first due to its cost-effectiveness compared to other ssris used for generalized anxiety disorder 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, diarrhea, 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 generalized anxiety disorder. 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, diarrhea, 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) is effective for treating gad. it 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 misuse 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 with gad despite having no evidence or varied evidence regarding efficacy. efficacy trials for cam medications often have 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 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 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 pediatric patients with gad. concern exists regarding the question as to whether silexan may cause unopposed estrogen exposure in boys due to disruption of steroid signaling. galphimia glauca extracts: while galphima glauca extracts have been the subject of two 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 single 12-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. multifaith 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 generalized anxiety disorder (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 percent 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 percent, and with panic disorder, 9.9 percent. patients with a diagnosed anxiety disorder also had high rates of comorbid depression, including 22.4 percent of patients with social phobia, 9.4 percent with agoraphobia, and 2.3 percent 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 categorized 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, ranging from genetic pleiotropy (i.e., gad and nonbipolar depression might represent different phenotypic expressions of a common etiology ) to impaired executive control or sleep problems and fatigue as potential bridging mechanisms between the two disorders. 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 a substance use disorder, bzds should be avoided due to their addictive properties. cbt has been found an effective treatment since it improves symptoms of gad and substance use. compared to the general population, patients with internalizing disorders such as depression, generalized anxiety disorder (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 percent 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