Anxiolytics panic disorder

Beginning in the 1960s, ben2odia2epiae anxiolytics and hypnotics rapidly became the standard prescription dmg treatment. In the 1980s, buspkone [36505-84-7] (3), which acts as a partial agonist at the serotonin [50-67-9] (5-hydroxytryptamine, 5-HT) type lA receptor, was approved as treatment for generali2ed anxiety. More recently, selective serotonin reuptake inhibitors (SSRIs) have been approved for therapy of panic disorder and obsessive—compulsive behavior. 

Inositol, the building block of the phosphoinositide intracellular signaling pathway, has been examined as a potential anxiolytic. In clinical trials, inositol has reported to be effective in both panic disorder [114, 115] and depression [116], and animal data are also favorable. Because of inositol s status as a dietary supplement, there is little financial backing for studies of its efficacy and safety. The mechanism of action of inositol is not entirely clear, but it is believed to facilitate phosphoinositide-signaling-coupled neurotransmission. 

It is considered a second-line agent for GAD because of inconsistent reports of efficacy, delayed onset of effect, and lack of efficacy for comorbid depressive and anxiety disorders (e.g., panic disorder or SAD). It is the agent of choice in patients who fail other anxiolytic therapies or in patients with a history of alcohol or substance abuse. It is not useful for situations requiring rapid antianxiety effects or as-needed therapy. 

Diazepam (Valium, Diastat) [C-IVj [Anxiolytic, Skeletal Muscle Relaxant, Anticonvulsant, Sedative/Hypnotic/ Benzodiazepine] Uses Anxiety, EtOH withdrawal, muscle spasm, status epilepticus, panic disorders, amnesia, preprocedure sedation Action Benzodiazepine Dose Adults. Status epilepticus 5-10 mg IV/IM Anxiety 2-5 mg IM/IV Preprocedure 5-10 mg IV just prior to procedure Peds. Status epilepticus 0.5-2 mg IV/IM Sedation 0.2-0.5 mg/kg IV (onset w/in 5IV and 30 min IM duration about 1 h IV and IM) Caution [D, / -] Contra Coma, CNS depression, resp d es-sion, NAG, severe uncontrolled pain, PRG Disp Tabs 2, 5, 10 mg soln 1, 5 mg/mL inj 5 mg/mL rectal gel 2.5, 5, 10, 20 mg/mL SE Sedation, amnesia, bradycardia, i BP, rash, X resp rate Interactions T Effects W/ antihistamines, azole antifungals, BBs, CNS depressants, cimetidine, ciprofloxin, disulfiram, INH, OCP, omeprazole, phenytoin, valproic acid, verapamil, EtOH, kava kava, valman T effects OF digoxin, diuretics X effects w/ barbiturates, carbamazepine. 

CCK8 concentrations were found to be lower in panic patients than in normal control subjects (Brambilla et al. 1993) and the CCK-B receptors were hyper-sensitive in panic disorders (Akiyoshi et al. 1996). Accordingly, CCK-B receptor agonists such as pentagastrin or CCK-4 have panic-like anxiogenic effects in humans (Radu et al. 2002). Clinical trials, however, have provided inconclusive data about the anxiolytic potential of CCK-B antagonists (Shlik et al. 1997). 

Imipramine, a TCA, was the first pharmacological agent noted to treat panic disorder (Klein 1964). Other TCAs, notably clomipramine, have also been found to have significant anxiolytic properties (den Boer et al. 1990 Modigh 1992). Studies of ethnic differences in the pharmacokinetics of the TCAs in... 

Redmond DE Jr (1981) Clonidine and the primate locus coeruleus evidence suggesting anxiolytic and anti-withdrawal effects. Prog Clin Biol Res 71 147-163 Reiman EM, Raichle ME, Robins E, Butler FK, Herscovitch P, Fox P, Perlmutter P (1986) The applications of positron emission tomography to the study of panic disorder. Am J Psychiatry 143 469-477... 

No satisfactory randomised controlled trials have been published demonstrating the efficacy of carbamazepine in anxiety disorders, although it has a history of use as an anxiolytic in panic disorder and PTSD. It has an unfavourable side-effect profile (nausea, dizziness, ataxia) and multiple drug interactions due to induction of liver enzymes. 

Taken together, the efficacy of antidepressants covers the spectrum of anxiety disorders, although there are important differences between drugs in the group (Table 3). Several new antidepressants have been marketed since the SS-RIs venlafaxine and mirtazapine are discussed later (Sects. 3.2.1.2 and 3.2.1.4) nefazodone, a serotonin reuptake inhibitor and postsynaptic 5-HT2 blocker showed promise in early studies but was recently withdrawn by its manufacturers reboxetine, a noradrenaline reuptake inhibitor (NARI) showed benefits in panic disorder in one published study (Versiani et al. 2002) and further evidence of its anxiolytic efficacy is awaited. 

In patients with panic disorder, basal ANP concentrations are lower when compared to healthy control subjects, but ANP concentrations are faster and more pronounced during experimentally induced panic attacks (Kellner et al. 1995). In line with these findings, there is evidence for an anxiolytic activity of ANP in humans ANP decreases CCK-4-induced panic anxiety in patients with panic disorder (StrOhle et al. 2001) and healthy control subjects, and attenuates HPA system activity by decreasing ACTH and cortisol stimulation (Wiedemann et al. 2001). Modulation of ANP concentrations or nonpeptidergic ANP receptor ligands maybe ultimately used in the pharmacological treatment of anxiety disorders, such as panic disorder. 

StrOhle A, Pasini A, Romeo E, Hermann B, Spalletta G, di Michele F, Holsboer F, Rupprecht R (2000) Fluoxetine decreases concentrations of 3a,5a-tetrahydrodeoxycorticosterone (3a,5a-THDOC) in major depression. J Psychiatr Res 34 183-186 StrOhle A, Kellner M, Holsboer F, Wiedemann K (2001) Anxiolytic activity of atrial natriuretic peptide in patients with panic disorder. Am J Psychiatry 158 1514-1516 StrOhle A, Romeo E, di Michele F, Pasini A, Yassouridis A, Holsboer F, Rupprecht R (2002) GABAA receptor modulatory neuroactive steroid composition in panic disorder and during paroxetine treatment. Am J Psychiatry 159 145-147 StrOhle A, Romeo E, di Michele F, Pasini A, Hermann B, Gajewsky G, Holsboer F, Rupprecht F (2003) Induced panic attacks shift GABAA receptor modulatory neuroactive steroid composition. Arch Gen Psychiatry 60 161-168 Szapiro G, Vianna MRM, McGaugh JL, Medina JH, Izquierdo I (2003) The role of NMDA glutamate receptors, PKA, MAPK, and CAMKII in the hippocampus in extinction of conditioned fear. Hippocampus 13 53-58... 

The anxiolytic activity of several compounds in some, but not all, animal models of anxiety in fact suggests that different receptor subtypes may modulate different types of anxiety as discussed below. It would not be surprising if the specific serotonin links to disorders of anxiety also differ among the various disorders of anxiety such as generalized anxiety versus obsessive-compulsive disorder versus panic disorder versus social phobia versus mixed anxiety depression. Such studies are in progress, and much further research is necessary to clarify the potential links between subtypes of anxiety and subtypes of serotonin receptors. 

Benzodiazepines, the most commonly used anxiolytic drugs in the treatment of chronic anxiety states, have also been investigated in the treatment of social phobia. These agents have been shown to be effective in the treatment of other anxiety disorders, including panic disorder and generalized anxiety disorder. Three benzodiazepines, all in the high-potency class of benzodiazepines have been investigated in the treatment of social phobia. 

Robinson DR, Shrotriya RC, Alms DR, et al Treatment of panic disorder nonbenzodiazepine anxiolytics, including buspirone. Psychopharmacol Bull 25 21-26, 1989... 

In some cases, anxiolytics serve a transitional purpose. For example, for a patient with acute-onset panic disorder, severe anticipatory anxiety, and a family history of depression, administration of an antidepressant medication that also has antipanic effects may be the optimal treatment, but this will not help the patient for several weeks, during which time there is a risk of progression to agoraphobia. For this patient, starting antidepressant therapy and also attempting to obtain acute symptom relief with a benzodiazepine may be helpful. After 4 weeks, the benzodiazepine dose should be slowly tapered so that the patient s condition is controlled with the antidepressant alone. 

Benzodiazepines are highly effective anxiolytics and sedatives. They also have muscle relaxant, amnestic, and anticonvulsant properties. Benzodiazepines effectively treat both acute and chronic generalized anxiety and panic disorder. The high-potency benzodiazepines alprazolam and clonazepam have received more attention as antipanic agents, but double-blind studies also have confirmed the efficacy of diazepam and lorazepam in the treatment of panic disorder. Although only a few benzodiazepines are specifically approved by the... 

Anxiolytics and Sedative-Hypnotics. Because of their large therapeutic index, measurement of anxiolytic or sedative-hypnotic serum concentrations is not usually necessary in clinical practice, unless abuse, overdose, or inadvertent toxicity are suspected. Some data indicate that plasma alprazolam levels of 40 ng/mL may be required to manage panic disorder ( 51) (see the sections Adverse Effects of Anxiolytics and Adverse Effects of Sedative-Hypnotics in Chapter 12). 

Beta-adrenoceptor antagonists, particularly propranolol, have been shown to be effective for anxiety symptoms particularly in situational anxiety and GAD. Buspirone, an azaspirodecanedione, is an agonist at 5-HTlA receptors and seems to have anxiolytic effects, though it is less potent than the BDZs and the effects take up to three weeks to become evident. There is high first pass metabolism and a considerable proportion of the effect is due to a metabolite (1-PP). The principal adverse effects of buspirone are nausea, gastrointestinal upset and headache. Antidepressant drugs, both the older tricyclic antidepressants and the newer drugs, have been demonstrated to have anxiolytic effects in mixed anxiety-depressive patients, GAD and panic disorder. 

Buspirone has minimal abuse liability. In marked contrast to the benzodiazepines, the anxiolytic effects of buspirone may take more than a week to become established, making the drug unsuitable for management of acute anxiety states. The drug is used in generalized anxiety states but is less effective in panic disorders. 

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