such as generalised anxiety disorder (GAD), social anxiety disorder, obsessive-compulsive disorder (OCD), post traumatic stress disorder (PTSD), and specific phobias.

Brief History

The use of exposure as a mode of therapy began in the 1950s, at a time when psychodynamic views dominated Western clinical practice and behavioural therapy was first emerging. South African psychologists and psychiatrists first used exposure as a way to reduce pathological fears, such as phobias and anxiety-related problems, and they brought their methods to England in the Maudsley Hospital training programme.

Joseph Wolpe (1915-1997) was one of the first psychiatrists to spark interest in treating psychiatric problems as behavioural issues. He sought consultation with other behavioural psychologists, among them James G. Taylor (1897-1973), who worked in the psychology department of the University of Cape Town in South Africa. Although most of his work went unpublished, Taylor was the first psychologist known to use exposure therapy treatment for anxiety, including methods of situational exposure with response prevention – a common exposure therapy technique still being used. Since the 1950s several sorts of exposure therapy have been developed, including systematic desensitisation, flooding, implosive therapy, prolonged exposure therapy, in vivo exposure therapy, and imaginal exposure therapy.

Medical Uses

Generalised Anxiety Disorder

There is empirical evidence that exposure therapy can be an effective treatment for people with generalised anxiety disorder, citing specifically in vivo exposure therapy, which has greater effectiveness than imaginal exposure in regards to generalized anxiety disorder. The aim of in vivo exposure treatment is to promote emotional regulation using systematic and controlled therapeutic exposure to traumatic stimuli.

Phobia

Exposure therapy is the most successful known treatment for phobias. Several published meta-analyses included studies of one-to-three hour single-session treatments of phobias, using imaginal exposure. At a post-treatment follow-up four years later 90% of people retained a considerable reduction in fear, avoidance, and overall level of impairment, while 65% no longer experienced any symptoms of a specific phobia.

Agoraphobia and social anxiety disorder are examples of phobias that have been successfully treated by exposure therapy.

Post Traumatic Stress Disorder

Virtual reality exposure (VRE) therapy is a modern but effective treatment of post-traumatic stress disorder (PTSD). This method was tested on several active duty Army soldiers, using an immersive computer simulation of military settings over six sessions. Self-reported PTSD symptoms of these soldiers were greatly diminished following the treatment. Exposure therapy has shown promise in the treatment of co-morbid PTSD and substance abuse.

Obsessive Compulsive Disorder

Exposure and response prevention (also known as exposure and ritual prevention; ERP or EX/RP) is a variant of exposure therapy that is recommended by the American Academy of Child and Adolescent Psychiatry (AACAP), the American Psychiatric Association (APA), and the Mayo Clinic as first-line treatment of obsessive compulsive disorder (OCD) citing that it has the richest empirical support for both youth and adolescent outcomes.

ERP is predicated on the idea that a therapeutic effect is achieved as subjects confront their fears, but refrain from engaging in the escape response or ritual that delays or eliminates distress. In the case of individuals with OCD or an anxiety disorder, there is a thought or situation that causes distress. Individuals usually combat this distress through specific behaviours that include avoidance or rituals. However, ERP involves purposefully evoking fear, anxiety, and or distress in the individual by exposing him/her to the feared stimulus. The response prevention then involves having the individual refrain from the ritualistic or otherwise compulsive behaviour that functions to decrease distress. The patient is then taught to tolerate distress until it fades away on its own, thereby learning that rituals are not always necessary to decrease distress or anxiety. Over repeated practice of ERP, patients with OCD expect to find that they can have obsessive thoughts and images but not have the need to engage in compulsive rituals to decrease distress.

The AACAP’s practise parameters for OCD recommends cognitive behavioural therapy, and more specifically ERP, as first line treatment for youth with mild to moderate severity OCD and combination psychotherapy and pharmacotherapy for severe OCD. The Cochrane Review’s examinations of different randomised control trials echoes repeated findings of the superiority of ERP over waitlist control or pill-placebos, the superiority of combination ERP and pharmacotherapy, but similar effect sizes of efficacy between ERP or pharmacotherapy alone.

Techniques

Exposure therapy is based on the principle of respondent conditioning often termed Pavlovian extinction. The exposure therapist identifies the cognitions, emotions and physiological arousal that accompany a fear-inducing stimulus and then tries to break the pattern of escape that maintains the fear. This is done by exposing the patient to progressively stronger fear-inducing stimuli. Fear is minimised at each of a series of steadily escalating steps or challenges (a hierarchy), which can be explicit (“static”) or implicit (“dynamic” – refer to Method of Factors) until the fear is finally gone. The patient is able to terminate the procedure at any time.

There are three types of exposure procedures. The first is in vivo or “real life.” This type exposes the patient to actual fear-inducing situations. For example, if someone fears public speaking, the person may be asked to give a speech to a small group of people. The second type of exposure is imaginal, where patients are asked to imagine a situation that they are afraid of. This procedure is helpful for people who need to confront feared thoughts and memories. The third type of exposure is interoceptive, which may be used for more specific disorders such as panic or post-traumatic stress disorder. Patients confront feared bodily symptoms such as increased heart rate and shortness of breath. All types of exposure may be used together or separately.

While evidence clearly supports the effectiveness of exposure therapy, some clinicians are uncomfortable using imaginal exposure therapy, especially in cases of PTSD. They may not understand it, are not confident in their own ability to use it, or more commonly, they see significant contraindications for their client.

Flooding therapy also exposes the patient to feared stimuli, but it is quite distinct in that flooding starts at the most feared item in a fear hierarchy, while exposure starts at the least fear-inducing.

Exposure and Response Prevention

In the exposure and response prevention (ERP or EX/RP) variation of exposure therapy, the resolution to refrain from the escape response is to be maintained at all times and not just during specific practice sessions. Thus, not only does the subject experience habituation to the feared stimulus, but they also practice a fear-incompatible behavioural response to the stimulus. The distinctive feature is that individuals confront their fears and discontinue their escape response. The American Psychiatric Association recommends ERP for the treatment of OCD, citing that ERP has the richest empirical support.

While this type of therapy typically causes some short-term anxiety, this facilitates long-term reduction in obsessive and compulsive symptoms. Generally, ERP incorporates a relapse prevention plan toward the end of the course of therapy.

Mindfulness

A 2015 review pointed out parallels between exposure therapy and mindfulness, stating that mindful meditation “resembles an exposure situation because [mindfulness] practitioners ‘turn towards their emotional experience’, bring acceptance to bodily and affective responses, and refrain from engaging in internal reactivity towards it.” Imaging studies have shown that the ventromedial prefrontal cortex, hippocampus, and the amygdala are all affected by exposure therapy; imaging studies have shown similar activity in these regions with mindfulness training.

Research

Exposure therapy can be investigated in the laboratory using Pavlovian extinction paradigms. Using rodents such as rats or mice to study extinction allows for the investigation of underlying neurobiological mechanisms involved, as well as testing of pharmacological adjuncts to improve extinction learning.

Is It Useful to Screen for Anxiety using the GAD-7 in Pregnant Women?

Research Paper Title

Validation of the Generalised Anxiety Disorder Screener (GAD-7) in Spanish Pregnant Women.

Background

Anxiety during pregnancy is one of the most common mental health problems and a significant risk factor for postpartum depression. The Generalised Anxiety Disorder-7 (GAD-7) is one of the most widely used self-report measures of anxiety symptoms available in multiple languages. This study evaluates the psychometric properties and underlying factor structures of the Spanish GAD-7 among pregnant women in Spain.

Methods

Spanish-speaking pregnant women (N = 385) were recruited from an urban obstetrics setting in Northern Spain. Women completed the GAD-7 and the anxiety subscale of the Symptom Checklist (SCL90-R) at three time points, once per trimester. The reliability, concurrent validity, and factor analyses were conducted to evaluate the psychometric properties and factor structure, respectively.

Results

In the first trimester, the GAD-7 demonstrated good internal consistency (a = 0.89). GAD-7 is positively correlated with SCL90-R (anxiety subscale; r=0.75; p < 0.001). The proposed one-factor structure is found using exploratory factor analysis -FACTOR programme – with Unweighted Least Squares procedure and optimal implementation of parallel analysis (GFI = 0.99).

Conclusions

Health providers should screen for anxiety using the GAD-7 during pregnancy among urban Spanish-speaking samples to provide appropriate follow-up care.

Reference

Soto-Balbuena, C. Rodriguez-Munoz, M.F. & Le, H-N. (2021) Validation of the Generalized Anxiety Disorder Screener (GAD-7) in Spanish Pregnant Women. Psicothema. 33(1), pp.164-170. doi: 10.7334/psicothema2020.167.

What is Panic Disorder?

Introduction

Panic disorder is an anxiety disorder characterised by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath, numbness, or a feeling that something terrible is going to happen. The maximum degree of symptoms occurs within minutes. There may be ongoing worries about having further attacks and avoidance of places where attacks have occurred in the past.

The cause of panic disorder is unknown. Panic disorder often runs in families. Risk factors include smoking, psychological stress, and a history of child abuse. Diagnosis involves ruling out other potential causes of anxiety including other mental disorders, medical conditions such as heart disease or hyperthyroidism, and drug use. Screening for the condition may be done using a questionnaire.

Panic disorder is usually treated with counselling and medications. The type of counselling used is typically cognitive behavioural therapy (CBT) which is effective in more than half of people. Medications used include antidepressants and occasionally benzodiazepines or beta blockers. Following stopping treatment up to 30% of people have a recurrence.

Panic disorder affects about 2.5% of people at some point in their life. It usually begins during adolescence or early adulthood but any age can be affected. It is less common in children and older people. Women are more often affected than men.

Signs and Symptoms

Panic disorder sufferers usually have a series of intense episodes of extreme anxiety during panic attacks. These attacks typically last about ten minutes, and can be as short-lived as 1-5 minutes, but can last twenty minutes to more than an hour, or until helpful intervention is made. Panic attacks can wax and wane for a period of hours (panic attacks rolling into one another), and the intensity and specific symptoms of panic may vary over the duration.

In some cases, the attack may continue at unabated high intensity or seem to be increasing in severity. Common symptoms of an attack include rapid heartbeat, perspiration, dizziness, dyspnoea, trembling, uncontrollable fear such as: the fear of losing control and going crazy, the fear of dying and hyperventilation. Other symptoms are a sensation of choking, paralysis, chest pain, nausea, numbness or tingling, chills or hot flashes, faintness, crying and some sense of altered reality. In addition, the person usually has thoughts of impending doom. Individuals suffering from an episode have often a strong wish of escaping from the situation that provoked the attack. The anxiety of panic disorder is particularly severe and noticeably episodic compared to that from generalised anxiety disorder. Panic attacks may be provoked by exposure to certain stimuli (e.g. seeing a mouse) or settings (e.g. the dentist’s office). Nocturnal panic attacks are common in people with panic disorder. Other attacks may appear unprovoked. Some individuals deal with these events on a regular basis, sometimes daily or weekly.

Limited symptom attacks are similar to panic attacks but have fewer symptoms. Most people with PD experience both panic attacks and limited symptom attacks.

Interoceptive

Studies investigating the relationship between interoception and panic disorder have shown that people with panic disorder feel heartbeat sensations more intensely when stimulated by pharmacological agents, suggesting that they experience heightened interoceptive awareness compared to subjects without PD.

Causes

Psychological Models

While there is not just one explanation for the cause of panic disorder, there are certain perspectives researchers use to explain the disorder. The first one is the biological perspective. Past research concluded that there is irregular norepinephrine activity in people who have panic attacks. Current research also supports this perspective as it has been found that those with panic disorder also have a brain circuit that performs improperly. This circuit consists of the amygdala, central gray matter, ventromedial nucleus of the hypothalamus, and the locus ceruleus.

There is also a cognitive perspective. Theorists believe that people with panic disorder may experience panic reactions because they mistake their bodily sensations for life-threatening situations. These bodily sensations cause some people to feel as though are out of control which may lead to feelings of panic. This misconception of bodily sensations is referred to as anxiety sensitivity, and studies suggest that people who score higher on anxiety sensitivity surveys are fives times more likely to be diagnosed with panic disorder.

Panic disorder has been found to run in families, which suggests that inheritance plays a strong role in determining who will get it.

Psychological factors, stressful life events, life transitions, and environment as well as often thinking in a way that exaggerates relatively normal bodily reactions are also believed to play a role in the onset of panic disorder. Often the first attacks are triggered by physical illnesses, major stress, or certain medications. People who tend to take on excessive responsibilities may develop a tendency to suffer panic attacks. Post-traumatic stress disorder (PTSD) patients also show a much higher rate of panic disorder than the general population.

Prepulse inhibition has been found to be reduced in patients with panic disorder.

Substance Misuse

Substance abuse is often correlated with panic attacks. In a study, 39% of people with panic disorder had abused substances. Of those who used alcohol, 63% reported that the alcohol use began prior to the onset of panic, and 59% of those abusing illicit drugs reported that drug use began first. The study that was conducted documented the panic-substance abuse relationship. Substance abuse began prior to the onset of panic and substances were used to self-medicate for panic attacks by only a few subjects.

In another study, 100 methamphetamine-dependent individuals were analysed for co-morbid psychiatric disorders; of the 100 individuals, 36% were categorised as having co-morbid psychiatric disorders. Mood and Psychotic disorders were more prevalent than anxiety disorders, which accounted for 7% of the 100 sampled individuals.

Smoking

Tobacco smoking increases the risk of developing panic disorder with or without agoraphobia and panic attacks; smoking started in adolescence or early adulthood particularly increases this risk of developing panic disorder. While the mechanism of how smoking increases panic attacks is not fully understood, a few hypotheses have been derived. Smoking cigarettes may lead to panic attacks by causing changes in respiratory function (e.g. feeling short of breath). These respiratory changes in turn can lead to the formation of panic attacks, as respiratory symptoms are a prominent feature of panic. Respiratory abnormalities have been found in children with high levels of anxiety, which suggests that a person with these difficulties may be susceptible to panic attacks, and thus more likely to subsequently develop panic disorder. Nicotine, a stimulant, could contribute to panic attacks. However, nicotine withdrawal may also cause significant anxiety which could contribute to panic attacks.

It is also possible that panic disorder patients smoke cigarettes as a form of self-medication to lessen anxiety. Nicotine and other psychoactive compounds with antidepressant properties in tobacco smoke which act as monoamine oxidase inhibitors in the brain can alter mood and have a calming effect, depending on dose.

Stimulants

A number of clinical studies have shown a positive association between caffeine ingestion and panic disorder and/or anxiogenic effects. People who have panic disorder are more sensitive to the anxiety-provoking effects of caffeine. One of the major anxiety-provoking effects of caffeine is an increase in heart rate.

Certain cold and flu medications containing decongestants may also contain pseudoephedrine, ephedrine, phenylephrine, naphazoline and oxymetazoline. These may be avoided by the use of decongestants formulated to prevent causing high blood pressure.

Alcohol and Sedatives

About 30% of people with panic disorder use alcohol and 17% use other psychoactive drugs. This is in comparison with 61% (alcohol) and 7.9% (other psychoactive drugs) of the general population who use alcohol and psychoactive drugs, respectively. Utilisation of recreational drugs or alcohol generally make symptoms worse. Most stimulant drugs (caffeine, nicotine, cocaine) would be expected to worsen the condition, since they directly increase the symptoms of panic, such as heart rate.

Deacon and Valentiner (2000) conducted a study that examined co-morbid panic attacks and substance use in a non-clinical sample of young adults who experienced regular panic attacks. The authors found that compared to healthy controls, sedative use was greater for non-clinical participants who experienced panic attacks. These findings are consistent with the suggestion made by Cox, Norton, Dorward, and Fergusson (1989) that panic disorder patients self-medicate if they believe that certain substances will be successful in alleviating their symptoms. If panic disorder patients are indeed self-medicating, there may be a portion of the population with undiagnosed panic disorder who will not seek professional help as a result of their own self-medication. In fact, for some patients panic disorder is only diagnosed after they seek treatment for their self-medication habit.

While alcohol initially helps ease panic disorder symptoms, medium- or long-term alcohol abuse can cause panic disorder to develop or worsen during alcohol intoxication, especially during alcohol withdrawal syndrome. This effect is not unique to alcohol but can also occur with long-term use of drugs which have a similar mechanism of action to alcohol such as the benzodiazepines which are sometimes prescribed as tranquilisers to people with alcohol problems. The reason chronic alcohol misuse worsens panic disorder is due to distortion of the brain chemistry and function.

Approximately 10% of patients will experience notable protracted withdrawal symptoms, which can include panic disorder, after discontinuation of benzodiazepines. Protracted withdrawal symptoms tend to resemble those seen during the first couple of months of withdrawal but usually are of a subacute level of severity compared to the symptoms seen during the first 2 or 3 months of withdrawal. It is not known definitively whether such symptoms persisting long after withdrawal are related to true pharmacological withdrawal or whether they are due to structural neuronal damage as a result of chronic use of benzodiazepines or withdrawal. Nevertheless, such symptoms do typically lessen as the months and years go by eventually disappearing altogether.

A significant proportion of patients attending mental health services for conditions including anxiety disorders such as panic disorder or social phobia have developed these conditions as a result of alcohol or sedative abuse. Anxiety may pre-exist alcohol or sedative dependence, which then acts to perpetuate or worsen the underlying anxiety disorder. Someone suffering the toxic effects of alcohol abuse or chronic sedative use or abuse will not benefit from other therapies or medications for underlying psychiatric conditions as they do not address the root cause of the symptoms. Recovery from sedative symptoms may temporarily worsen during alcohol withdrawal or benzodiazepine withdrawal.

Mechanism

The neuroanatomy of panic disorder largely overlaps with that of most anxiety disorders. Neuropsychological, neurosurgical, and neuroimaging studies implicate the insula, amygdala, hippocampus, anterior cingulate cortex (ACC), lateral prefrontal cortex, and periaqueductal grey. During acute panic attacks, viewing emotionally charged words, and rest, most studies find elevated blood flow or metabolism. However, the observation of amygdala hyperactivity is not entirely consistent, especially in studies that evoke panic attacks chemically. Hippocampus hyperactivity has been observed during rest and viewing emotionally charged pictures, which has been hypothesized to be related to memory retrieval bias towards anxious memories. Insula hyperactivity during the onset of and over the course of acute panic episodes is thought to be related to abnormal introceptive processes; the perception that bodily sensations are “wrong” is a transdiagnostic finding(i.e. found across multiple anxiety disorders), and may be related to insula dysfunction. Rodent and human studies heavily implicate the periaqueductal grey in generating fear responses, and abnormalities related to the structure and metabolism in the PAG have been reported in panic disorder. The frontal cortex is implicated in panic disorder by multiple lines of evidence. Damage to the dorsal ACC has been reported to lead to panic disorder. Elevated ventral ACC and dorsolateral prefrontal cortex during symptom provocation and viewing emotional stimuli have also been reported, although findings are not consistent.

Researchers studying some individuals with panic disorder propose they may have a chemical imbalance within the limbic system and one of its regulatory chemicals gamma-aminobutyric acid (GABA-A). The reduced production of GABA-A sends false information to the amygdala which regulates the body’s “fight or flight” response mechanism and, in return, produces the physiological symptoms that lead to the disorder. Clonazepam, an anticonvulsant benzodiazepine with a long half-life, has been successful in keeping the condition under control.

Recently, researchers have begun to identify mediators and moderators of aspects of panic disorder. One such mediator is the partial pressure of carbon dioxide, which mediates the relationship between panic disorder patients receiving breathing training and anxiety sensitivity; thus, breathing training affects the partial pressure of carbon dioxide in a patient’s arterial blood, which in turn lowers anxiety sensitivity. Another mediator is hypochondriacal concerns, which mediate the relationship between anxiety sensitivity and panic symptomatology; thus, anxiety sensitivity affects hypochondriacal concerns which, in turn, affect panic symptomatology.

Perceived threat control has been identified as a moderator within panic disorder, moderating the relationship between anxiety sensitivity and agoraphobia; thus, the level of perceived threat control dictates the degree to which anxiety sensitivity results in agoraphobia. Another recently identified moderator of panic disorder is genetic variations in the gene coding for galanin; these genetic variations moderate the relationship between females suffering from panic disorder and the level of severity of panic disorder symptomatology.

Diagnosis

The DSM-IV-TR diagnostic criteria for panic disorder require unexpected, recurrent panic attacks, followed in at least one instance by at least a month of a significant and related behaviour change, a persistent concern of more attacks, or a worry about the attack’s consequences. There are two types, one with and one without agoraphobia. Diagnosis is excluded by attacks due to a drug or medical condition, or by panic attacks that are better accounted for by other mental disorders.

The ICD-10 diagnostic criteria:

  • The essential feature is recurrent attacks of severe anxiety (panic), which are not restricted to any particular situation or set of circumstances and are therefore unpredictable.

The dominant symptoms include:

  • Sudden onset of palpitations.
  • Chest pain.
  • Choking sensations.
  • Dizziness.
  • Feelings of unreality (depersonalisation or derealisation).
  • Secondary fear of dying, losing control, or going mad.
  • Panic disorder should not be given as the main diagnosis if the person has a depressive disorder at the time the attacks start; in these circumstances, the panic attacks are probably secondary to depression.

The Panic Disorder Severity Scale (PDSS) is a questionnaire for measuring the severity of panic disorder.

Treatment

Panic disorder is a serious health problem that in many cases can be successfully treated, although there is no known cure. Identification of treatments that engender as full a response as possible, and can minimise relapse, is imperative. CBT and positive self-talk specific for panic are the treatments of choice for panic disorder. Several studies show that 85% to 90% of panic disorder patients treated with CBT recover completely from their panic attacks within 12 weeks. When CBT is not an option, pharmacotherapy can be used. SSRIs are considered a first-line pharmacotherapeutic option.

Psychotherapy

Panic disorder is not the same as phobic symptoms, although phobias commonly result from panic disorder. CBT and one tested form of psychodynamic psychotherapy have been shown efficacious in treating panic disorder with and without agoraphobia. A number of randomized clinical trials have shown that CBT achieves reported panic-free status in 70-90% of patients about 2 years after treatment.

A 2009 Cochrane review found little evidence concerning the efficacy of psychotherapy in combination with benzodiazepines such that recommendations could not be made.

Symptom inductions generally occur for one minute and may include:

  • Intentional hyperventilation creates lightheadedness, derealisation, blurred vision, and dizziness.
  • Spinning in a chair creates dizziness and disorientation.
  • Straw breathing creates dyspnoea and airway constriction.
  • Breath holding creates sensation of being out of breath.
  • Running in place creates increased heart rate, respiration, and perspiration.
  • Body tensing creates feelings of being tense and vigilant.

Another form of psychotherapy that has shown effectiveness in controlled clinical trials is panic-focused psychodynamic psychotherapy, which focuses on the role of dependency, separation anxiety, and anger in causing panic disorder. The underlying theory posits that due to biochemical vulnerability, traumatic early experiences, or both, people with panic disorder have a fearful dependence on others for their sense of security, which leads to separation anxiety and defensive anger. Therapy involves first exploring the stressors that lead to panic episodes, then probing the psychodynamics of the conflicts underlying panic disorder and the defence mechanisms that contribute to the attacks, with attention to transference and separation anxiety issues implicated in the therapist-patient relationship.

Comparative clinical studies suggest that muscle relaxation techniques and breathing exercises are not efficacious in reducing panic attacks. In fact, breathing exercises may actually increase the risk of relapse.

Appropriate treatment by an experienced professional can prevent panic attacks or at least substantially reduce their severity and frequency – bringing significant relief to 70% to 90% of people with panic disorder. Relapses may occur, but they can often be effectively treated just like the initial episode.

vanApeldoorn, F.J. et al. (2011) demonstrated the additive value of a combined treatment incorporating an SSRI treatment intervention with CBT. Gloster et al. (2011) went on to examine the role of the therapist in CBT. They randomised patients into two groups: one being treated with CBT in a therapist guided environment, and the second receiving CBT through instruction only, with no therapist guided sessions. The findings indicated that the first group had a somewhat better response rate, but that both groups demonstrated a significant improvement in reduction of panic symptomatology. These findings lend credibility to the application of CBT programs to patients who are unable to access therapeutic services due to financial, or geographic inaccessibility. Koszycky et al. (2011) discuss the efficacy of self-administered CBT (SCBT) in situations where patients are unable to retain the services of a therapist. Their study demonstrates that it is possible for SCBT in combination with an SSRI to be as effective as therapist-guided CBT with SSRI. Each of these studies contributes to a new avenue of research that allows effective treatment interventions to be made more easily accessible to the population.

Cognitive Behavioural Therapy (CBT)

CBT encourages patients to confront the triggers that induce their anxiety. By facing the very cause of the anxiety, it is thought to help diminish the irrational fears that are causing the issues to begin with. The therapy begins with calming breathing exercises, followed by noting the changes in physical sensations felt as soon as anxiety begins to enter the body. Many clients are encouraged to keep journals. In other cases, therapists may try and induce feelings of anxiety so that the root of the fear can be identified.

Comorbid clinical depression, personality disorders and alcohol abuse are known risk factors for treatment failure.

As with many disorders, having a support structure of family and friends who understand the condition can help increase the rate of recovery. During an attack, it is not uncommon for the sufferer to develop irrational, immediate fear, which can often be dispelled by a supporter who is familiar with the condition. For more serious or active treatment, there are support groups for anxiety sufferers which can help people understand and deal with the disorder.

Current treatment guidelines American Psychiatric Association and the American Medical Association primarily recommend either CBT or one of a variety of psychopharmacological interventions. Some evidence exists supporting the superiority of combined treatment approaches.

Another option is self-help based on principles of CBT. Using a book or a website, a person does the kinds of exercises that would be used in therapy, but they do it on their own, perhaps with some email or phone support from a therapist. A systematic analysis of trials testing this kind of self-help found that websites, books, and other materials based on CBT could help some people. The best-studied conditions are panic disorder and social phobia.

Interoceptive Techniques

Interoceptive exposure is sometimes used for panic disorder. People’s interoceptive triggers of anxiety are evaluated one-by-one before conducting interoceptive exposures, such as addressing palpitation sensitivity via light exercise. Despite evidence of its clinical efficacy, this practice is reportedly used by only 12-20% of psychotherapists. Potential reasons for this underutilisation include “lack of training sites, logistical hurdles (e.g. occasional need for exposure durations longer than a standard therapy session), policies against conducting exposures outside of the workplace setting, and perhaps most tellingly, negative therapist beliefs (e.g. that interoceptive exposures are unethical, intolerable, or even harmful).”

Medication

Appropriate medications are effective for panic disorder. Selective serotonin reuptake inhibitors are first line treatments rather than benzodiazepines due to concerns with the latter regarding tolerance, dependence and abuse. Although there is little evidence that pharmacological interventions can directly alter phobias, few studies have been performed, and medication treatment of panic makes phobia treatment far easier (an example in Europe where only 8% of patients receive appropriate treatment).

Medications can include:

  • Antidepressants (SSRIs, MAOIs, tricyclic antidepressants and norepinephrine reuptake inhibitors).
  • Antianxiety agents (benzodiazepines):
    • Use of benzodiazepines for panic disorder is controversial.
    • The American Psychiatric Association states that benzodiazepines can be effective for the treatment of panic disorder and recommends that the choice of whether to use benzodiazepines, antidepressants with anti-panic properties or psychotherapy should be based on the individual patient’s history and characteristics.
    • Other experts believe that benzodiazepines are best avoided due to the risks of the development of tolerance and physical dependence.
    • The World Federation of Societies of Biological Psychiatry, say that benzodiazepines should not be used as a first-line treatment option but are an option for treatment-resistant cases of panic disorder.
    • Despite increasing focus on the use of antidepressants and other agents for the treatment of anxiety as recommended best practice, benzodiazepines have remained a commonly used medication for panic disorder.
    • They reported that in their view there is insufficient evidence to recommend one treatment over another for panic disorder.
    • The APA noted that while benzodiazepines have the advantage of a rapid onset of action, that this is offset by the risk of developing a benzodiazepine dependence.
    • The UKs National Institute of Clinical Excellence (NICE) came to a different conclusion, they pointed out the problems of using uncontrolled clinical trials to assess the effectiveness of pharmacotherapy and based on placebo-controlled research they concluded that benzodiazepines were not effective in the long-term for panic disorder and recommended that benzodiazepines not be used for longer than 4 weeks for panic disorder.
    • Instead NICE clinical guidelines recommend alternative pharmacotherapeutic or psychotherapeutic interventions.
    • When compared to placebos, benzodiazepines demonstrate possible superiority in the short term but the evidence is low quality with limited applicability to clinical practice.

Other Treatments

For some people, anxiety can be greatly reduced by discontinuing the use of caffeine. Anxiety can temporarily increase during caffeine withdrawal.

Epidemiology

Panic disorder typically begins during early adulthood; roughly half of all people who have panic disorder develop the condition between the ages of 17 and 24, especially those subjected to traumatic experiences. However, some studies suggest that the majority of young people affected for the first time are between the ages of 25 and 30. Women are twice as likely as men to develop panic disorder and it occurs far more often in people with above average intelligence.

Panic disorder can continue for months or years, depending on how and when treatment is sought. If left untreated, it may worsen to the point where one’s life is seriously affected by panic attacks and by attempts to avoid or conceal the condition. In fact, many people have had problems with personal relationships, education and employment while struggling to cope with panic disorder. Some people with panic disorder may conceal their condition because of the stigma of mental illness. In some individuals, symptoms may occur frequently for a period of months or years, then many years may pass with little or no symptoms. In some cases, the symptoms persist at the same level indefinitely. There is also some evidence that many individuals (especially those who develop symptoms at an early age) may experience symptom cessation later in life (e.g. past age 50).

In 2000, the World Health Organisation found prevalence and incidence rates for panic disorder to be very similar across the globe. Age-standardised prevalence per 100,000 ranged from 309 in Africa to 330 in East Asia for men and from 613 in Africa to 649 in North America, Oceania, and Europe for women.

Children

A retrospective study has shown that 40% of adult panic disorder patients reported that their disorder began before the age of 20. In an article examining the phenomenon of panic disorder in youth, Diler et al. (2004) found that only a few past studies have examined the occurrence of juvenile panic disorder. They report that these studies have found that the symptoms of juvenile panic disorder almost replicate those found in adults (e.g. heart palpitations, sweating, trembling, hot flashes, nausea, abdominal distress, and chills). The anxiety disorders co-exist with staggeringly high numbers of other mental disorders in adults. The same comorbid disorders that are seen in adults are also reported in children with juvenile panic disorder. Last and Strauss (1989) examined a sample of 17 adolescents with panic disorder and found high rates of comorbid anxiety disorders, major depressive disorder, and conduct disorders. Eassau et al. (1999) also found a high number of comorbid disorders in a community-based sample of adolescents with panic attacks or juvenile panic disorder. Within the sample, adolescents were found to have the following comorbid disorders: major depressive disorder (80%), dysthymic disorder (40%), generalised anxiety disorder (40%), somatoform disorders (40%), substance abuse (40%), and specific phobia (20%). Consistent with this previous work, Diler et al. (2004) found similar results in their study in which 42 youths with juvenile panic disorder were examined. Compared to non-panic anxiety disordered youths, children with panic disorder had higher rates of comorbid major depressive disorder and bipolar disorder.

Children differ from adolescents and adults in their interpretation and ability to express their experience. Like adults, children experience physical symptoms including accelerated heart rate, sweating, trembling or shaking, shortness of breath, nausea or stomach pain, dizziness or light-headedness. In addition, children also experience cognitive symptoms like fear of dying, feelings of being detached from oneself, feelings of losing control or going crazy, but they are unable to vocalize these higher-order manifestations of fear. They simply know that something is going wrong and that they are very afraid. Children can only describe physical symptoms. They have not yet developed the constructs to put these symptoms together and label them as fear. Parents often feel helpless when they watch a child suffer. They can help children give a name to their experience, and empower them to overcome the fear they are experiencing.

The role of the parent in treatment and intervention for children diagnosed with panic disorder is discussed by McKay & Starch (2011). They point out that there are several levels at which parental involvement should be considered. The first involves the initial assessment. Parents, as well as the child, should be screened for attitudes and treatment goals, as well as for levels of anxiety or conflict in the home. The second involves the treatment process in which the therapist should meet with the family as a unit as frequently as possible. Ideally, all family members should be aware and trained in the process of CBT in order to encourage the child to rationalize and face fears rather than employ avoidant safety behaviours. McKay & Storch (2011) suggest training/modelling of therapeutic techniques and in-session involvement of the parents in the treatment of children to enhance treatment efficacy.

Despite the evidence pointing to the existence of early-onset panic disorder, the DSM-IV-TR currently only recognizes six anxiety disorders in children: separation anxiety disorder, generalised anxiety disorder, specific phobia, obsessive-compulsive disorder, social anxiety disorder (a.k.a. social phobia), and post-traumatic stress disorder. Panic disorder is notably excluded from this list.