A recent systematic review and meta-analysis that compared benzodiazepines with antidepressants for anxiety disorders has triggered a debate among clinicians about first-line treatments, efficacy for specific disorders, and adverse effects. Their review encompassed 22 studies, 18 of which compared TCAs, such as amitriptyline, clomipramine, or imipramine, with benzodiazepines.
Eleven studies in the meta-analysis compared a ben-zodiazepine with a TCA for the treatment of panic disorder with or without agoraphobia. In their review, the authors cited results for various anxiety disorders.
Hackett and colleagues 2 compared diazepam and venlafaxine extended-release in patients with GAD. Results showed no significant differences in response rates between groups, but discontinuations and adverse effects were more frequent in patients treated with venlafaxine. Feltner and colleagues 3 compared lorazepam, paroxetine, and placebo for treatment of patients with GAD.
Nardi and colleagues 4 conducted a randomized, open-label, naturalistic 8-week study to compare the efficacy and safety of treatment with clonazepam and paroxetine in patients with panic disorder with or without agoraphobia.
Clonazepam resulted in fewer weekly panic attacks at week 4 and greater clinical improvements at week 8. Anxiety severity was significantly reduced with clonazepam at weeks 1 and 2, with no difference in panic disorder severity. Patients treated with clonazepam had fewer adverse events than patients treated with paroxetine.
Offidani and colleagues also cited a long-term follow-up study by Nardi and colleagues 5 that compared the efficacy and safety of clonazepam and paroxetine over 3 years of treatment. Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression of Improvement rating than treatment with paroxetine. Both treatments similarly reduced the number of panic attacks and severity of anxiety. Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine These disorders are associated with significant morbidity 3 and increased mortality, probably as a consequence of increased suicide rates among sufferers.
The direct and indirect costs to the health service and economy are considerable. Although persons who suffer from anxiety disorders are high consumers of all types of health services, only a minority receive specific help. The spectrum of anxiety disorders includes generalized anxiety disorder GAD , panic disorder PD and agoraphobia, obsessive-compulsive disorder OCD , phobic disorder including social phobia , and posttraumatic stress disorder PTSD.
With the discovery of new psychotropic medications, specific diagnosis within this spectrum is essential because each of these disorders responds to specific pharmacotherapy. The approach to anxiety should also recognize that anxiety and depression are often comorbid conditions. Selective serotonin reuptake inhibitors SSRIs , which were designed to treat depression, are also effective for many anxiety disorders.
They have revolutionized the treatment of anxiety, replacing chronic use of benzodiazepines BZs. Other antidepressants, including tianeptine, have proven effective in adjustment disorders in which both anxiety and depression are involved. Doses of SSRIs for anxiety disorders could be higher than those used for depression, but must be started at lower doses to minimize the shortterm agitation sometimes experienced with these medications. The patient should be counseled that side effects often diminish with time and also that empirical switching to another SSRI may be necessary.
Although tricyclic antidepressants TCAs have been used with success in anxiety disorders Table I , drowsiness, anticholinergic side effects, and toxicity have made these medications less popular. Also, monoamine oxidase inhibitors MAO Is are effective for anxiety, but their dietary restrictions and side-effect profile have limited their use.
BZs are the oldest, class of medications used to treat anxiety. Although they have the advantage of rapid onset of action, they carry the risk of dependence, sedation, and tolerance.
Withdrawal syndromes resulting in rebound anxiety, even reactions as severe as delirium tremens, are possible. BZs should be avoided in patients with a past, history of substance abuse, personality disorder, or dosage escalation.
These medications are ideal for patients who experience infrequent bouts of anxiety or episodes of anxiety-related insomnia. Buspirone is a. In head-to-head trials, it works as well as BZs for GAD, but has a slower onset, of action and lacks sedative properties. It is therefore less useful for the anxious patient who needs a sedative. It does not impair alertness and lacks abuse potential.
A number of well-controlled clinical trials support the empirical evidence of effective pharmacotherapy of anxiety disorders. However, the ideal anxiolytic does not. Pharmacological treatment evidence for each anxiety disorder will be briefly reviewed. Information from some 6 to 8 months' maintenance therapy trials have found continued efficacy over time, 14 - 17 but since GAD is often a long-term and unremitting disorder, 18 it needs to be stated that pharmacotherapy, whether with BZs or other drugs, may need to continue for many years in a significant, number of patients.
In long-term use, tolerance to side effects does occur, but tolerance to the anxiolytic effect of the BZs does not appear. For this reason, and because of the high prevalence of comorbid depression, attention has focused also on different medications and antidepressants as potential treatment for GAD Table II. It has been demonstrated to show efficacy in GAD 10 , 20 - 22 and has been associated with maintenance of efficacy over a period of several months.
It is not sedating like the BZs; it is not associated with psychomotor impairment, tolerance, dependence, or withdrawal; and it docs not interact with alcohol. The drug works well when there are conspicuous symptoms of worry, apprehensive tension, and irritability, 10 and where depressive symptoms are intermixed with anxiety, 23 while it is less effective than BZs on somatic and autonomically driven symptoms.
Other azapironc drugs have been assessed in GAD, like gepirone, 27 , 28 ipsapirone, 29 and more recently flesinoxan and tandospirone, but with more equivocal results. Little attention has been given to the fact, that several studies have provided encouraging support for their efficacy. Perhaps the obscurity of these findings relates to the general uncertainty about the nature of GAD, its constantly changing criteria, and the apparent, belief that it is a highly placebo-responsive disorder.
Further controlled trials by Kahn et al, 32 Hoehn-Saric et al, 12 and Rickels et al 9 have provided evidence for the benefit of imipramine and trazodone in GAD.
Imipramine was more effective than diazepam on psychic anxiety symptoms, and it would also be expected to have significant, antidepressant effects. Its reuptake-inhibiting effects on serotonin and norepinephrine confer a double advantage relative to some of the more selective compounds mentioned above. However, due to its side-effect profile, trazodone is unlikely to be a first choice, but can be a useful backup drug for more difficult, to treat, or nonresponsive patients.
Its hypnotic properties are also useful where insomnia is a major problem. Nefazodone enjoys the advantage of greater patient acceptability and tolerability than trazodone. The most, recent, development in the pharmacotherapy of GAD, largely out of consideration of the results of the studies with TCAs, has been the controlled comprehensive trials with venlafaxine, a serotonin and norepinephrine reuptake inhibitor SNRI. In five placebo-controlled 8-week trials, venlafaxine has demonstrated efficacy significantly greater than placebo in the treatment, of GAD patients without, accompanying depression.
Although most of the improvement on venlafaxine occurred in the first 4 weeks, subjects continued to improve over the 6-month period. Mild side effects including nausea, insomnia, dry mouth, and dizziness were principally seen at the initiation of treatment and cleared up over time. Both drugs were superior to placebo, but venlafaxine showed an earlier effect and advantage over buspirone in secondary outcome measures, notably the Hamilton Depression Scale anxiety subscore.
The results of these studies indicate that antidepressants offer promise in GAD, even if they appear to be better in treating psychic anxiety symptoms, while BZs are probably superior in treating the somatic symptoms.
Several other drugs have been assessed in GAD. The well-established anxiolytic effects of BZs are modified by several drawbacks, primarily of physical dependence, withdrawal symptoms, and sedation. These BZ-like compounds should be effective anxiolytics, but less likely to produce sedation, tolerance, withdrawal, abuse liability, memory impairment, and ethanol potentiation. These newly developed compounds are either BZ derivatives or of a different, chemical structure, that is, imidazopyridine and P-carbolines.
The most comprehensively studied has been the P-carboline abecarnil. Further placebocontrolled studies 42 , 43 have shown modest treatment effects; however, at higher doses, there is some evidence of withdrawal symptoms. Finally, anecdotal experiences report, potential value of kava and passionflower extract in the treatment, of GAD. Alprazolam, the first licensed BZ for the treatment of panic, was studied in a large multinational placebo-con trolled trial Cross National Collaborative Panic Study conducted in two 8-week phases: during the first it was compared with placebo, and then it was compared with both placebo and imipramine.
Patients showed significant improvements in all major symptom areas, like number of panic attacks, avoidance behavior, and residual anxiety between attacks, 50 , 51 with improvements also maintained in longer-term studies.
BZs are usually well tolerated and they have a rapid onset of action weeks. Potential problems with long-term use of BZs in PD are tolerance, dependence, and withdrawal symptoms on discontinuation, but a 2. Although some studies have failed to observe a difference between alprazolam and imipramine in treatment of the common comorbid depressive symptoms, 55 several large meta-analyses have suggested a reduced efficacy for the BZs compared with TCAs 56 and antidepressants in general Table III.
Early in the s, investigators documented that imipramine 59 and the MAOIs, particularly phenelzine, 60 were both effective treatments of PD. Following the demonstration of efficacy of the non-SSRI clomipramine, a number of large randomized trials have now demonstrated the efficacy of SSRIs in PD,both in comparison with placebo and clomipramine.
Well-controlled trials provided evidence 62 that fluvoxaminc, paroxetine, citai opram, sertraline, and fluoxetine have similar efficacies, although comparison trials between different. SSRIs are generally lacking. A recent, effect-size analysis of controlled studies of treatment for PD also revealed no significant, differences between SSRIs and older antidepressants in terms of efficacy or tolerability in short-term trials.
Although there are different responses of each of these symptoms to these treatments eg, agoraphobic avoidance is the most difficult to treat , successful treatments effectively reduce all these aspects of the PD syndrome, but appropriate outcome measures for PD still remain a problem.
It is generally true that, the longer PD patients are treated, the more complete and comprehensive is their response. In the large Cross-National Collaborative Panic Study, 66 after 8 to 1 2 months of treatment, three fourths of patients were free of panic attacks.
This anxiety is reduced by all effective therapies with little difference between treatments. Agoraphobia is probably the most treatment-resistant symptom in PD. Although effective pharmacotherapy does significantly reduce agoraphobia avoidance, in vivo exposure is often employed to reduce avoidance behaviors.
There is no standard measure employed in the literature of improvement, in agoraphobic avoidance, making comparisons across studies and treatments difficult. Improvement in agoraphobic avoidance occurs with all the effective treatments, probably more or less equally, although this has not been rigorously studied. The BZs are as effective as antidepressants in reducing avoidance, although effects begin earlier with the BZs.
Recent trials suggest that a significant response to antidepressants may occur in the first 2 to 4 weeks, which is earlier than previously thought. Dietary restrictions and side effects have limited the use of MAO Is, but the introduction of the reversible inhibitors of monoamine oxidase A RIMAs , such as moclobemidc, renewed the interest, in this class of agents.
The results, though, so far are conflicting, with an 8-week study showing efficacy for moclobemide in PD, 73 and another one failing to do so. There is a limited number of controlled studies testing BZs in the treatment of social anxiety disorder.
There has been only one double-blind study of alprazolam, in which Gelernter et a! Only anecdotal evidence supports the efficacy of TCAs for the treatment of social anxiety disorder, 88 mainly due to early observations that, patients with atypical depression with marked interpersonal sensitivity and sociophobic features show a better response with MAOIs than TCAs.
These results were replicated by Heimbergetal 92 in In a comparison between phenelzine and moclobemide, phenelzine appeared roughly equivalent, but appeared to work faster. In the Gelernter et al 86 trial, phenelzine was also better than alprazolam in terms of efficacy. As mentioned above, RIMAs have also been studied. Another large multicenter trial, 97 as well a single study, 98 failed to confirm the efficacy of this drug in social anxiety.
Certainly the greatest amount of carefully controlled data are from the recent, paroxetine studies. Differences were observed in the second week and throughout the remainder of the trial.
These positive findings were confirmed by Baldwin et al and Allgulander. Other controlled trials with SSRIs include fluvoxamine, 88 , sertraline, , fluoxetine, venlafaxine, and nefazodone. Finally, open trials of citalopram - and buproprion have suggested that these drugs may be effective in the treatment, of social anxiety disorder, but controlled studies are needed to confirm preliminary results.
Buspirone has been shown to be effective as a primary treatment in two thirds of patients in early trials, , as well as an augmenting agent with SSRIs.
PTSD is a complex syndrome occurring after one or more traumatic events and involves multiple anxiety symptoms, including flashbacks, emotional numbing, avoidance of the reminders of the event, and so forth. This disorder was first recognized after military combat, but is now seen frequently after rape, assault, and accidents. Although there is no established pharmacotherapy for PTSD, there are multiple medications that seem to be effective in reducing these symptoms, particularly flashbacks, phobic avoidance, depression, anxiety, startle reaction, impulsivity, and hypervigilance Table IV.
BZs seem to be helpful in suppressing hyperarousal symptoms. Open trials with alprazolam and clonazepam came to similar results, but with drawal symptoms were particularly severe, especially considering the substantial comorbidity of PTSD with alcohol and drug abuse.
O'Brien and Nutt hypothesized that early BZ treatment of trauma survivors may protect toward future development, of PTSD, but the data are still controversial, especially concerning how soon after the event treatment has to be started to offer this protection. TCAs have been shown to be helpful in three controlled trials. An important finding arising from these studies is the lack of placebo response in PTSD compared with other anxiety disorders. In addition, the usual dietary and medication restrictions of the MAOIs are more problematic in this patient group, given the high incidence of substance abuse.
Pcnava et al conducted an effect-size analysis of controlled studies where fluoxetine showed the biggest effect compared with the other antidepressant and BZs studied so far. The anticonvulsant carbamazepine has been shown to decrease flashbacks, hyperarousal, and impulsivity.
Some case reports with atypical neuroleptics and an open-label study with olanzapine have been positive for the treatment of the core symptoms and the psychotic symptoms that PTSD patients may exhibit. Clonazepam, a BZ that, also affects serotonergic transmission, was compared with clomipramine and clonidine in a crossover, double-blind study with each treatment lasting for 6 weeks. Clonazepam provided an early improvement weeks , unrelated to changes in anxiety, and there was a significant cross-response between clomipramine and clonazepam, with patients who failed on clomipramine showing a clinically significant response to clonazepam.
Pharmacological investigations have demonstrated that OCD responds selectively to drugs that act as potent inhibitors of the synaptic reuptake of serotonin. This magnitude of change typically results in significant improvement in function; however, interfering symptoms usually persist.
Relative efficacy between the SRIs has been difficult to determine. Two meta-analysis suggested greater efficacy for chlorimipramine , ; however, these trials were performed over a 7- to year time period, during which placebo rates rose significantly, making any conclusion suspect.
In fact, in several head-to-head trials, clomipramine was found to have equal efficacy to fluoxetine, paroxetine, and sertraline, with SSRIs being better tolerated than clomipramine. A more recent meta-analysis generally failed to find any significant, difference between the SRIs, although it again suggested some advantage for clomipramine.
However, this metaanalysis involved many of the trials mentioned above and has the same problem in interpretation. Due to their similar effects, it is difficult to choose between SSRIs, and the selection of a drug largely depends upon personal preference, even if the possibility of a drug interaction or the various pharmacokinetic profiles could influence the choice. For this reason, it is helpful to warn patients about this from the outset, and slowly titrate doses upwards to avoid side effects.
Many patients will not respond or will partially respond to the first SSRI, but will respond to another antiobsessional agent. Therefore, sequential trials are frequently required, which easily can take up to a year to accomplish. In a large extension study by Greist et al, patients who had responded to 12 weeks' treatment with either sertraline or placebo continued their treatment, in a double-blind way, for 40 weeks.
Therapy gains with sertraline were maintained with continued medication as long as they remained on active medication, without tolerance developing. The 59 patients who completed this study were followed up for a second year on open-label sertraline, whereupon they showed additional clinical improvements. Furthermore, in patients who do respond to SRIs, the degree of improvement, is often incomplete, with few patients experiencing full symptom remission.
There is no agent that is routinely effective as an augmenting agent, although there is some support for clonazepam, clonidine, trazodone, nefazodone, tryptophan, and pindolol. Buspirone produced an effect, similar to clomipramine in a small double-blind study with 18 patients, but the results from controlled trials of buspirone augmentation to SRIs were less encouraging. National Center for Biotechnology Information , U.
Journal List Dialogues Clin Neurosci v. Dialogues Clin Neurosci. Giovanni B. Cassano , MD Giovanni B. Author information Copyright and License information Disclaimer.
This article has been cited by other articles in PMC. Abstract Exposure of the general population to a lifetime risk of disabling anxiety has inspired generations of fundamental and clinical psychopharmacologists, from the era of the earliest benzodiazepines BZ to that of the selective serotonin reuptake inhibitors SSRIs and related compounds, eg, the serotonin and norepinephrine reuptake inhibitors SNRIs.
Keywords: generalized anxiety disorder , panic disorder , social anxiety disorder , posttraumatic stress disorder , obsessive compulsive disorder , benzodiazepine , antidepressant.
Table I. Common medications used in the treatment of anxiety. Open in a separate window. Table II. Generalized anxiety disorder GAD : therapeutic strategies. Other drugs Several other drugs have been assessed in GAD. Panic disorder Benzodiazepines Alprazolam, the first licensed BZ for the treatment of panic, was studied in a large multinational placebo-con trolled trial Cross National Collaborative Panic Study conducted in two 8-week phases: during the first it was compared with placebo, and then it was compared with both placebo and imipramine.
Panic disorder PD : therapeutic strategies. Antidepressants Early in the s, investigators documented that imipramine 59 and the MAOIs, particularly phenelzine, 60 were both effective treatments of PD. Social anxiety disorder Benzodiazepines There is a limited number of controlled studies testing BZs in the treatment of social anxiety disorder.
Antidepressants Only anecdotal evidence supports the efficacy of TCAs for the treatment of social anxiety disorder, 88 mainly due to early observations that, patients with atypical depression with marked interpersonal sensitivity and sociophobic features show a better response with MAOIs than TCAs.
Other drugs Buspirone has been shown to be effective as a primary treatment in two thirds of patients in early trials, , as well as an augmenting agent with SSRIs. People with diabetes should take them with caution and speak to a doctor about the possible risks. These medications also interact with several other drugs as well as some foods and drinks. Anyone taking MAOIs should ask their doctor for a complete list of the medicines, foods, and drinks that they need to avoid.
The United States Food and Drug Administration FDA require all antidepressants to carry a black-box warning relating to the risk of suicide in children and young adults.
People under 25 years of age may experience an increase in suicidal thoughts and behaviors while taking antidepressants, particularly within the first few weeks of use. Anyone experiencing symptoms of an anxiety disorder should see their doctor, who can recommend therapy, medications, or a combination of both. To diagnose an anxiety disorder, doctors will typically carry out a physical examination to check for any underlying conditions and ask a person about their symptoms.
Anxiety is a common condition that affects many people during their lifetime. Several types of medication can treat anxiety, especially in combination with therapy. People who have an anxiety disorder should work with their doctor to find the right treatment plan for their needs.
If a person notices any side effects from their medication, they should speak to a doctor or pharmacist. To alleviate side effects, a doctor may adjust the dosage slowly or recommend another medication or form of therapy. It is essential never to stop taking medication without medical supervision as it may cause withdrawal symptoms. Anxiety and related mental health conditions can cause ear ringing or tinnitus, and tinnitus can exacerbate existing anxiety.
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Please try again. Something went wrong on our side, please try again. Show references Depression: FDA-approved medications may help. Food and Drug Administration. Accessed Nov. Depression basics. National Institute of Mental Health. National Alliance on Mental Illness. Kovich H, et al. Common questions about the pharmacologic management of depression in adults.
American Family Physician. Perlman K, et al. A systematic meta-review of predictors of antidepressant treatment outcome in major depressive disorder. Journal of Affective Disorders. Ritter JM, et al. Antidepressant drugs. In: Rang and Dale's Pharmacology. Elsevier; Revisions to product labeling. Gabriel M, et al.
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