Anxiety disorders SSRIs

Several neurochemical hypotheses have been set forth to explain the mechanisms leading to the clinical manifestations of anxiety disorders. Although a detailed account goes beyond the scope of this book, it is enough to state that norepinephrine, serotonin, and GABA (gamma-aminobutyric acid) are three of the neurotransmitters most often implicated. The medications found to be most useful for the treatment of anxiety disorders—SSRIs, TCAs, MAOIs, and benzodiazepines—have profound effects on these neurotransmitters and their respective neuroreceptors. 

FIGURE 69-3. Algorithm for the pharmacotherapy of social anxiety disorder. SSRI = selective serotonin reuptake inhibitor, BZ = benzodiazepine. (Compiled from Ballenger et al, Van Amerigen and Mancini, and Blanco... 

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

Anxiety disorders are common in the population of opioid-addicted individuals however, treatment studies are lacking. It is uncertain whether the frequency of anxiety disorders contributes to high rates of illicit use of benzodiazepines, which is common in methadone maintenance programs (Ross and Darke 2000). Increased toxicity has been observed when benzodiazepines are co-administered with some opioids (Borron et al. 2002 Caplehorn and Drummer 2002). Although there is an interesting report of clonazepam maintenance treatment for methadone maintenance patients who abuse benzodiazepines, further studies are needed (Bleich et al. 2002). Unfortunately, buspirone, which has low abuse liability, was not effective in an anxiety treatment study in opioid-dependent subjects (McRae et al. 2004). Current clinical practice is to prescribe SSRIs or other antidepressants that have antianxiety actions for these patients. Carefully controlled benzodiazepine prescribing is advocated by some practitioners. 

Tricyclic antidepressants are not licensed for use in the anxiety disorders, so in theory the SSRIs should not be compared with them in cost-effectiveness terms. The SSRIs and venlafaxine are supplanting benzodiazepines as the latter s long-term problems become more appreciated. The SSRIs will take an increasing proportion of the market. However, in comparison with the overall costs of the anxiety disorders, this drug expenditure can be justified. Further cost-offset and cost-effectiveness studies will help hammer this point home. 

Selective serotonin reuptake inhibitors (SSRIs) are considered the drugs of choice based on their tolerability and efficacy for social anxiety disorder as well as comorbid disorders. 

Sleep disturbances are common in the elderly. These disturbances are often secondary to medical illness and/or medication use (Martin et al. 2000). Illnesses could be anxiety disorders or any illness that may disturb sleep due to pain or nocturia. Medications that may cause sleep disturbances are e.g. beta-blockers, corticosteroids and SSRIs. If the sleep disturbance is secondary the treatment should be focused on the underlying cause. If there is no such cause the sleep disturbance is said to be primary. First-line treatment should then be improvement of sleep hygiene (Box 4.1). 

Fluvoxamine (Luvox). This is actually the oldest of the SSRIs. It is approved iu this couutry for the treatmeut of OCD but is also an effective treatment for major depression and many other anxiety disorders. It should be started at 50mg/day, and the effective dose range is from 100 to 300mg/day. Fluvoxamine is the only SSRI that must be takeu twice a day. The common side effects of fluvoxamine are comparable to other SSRIs. 

Sertraline (Zoloft). Sertraline was the second SSRI released in the United States and is approved for the treatment of major depression and many anxiety disorders. It should be started at 25-50 mg/day and increased to lOOmg/day over the first 10-14 days. Many patients require doses nearing 150 mg/day for full benefit. The side effects of sertraline are comparable to other SSRIs. 

Other Antidepressants. Antidepressant refinements for the next 30 years primarily consisted of the development of new TCAs. However, in 1988, a novel antidepressant class, the selective serotonin reuptake inhibitors (SSRIs), was introduced in the United States. The chief innovation of the SSRIs was that they afforded the comparable effectiveness of the TCAs with fewer side effects and minimal toxicity. The debut of the SSRIs coincided with the reworking of the nosology of the anxiety disorders in DSM-III and DSM-IV. As a result, the SSRIs have been studied extensively in each of the respective anxiety disorders and in many cases have obtained FDA approval for the treatment of one or more of these anxiety syndromes. The SSRIs currently available in the United States include citalopram (Celexa), escitalo-pram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). 

Early controlled studies demonstrated the effectiveness of irreversible MAOIs, particularly phenelzine and tranylcypromine, for generalized social anxiety disorder. Prior to the advent of the SSRIs, MAOis were considered the gold standard treatment for social anxiety disorder. The best studied of the MAOis, phenelzine, has proved snperior to both beta blockers and the benzodiazepine alprazolam in treating generalized social anxiety disorder. 

SSRis and SNRis. The introduction of the SSRIs and SNRIs has provided treatments for social anxiety disorder that are not only equally effective but safer and... 

Buspirone. Although initial open label results were promising, a controlled study of buspirone, approved by the FDA for treatment of GAD, failed to demonstrate any effectiveness in the treatment of social anxiety disorder. However, a subsequent controlled study indicated that buspirone administered at 30-60 mg/day is an effective augmentation strategy for patients with social anxiety disorder who have only experienced a partial response to SSRI therapy. 

Generalized Sociai Anxiety Disorder, Treatment Resistance. A significant minority of patients will not experience a satisfactory treatment response to antidepressant therapy, even after a trial of adequate duration at full strength doses. For those with comorbid depression who are experiencing no benefit from SSRI treatment for either the anxiety or depression, then switching treatment is advisable. The options include switching to another SSRI, a SNRI (venlafaxine or perhaps dulox-etine), or, when other alternatives fail, phenelzine. 

Serotonin-Boosting Antidepressants. The SSRIs have also been studied in the treatment of generalized social anxiety disorder, and paroxetine, sertraline, and venlafaxine are effective. Preliminary data suggests that the serotonin-boosting atypical antidepressants (mirtazapine and nefazodone) may also be helpful. Like the MAOIs, they appear to be effective at doses comparable to those used to treat depression. They may help avoidant patients to gradually increase their social interaction and become more assertive. 

Antidepressants. The most widely used psychiatric medicines with the broadest range of application in TBI patients are undoubtedly the SSRI antidepressants. They are well tolerated, unlikely to worsen any of the preexisting deficits associated with TBI, and offer relief from not only depression but also impulsivity and virtually all variants of anxiety in these patients. As such, SSRIs are the preferred first-line treatment for all anxiety disorders after TBI. Other newer antidepressants that also work (at least in part) by boosting serotonin activity, namely, mirtazapine (Remeron), nefazodone (Serzone), venlafaxine (Effexor XR), and duloxetine (Cymbalta) can also be considered, but they have not been well studied in patients with TBI. In... 

With regard to generalized anxiety disorder, it has been postulated that an overactivity of the stimulatory 5-HT pathways occurs. Drugs such as buspirone and ipsapirone are effective in such conditions because they stimulate the inhibitory S-HT a autoreceptors on the raphe nuclei and thereby reduce serotonergic function. It is noteworthy that the SSRIs often worsen anxiety initially because they temporarily enhance serotonergic function. Adaptive changes in the pre- and postsynaptic 5-HT receptors then occur leading to a reduction in the anxiety state. 

In recent years many of these primary care cases that would formerly have been seen as anxiety disorders have been portrayed as anxious-depressives and have led to treatment with antidepressants, in particular the more recent serotonin reuptake inhibitors. As part of this rebranding a variety of states such as panic disorder, post-traumatic stress disorder, social phobia and generalized anxiety disorder have appeared, along with more traditional disorders such as obsessive compulsive disorder (OCD). Many of these diagnoses are likely to lead to prescriptions of an SSRI although the evidence for benefit from SSRIs is poor except for OCD. 

Kessler RC (2001) Comorbidity of depression and anxiety disorders. In Montgomery SA, den Boer JA (eds) SSRIs in depression and anxiety. Wiley, Chichester, pp 87-106 Kessler RC, Price RH (1993) Primary prevention of secondary disorders a proposal and agenda. Am J Community Psychol 21 607-633 Kessler RC, McGonagle KA, Zhao S (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 51 (1) 8-19... 

The growth during the 1990s in the use of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), for the treatment of anxiety disorders represented a major advance in the pharmacotherapy of anxiety. The efficacy of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) had been established alongside their antidepressantw actions several decades... 

SSRI/SNRI GAD OCD Panic disorder PTSD Social anxiety disorder Onset worsening side-effects on initiation few long-term effects Relatively safe in overdose (venlafaxine possibly less safe) Well-described more common with paroxetine uncommon with fiuoxetine... 

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