It is uncertain whether, unlike generalized anxiety disorder, panic disorder and obsessive-compulsive disorder, social phobia has a genetic basis.

The biological basis of social phobia appears to reflect a hyperactivity of the central and peripheral sympathetic systems. Patients with the condition complain of tachycardia, tremor and blushing when placed in difficult social situations. Both the hypothalamic-pituitary-thyroid and adrenal axes appear to be normal, although there is evidence that the cortisol response to fenfluramine (a 5-HT releasing agent) is enhanced. It has also been suggested that the 5-HT2c receptors are hyperactive in these patients. In addition, SPECT studies have indicated that the density of the dopamine transporters in the basal ganglia are reduced.

Thus it would appear that the neurobiology of social phobia remains obscure. Nevertheless, the use of SSRI and MAOI antidepressants suggests that the primary disorder is related to a disorder of the serotonergic system.

Post traumatic stress disorder (PTSD) is the only psychiatric condition whose definition demands a particular stressor to precede its appearance. Unlike the other anxiety disorders, it is only in the past decade that the biology of PTSD has come under scrutiny. Furthermore, although PTSD can occur following various traumatic events (for example, sexual abuse, accidents and torture), most emphasis has been placed on combat-related disorders.

With regard to the neurobiology of PTSD, there is only limited evidence that the sympathetic system is hyperfunctional. A disrupted sleep pattern is a common feature of the disorder, particularly involving REM sleep dysregulation (flashbacks during the day and anxiety dreams during the night). Unlike other stress-related and anxiety disorders, patients with PTSD have reduced plasma cortisol and 24-hour cortisol excretion. Combat veterans have also shown a greater suppression of cortisol with low doses of dexamethasone (0.5 mg) than control subjects. This suggests that there is an increased glucocorticoid receptor sensitivity in these patients.

Imaging studies (MRI) have shown that combat veterans have a reduced hippocampal volume which may relate to their short-term memory deficits. However, the possibility that alcohol abuse, a common co-morbid condition, is also responsible has not been ruled out.

A major problem in interpreting the biological factors that are causally related to PTSD arises from the difficulty in differentiating the changes due to depression and drug abuse, which are common co-morbid conditions, and the limitation of most studies to combat victims.

Treatment of PTSD has largely been dependent on antidepressants (TCAs, MAOs and more recently the SSRIs) but other approaches have been to use anti-adrenergic drugs (such as propranolol and clonidine), carbamazepine (to reduce anger and aggressive outbursts) and lithium. However, the evidence for the efficacy of such drugs is largely based on

''open'' trials or anecdotal case reports. Benzodiazepines will reduce many of the symptoms but can also increase the frequency of anger and aggression due to cortical dysinhibition.

In SUMMARY, it is apparent that the biological basis of PTSD remains obscure although there is evidence that the hypothalamic-pituitary-adrenal axis is hypofunctional. So far there is no convincing evidence that any of the classical neurotransmitter pathways are directly involved although there is limited evidence that the opioid system could be hyperactive which might contribute to the suppression of memory recall which is often exhibited by victims of torture and sexual abuse.

Summary of the treatment decisions for the anxiety disorders

Treatment decisions for panic disorder

• Switching - alternative SSRI; a second-generation antidepressant; a high potency benzodiazepine such as alprazolam.

• Augmentation - add a high potency benzodiazepine.

• Other options - a non-specific MAOI (e.g. phenelzine), RIMA (e.g. moclobemide), clomipramine.

Treatment decisions for social anxiety

• Treatment of choice - an SSRI (plus cognitive behavioural therapy).

• Switching - an alternative SSRI; MAOI; moclobemide.

• Augmentation - SSRI plus buspirone (? efficacy).

Treatment decisions for post traumatic stress disorder

• Switching - a second-generation antidepressant.

• Augmentation - a mood stabilizer; an atypical antipsychotic.

• Other options - nefazodone, venlafaxine.

Treatment decisions for obsessive-compulsive disorder

• Switching - an alternative SSRI; clomipramine.

• Augmentation - an atypical antipsychotic; clonazepam.

• Other options - venlafaxine, MAOI.

The benzodiazepine receptor and GABA function

Schmidt and colleagues in 1967 were the first to show that diazepam could potentiate the inhibitory effect of GABA on the cat spinal cord. Later it was shown that the effect of diazepam could be abolished if the endogenous GABA content was depleted, thus establishing that diazepam, and related benzodiazepines, did not act directly on GABA receptors but in some way modulated inhibitory transmission via GABA. It was subsequently demonstrated that the benzodiazepines bind with high affinity and specificity to neuronal elements in the mammalian brain and that there is an excellent correlation between their affinity for these specific binding sites and their pharmacological potencies in alleviating anxiety in both man and animals. The binding of a benzodiazepine to this receptor site is enhanced in the presence of GABA or a GABA agonist, thereby suggesting that a functional, but independent, relationship exists between the GABA receptor and the benzodiazepine receptor.

The barbiturates, and to some extent alcohol, also seem to produce their anxiolytic and sedative effects by facilitating GABAergic transmission. This action of chemically unrelated compounds can be explained by their ability to stimulate specific sites on the GABA receptor complex, the most marked effect being due to the benzodiazepines when they activate their specific receptor site. Thus benzodiazepines bind with high affinity to the benzodiazepine receptor and, as a result, change the structural conformation of the GABA receptor so that the action of GABA on its receptor is enhanced. This enables GABA to produce a stronger inhibition of the postsynaptic neuron than would occur in the absence of the benzodiazepine, the anxiolytic effect being produced by an allosteric enhancement of the action of GABA. The relationship between the various components of the GABA receptor and the GABA nerve terminal is shown in Figure 2.11 (see p. 56).

The inhibitory effect of GABA is mediated by chloride ion channels. When the GABA receptor is occupied by GABA, or by a drug acting as an agonist such as muscimol, the chloride channels open and chloride ions diffuse into the cell (see p. 56 for details). The chloride ion channel contains at least two binding sites. One of these sites is activated by barbiturates that have weak anxiolytic and hypnotic properties (e.g. pentobarbitone and phenobarbi-tone). Such drugs facilitate inhibitory transmission by increasing the duration of opening of the chloride ion channel. Another class of experimental anxiolytic agents that are not structurally related to the benzodiazepines (the pyrazolopyridines, of which etazolate is a clinically active example) also act at a specific site within the chloride ion channel and enhance GABAergic function by increasing the frequency of channel opening. The structure of the various sub-units that comprise the GABA-A receptor are shown in Figure 9.11.

Figure 9.11. Structure of the sub-units that comprise the GABA-A receptor.

Thus it may be concluded that the ''classical'' benzodiazepines such as diazepam, and structurally related drugs, act as anxiolytics by activating a specific benzodiazepine receptor which facilitates inhibitory GABAergic transmission. Other drugs with anxiolytic properties, such as some of the barbiturates and alcohol, also facilitate GABAergic transmission by acting on sites associated more directly with the chloride ion channel.

Types of benzodiazepine receptors

Two types of receptor have been identified, termed Bz1 and Bz2. These receptors occupy different sub-units of the GABA-A receptor and therefore have different affinities for the benzodiazepine ligands. For example, the potent hypnotic zolpidem binds to the Bz1 receptor that is linked to the alpha-1 site on the GABA-A receptor while the hypnotic zopiclone binds to the Bz2 receptor which occupies both the alpha-2 and 3 sites on the GABA receptor. This selectivity for the Bz1 receptor may account for the fewer side effects of zolpiden in comparison to other hypnotic benzodiazepines.

The third type of benzodiazepine receptor is the so-called peripheral benzodiazepine receptor (pBz). This was first discovered in the rat adrenal gland, hence the term ''peripheral''. However, it is now known to occur on the platelet membrane, on immune cells and also in the mammalian brain.

The pBz receptor is distinct from the Bz1 and 2 receptors and does not activate GABA-A receptors. It is occupied by the isoquinoline PK 11195 and the benzodiazepine Ro 4864, neither of which has affinity for the brain Bz1 or 2 receptors. In the brain the pBz receptor is associated with the outer membrane of the mitochondria and with the glia cells.

The primary function of the pBz receptor is in the regulation of cholesterol uptake and the synthesis of neurosteroids. The latter compounds have an affinity for the GABA-A receptors which provide an indirect coupling between the pBz and the GABA receptors in the brain.

Most of the benzodiazepines that are currently available are full agonists occupying the Bz1 and 2 receptors. However, several drugs have been developed which act as partial agonists (for example, bretazenil which is a non-sedative anxiolytic) and partial inverse agonists such as sarmazenil. The beta carboline abercarnil is in development as a partial agonist. The properties of agonists and inverse agonists will be discussed further.

Diversity of drugs acting on the benzodiazepine receptor

Until about 1980, it was widely accepted that the benzodiazepine structure was a prerequisite for the anxiolytic profile and for the recognition of and binding to the benzodiazepine receptor. More recently, however, a chemically unrelated drug, the cyclopyrrolone zopiclone, has been shown to be a useful sedative hypnotic with a benzodiazepine-like profile. Other chemical classes of drugs that are also structurally dissimilar to the benzodiazepines (e.g. triazolopyridazines) have also been developed and shown to have anxiolytic activity in man; these non-benzodiazepines also act via the benzodiazepine receptor. Thus the term ''benzodiazepine receptor ligand'' has been introduced to describe all drugs, irrespective of their chemical structure, that act on benzodiazepine receptors and thereby modulate inhibitory transmission in the brain.

Over the last decade there has been an increase in our knowledge of the relationship between the structure of benzodiazepine receptor ligands and their pharmacological properties. This has led to the development of potent receptor agonists that stimulate the receptor and produce pharmacological effects qualitatively similar to diazepam and related ''classical'' benzo-diazepines, antagonists, which block the effects of the agonists without having any effects themselves, and a group of drugs that have a mixture of agonist and antagonist properties (so-called partial agonists). In addition, an intriguing group of compounds have been developed that have the opposite effect on the benzodiazepine receptor to the pure agonists. These are known as inverse agonists. The pharmacological properties of these different types of benzodiazepine receptor ligands are summarized in Figure 9.12.

FULL AGONISTS (e.g. diazepam, midazolam)


PARTIAL AGONISTS (e.g. RO 16-6028)


ANTAGONIST (e.g. flumazenil)

Anxiolytic Anticonvulsant Myorelaxant Amnesic Facilitates GABA

Little direct effect on receptor

Blocks effects of agonists and inverse agonists


Convulsant or proconvulsant




Depresses GABA

transmission transmission

Figure 9.12. Properties of the various types of benzodiazepine receptor ligands.

At the molecular level, the differences between the agonist and antagonist benzodiazepines are ascribed to the ability of the drug to induce a conformational change in the fine structure of the receptor molecule that produces functional consequences in terms of cellular changes. The partial agonists have intrinsic activity that lies between the full agonists and the antagonists. When administered they have qualitatively similar effects to full agonists, but may not be quite as potent; when given with full agonists they reduce the potency of the full agonist. Some 12 years ago, the Danish investigators Braestup and Nielsen found that a group of non-benzodiazepine compounds, the beta-carbolines, not only antagonized the actions of the full agonists but also had intrinsic activity themselves. Such compounds were clearly not pure antagonists, which lack intrinsic activity, but were found to be inverse agonists because they had the exact opposite biological effects to the pure agonists, i.e. they caused anxiety, convulsions and facilitated memory function. Thus the benzodiazepine receptor is so far unique in that it has a bidirectional function. This discovery could be of major importance in designing drugs in which the adverse effects of the ''classical'' benzodiazepines could be reduced but their beneficial effects maintained. The development of partial agonists may be particularly important in the production of anxiolytics that lack the sedative and amnestic properties of full agonists such as diazepam.

Are there natural ligands for the benzodiazepine receptor in the brain?

The presence of benzodiazepine receptors in the brain would suggest that there are natural ligands present which modulate these receptors. To date, a

Table 9.2. Putative endogenous ligands for the benzo-diazepine receptor in the mammalian brain


Inosine and hypoxanthine

Ethyl-beta-carboline-3 carboxylate



Diazepam-displacing activity in human cerebrospinal fluid Diazepam-binding inhibitor (DBI)

specific compound has not been unequivocally identified, but a number of candidates have been isolated that show agonist or inverse agonist activity. Some of these candidates are listed in Table 9.2.

Of the putative ligands for the benzodiazepine receptors that are listed in Table 9.2, diazepam-binding inhibitor (DBI), nephentin and tribulin appear to be particularly interesting. DBI is a polypeptide that has been isolated, and its structure elucidated, from mammalian and human brain. It is called ''diazepam-binding inhibitor'' because it can inhibit the binding of tritiated diazepam to the benzodiazepine receptor; recently it has also been shown to inhibit the binding of antagonists and inverse agonists to this receptor. Pharmacological studies show that DBI has anxiogenic properties and its concentration in the brain appears to be sufficiently high to block benzodiazepine receptors under appropriate conditions. It is only present in trace amounts in tissues other than the brain.

Tribulin is a relatively low molecular weight compound with acidic or neutral properties that has been isolated from human urine by Sandler and colleagues in the UK. The presence of this compound increases following stress and it has been found to inhibit the binding of benzodiazepines to their receptor site. In 1983 Sandler suggested that tribulin might be related to the endogenous anxiogenic factor and structurally related to the beta-carbolines. More recently it has been shown that tribulin is a mixture of at least three low molecular weight compounds.

Nephentin is also a large polypeptide that has been shown to have a relatively high affinity for the benzodiazepine receptor and does not have any effect upon other neurotransmitter receptors. Unlike DBI, however, the concentration of nephentin is much higher in non-nervous peripheral tissues such as the bile duct than it is in the brain. Furthermore, the distribution of nephentin in the brain does not coincide with that of the benzodiazepine receptors. It is possible, nevertheless, that nephentin is a precursor of a lower molecular weight peptide that can block the benzodiazepine receptor.

Less progress has been made in the detection of natural compounds that may act as agonists on the benzodiazepine receptor. Three non-peptides (nicotinamide, inosine and hypoxanthine) have been shown to have low affinities for the benzodiazepine receptor and there is some experimental evidence suggesting that they have mixed agonist-antagonist properties. Nevertheless, the consensus of opinion would appear to suggest that these substances are not the endogenous ligands for the benzodiazepine receptor. It is possible that purinergic mechanisms are activated by inosine and hypoxanthine and that the modulation of benzodiazepine receptor function is a secondary consequence of this.

There is some evidence to suggest that the benzodiazepines exist not only in plants such as the potato but also in the mammalian brain, including the brains of individuals who have never taken benzodiazepine anxiolytics or hypnotics. While such findings are still controversial, they do point to the possibility that the benzodiazepines are endogenous modulators of the GABA receptor and that a defect in their synthesis may have a role to play in the aetiology of anxiety disorders.

It may be concluded that there is some evidence to suggest that anxiety arises as a consequence either of a deficiency of an endogenous agonist or the presence of an endogenous inverse agonist acting on the benzodiaze-pine-GABA receptor complex. Thus one possible approach to drug design in the future may be the development of drugs that either facilitate the synthesis of endogenous agonists or reduce the synthesis of inverse agonists at the benzodiazepine receptor sites.

Changes in benzodiazepine receptor function following chronic administration of benzodiazepines

It is a well-established biological phenomenon that receptors adapt to the prolonged presence or absence of an agonist by changing their sensitivity, thereby attempting to return their function to normal levels. Thus prolonged blockade of dopamine receptors in the basal ganglia by neuroleptics such as chlorpromazine or haloperidol causes a supersensitivity of these receptors. Conversely, conditions in which the receptor is chronically stimulated by its endogenous neurotransmitter, or by an agonist drug, result in a decrease in the functioning of the postsynaptic receptors; this phenomenon is known as subsensitivity, an event which may be accompanied by a decrease in the number of receptors. Such changes, sometimes termed ''up''- or ''down''-regulation, may develop slowly or rapidly, the former being due to changes in the synthesis of the receptor while the latter probably reflects the movement of receptors into, or out of, the neuronal membrane.

Experimental studies in rodents have clearly demonstrated that high doses of ''classical'' benzodiazepines such as diazepam, lorazepam and flurazepam cause a decrease in benzodiazepine receptors in the cortex of the brain but the number of receptors rapidly returns to normal (after approximately 5 days) following the abrupt cessation of drug treatment. There is also electro-physiological evidence to show that the functional activity of the GABA receptors that are linked to the benzodiazepine receptors is also decreased following prolonged treatment with chlordiazepoxide, even though the actual number of GABA receptors is increased. In vitro evidence suggests that chronic benzodiazepine treatment results in an uncoupling of the benzodiazepine receptor from the GABA receptor complex.

Functional tolerance following chronic treatment with the benzodiazepines is well documented in animals and man and represents a pharmacody-namic rather than pharmacokinetic phenomenon. Tolerance appears to occur more rapidly with the sedative and anticonvulsant rather than the anxiolytic properties of the ''classical'' benzodiazepines. However, since clinically relevant tolerance develops with therapeutic doses, but changes in receptor tolerance only occur with very high doses of the drugs that are usually far in excess of those used clinically, little experimental evidence exists at present whereby the functional tolerance to benzodiazepines can be explained on the basis of benzodiazepine receptor desensitization. However, one must be cautious in extrapolating the results of animal experiments to the patient with an anxiety disorder who is being treated with a benzodiazepine. The benzodiazepine receptor complex shows marked plasticity in the animal brain, but relatively few changes have been noted in this receptor system in samples obtained from post-mortem human brain, even when the patients suffered from epilepsy at the time of death. This suggests that the regulation or plasticity of the benzodiazepine receptor in the human brain differs considerably from that in the brain of the experimental animal, although the molecular properties of the benzodiazepine receptor appear to be remarkably similar.

Adverse effects of benzodiazepines

The short-term effects are mainly those of sedation but following longer-term use accumulation may occur, particularly in the case of drugs like diazepam and chlordiazepoxide that have long half-lives due to their active metabolites. After long-term administration (weeks to months) tolerance develops. While most patients rapidly become tolerant to the sedative side effects of these drugs, some patients, particularly the elderly, experience excessive sedation, poor memory and concentration, motor incoordination and muscle weakness. In extreme cases in the elderly, an acute confusional state may arise which simulates dementia. All sedatives, including the benzodiazepines, interact with alcohol and therefore these drugs should not be taken in combination.

In addition to the tolerance that occurs following the long-term treatment of a patient with a benzodiazepine, dependence also arises. Dependence is defined as a situation occurring as a consequence of the compensatory adaptive changes in the brain as a result of chronic drug administration. Evidence for physical dependence is obtained from the withdrawal effects that arise on discontinuation of the medication. Rebound effects are defined as an increase in the severity of the initial symptoms beyond that occurring in the patient before treatment started. Rebound insomnia following abrupt discontinuation of benzodiazepine hypnotics is well described, and rebound anxiety arises not uncommonly in those patients in whom an anxiolytic benzodiazepine has been suddenly terminated. Slowly tapering the dose of a benzodiazepine over a period of many days or weeks largely overcomes the problem of rebound effects.

Sudden withdrawal from a high chronic dose of benzodiazepine has long been known to provide a variety of side effects, including seizures and paranoid behaviour in extreme cases. Withdrawal symptoms include psychological changes such as anxiety, apprehension, irritability, insomnia and dysphoria, bodily symptoms such as palpitations, tremor, vertigo and sweating, and perceptual disturbances, including hypersensitivity to light, sound and pain, and depersonalization. The perceptual disturbances that occur on withdrawal are not generally seen in those patients exhibiting rebound effects and it therefore may be possible to distinguish between these two phenomena. It has been estimated that 15-30% of patients on benzodiazepines for longer than a year may encounter problems in trying to discontinue their medication.

Use of non-benzodiazepines in the treatment of anxiety disorders

The barbiturates and meprobamate have been entirely superseded by the benzodiazepines and because of their low benefit-to-risk ratio (dependence producing, lethality in overdose, potent sedative effects) they should never be used as anxiolytics. Despite their popularity as short-term sedatives, antihistamines are ineffective anxiolytics, while the use of sedative antidepressants such as amitriptyline should be limited to the treatment of patients with symptoms of both anxiety and depression due to their limited efficacy and the poor patient compliance associated with their adverse effects. However, patients with panic disorder do appear to show a beneficial response to antidepressants (see Chapter 6). A similar argument can be made regarding the use of low doses of antipsychotics, although drugs such as chlorpromazine may have some value in treating severely anxious patients who had previously been dependent on sedatives. Beta adrenoceptor antagonists such as propranolol may have a place in the treatment of anxious patients with pronounced autonomic symptoms (palpitations, tremor and gastrointestinal upset).

The azaspirodecanedione anxiolytics

A series of non-benzodiazepine anxiolytics have recently been introduced which, unlike the benzodiazepines, do not facilitate GABAergic function but appear to act as agonists at 5-HT1A receptors. Buspirone is an example of this novel class of anxiolytics, and is structurally similar to gepirone and ipsapirone. The latter compounds are reported to show both anxiolytic and antidepressant properties. The structure of these novel compounds is shown in Figure 9.13.

Figure 9.13. Chemical structure of some azaspirodecanedione anxiolytics.

In vitro ligand binding studies have shown that buspirone binds with high affinity to 5-HT1A and D2 receptor sites. However, it is known that in vivo the main metabolite of buspirone and ipsapirone is 1-pyrimidylpiperazine (1-PP), which also has a high affinity for alpha2 adrenoceptors. Thus the pharmacological activity of buspirone and related compounds may be the result of a complex interaction between the parent compound and the pharmacologically active metabolite. It seems possible that the antagonist effect of the 1-PP metabolite on alpha2 adrenoceptors might account for the presumed antidepressant action of such drugs, as it is known that some atypical antidepressants such as mianserin and idazoxan also show an antagonistic activity on such receptors. Another interesting aspect of the action of buspirone lies in its specificity of action of 5-HT1A receptors in the brain. Thus experimental studies have shown that it has a more marked effect in reducing the turnover of 5-HT in the hippocampus, and to a lesser extent the cortex, than it does in the striatum. From such studies of the effects of buspirone-like drugs on central neurotransmission, it may be concluded that their anxiolytic action is due to a reduction in 5-HT turnover in the limbic region of the brain, while the possible antidepressant effect could be attributed to a selective enhancement of noradrenaline turnover in this region. Such an explanation must be treated with caution, however, as it is well established that alpha2 adrenoceptor antagonists such as yohimbine induce anxiety states in both man and animals. Whether buspirone-like drugs selectively enhance noradrenaline turnover only in the limbic region, and do not cause a hyperarousal state which could induce anxiety, is a matter of conjecture. The pharmacological consequences of the interaction of buspirone with D2 receptor sites is uncertain; there is little evidence that buspirone has neuroleptic properties at those doses which are known to be anxiolytic. The slight abdominal discomfort occasionally associated with the initial administration of buspirone could be due to the stimulation of 5-HT receptors in the gastrointestinal tract.

Clinical trials of buspirone have shown the drug to be slower in onset of action compared with diazepam, but it produces significantly less sedation and fewer detrimental effects on psychomotor function than the benzodiazepines. The main advantage of buspirone would therefore appear to be in its lack of dependence, amnestic and sedative effects. However, its slower onset of action and its lower efficacy in alleviating the somatic symptoms of anxiety make it unlikely that it will replace the therapeutically effective and proven benzodiazepines, despite the greater frequency of their side effects. Whether ipsapirone and gepirone, which are still in clinical development, will be therapeutically superior to buspirone can only be assessed after they become more widely available for clinical use.

Clinical studies show that buspirone is an effective anxiolytic with an advantage over the benzodiazepines of lacking a sedative effect, not interacting with alcohol and not exhibiting any dependence effects following prolonged use. Its main clinical disadvantage lies in the delay in onset of its therapeutic effect (up to 2 weeks in some cases) and its limited efficacy in attenuating anxiety in those patients who had previously responded to benzodiazepines. Furthermore, unlike the benzodiazepines, it does not appear to have beneficial effects in patients with panic disorder.

The failure of buspirone to exhibit cross-tolerance with the benzodiaze-pines in both animal and man suggests that the drug alleviates anxiety by a different mechanism. Experimental studies have shown that buspirone, gepirone and ipsapirone act as full or partial agonists on 5-HT1A receptor subtypes. Experimental studies show that potent 5-HT1A agonists such as 8-hydroxy-2-(dipropylamino)tetralin (8OH-DPAT) are anxiolytic in some animal models of anxiety. This suggests that this novel class of anxiolytics modulate central serotonergic transmission, which probably accounts for the relative lack of those side effects that the benzodiazepines exhibit due to their facilitating action on GABA receptors (sedation, dependence, etc.). Modulation of 5-HT1A receptor function may also account for the antidepressant properties which this series of drugs are claimed to show.

In CONCLUSION, evidence has been presented to show that the benzodiazepines produce their variety of pharmacological effects by activating specific receptors that form part of the main inhibitory neuro-transmitter receptor system, the GABA receptor, in the mammalian brain. Different classes of benzodiazepine receptor ligands have been developed which can alleviate anxiety or produce anxiety according to the fine structural changes that occur when the drugs interact with the benzodiazepine receptor.

There is some evidence that natural substances occur in the human brain that can cause either an increase or a reduction in the anxiety state by acting on the benzodiazepine receptor. The unique nature of the benzodiazepine receptor, and the disparate properties of the drugs that act on this receptor, should allow plenty of scope for the development of novel compounds with selective anxiolytic and other properties in the future. Despite the evidence from animal studies that benzodiazepine receptor function changes in response to chronic drug treatment, there is little evidence from human brain studies that such changes are relevant to the phenomena of tolerance, dependence and withdrawal effects that have been the recent cause for public concern. Novel anxiolytics such as buspirone that are structurally unrelated to the benzodiazepines and which do not modulate GABAergic function have the advantage of lacking the sedative and dependence-producing effects of the benzodiazepines. Nevertheless, the relative lack of efficacy of such drugs, and the delay in their onset of therapeutic effect, make it unlikely that they will replace the benzodiazepines as the drugs of choice in the treatment of anxiety disorders.

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