If you wish to discuss the below document by Perseverance, please visit the original discussion thread:
http://www.benzobuddies.org/forum/index.php?topic=110964.0
I put this review together for professionals in the field of psychology/psychiatry in my neck of the woods to help them understand how benzos can cause anxiety. I decided to also post it here on benzobuddies as I thought it might help members explain their protracted symptoms of anxiety to medical professionals who may be unaware of the effects of benzos.
HOW BENZOS CAUSE ANXIETY
Benzodiazepines (BZDs) have been shown to cause anxiety and worsen pre-existing anxiety.(16,18,19,29,31-33) This review will examine research regarding the effects of benzodiazepine (BZD) usage and discontinuation and how they relate to symptoms of anxiety. Topics discussed will include GABAA receptors (GABAARs), Glutamate receptors, Hypothalamic-Pituitary-Adrenal (HPA) Axis, and procedural memory.
Reductions in BZD binding sites on GABAARs and changes to GABAAR function have been observed in people with anxiety disorders:
“…A localized reduction in benzodiazepine binding in the temporal lobe has also been reported in generalized anxiety disorders. Furthermore, magnetic resonance spectroscopy has been used to show decreased cortical levels of GABA in patients with panic disorders. These findings are consistent with the view that at least some anxiety disorders are linked to a defective GABAergic neuroinhibitory process” (1)
“Changes in the number and function of GABAARs have been associated with different neuropsychiatric disorders such as anxiety, epilepsy, and schizophrenia.” (9)
“Brain imaging and pharmacological studies have shown that there is a decreased density (decreased numbers) and subsensitivity of brain GABA/benzodiazepine receptors in patients with generalised anxiety disorder and panic disorder...” (21)
BZD administration has been shown to cause reductions in BZD binding sites through subsensitivity, or uncoupling, of GABAARs. Mechanisms underlying GABAAR uncoupling may include: receptor down-regulation; changes in receptor gene expression; and changes to receptor subunit configurations that result in reduced GABA potentiation:
“…uncoupling mechanism involves an initial increase in receptor internalization [down-regulation] followed by activation of a signaling cascade that leads to selective changes in receptor subunit levels. These changes might result in the assembly of receptors with altered subunit compositions that display a lower degree of coupling between GABA and benzodiazepine sites.” (10)
BDZs bind to GABAARs that contain α1, α2, α3 or α5 subunits plus a γ subunit:
“The binding site for benzodiazepines is formed by one of the α subunits α1, α2, α3, and α5 and a γ subunit, typically the γ2 subunit, which is present in approximately 90% of GABAA receptors.” (3)
An example of a GABAAR with the α1-γ2 subunit configuration is shown below.(11) In this example the BZD binding site is located between the α1 and γ2 subunits:
On the GABAAR, the BZD binding site is coupled to the GABA neurotransmitter binding site. When BZDs bind to the GABAAR they alter the receptor conformation (3 dimensional shape). This results in an increase in the receptors binding affinity (tendency or strength of binding(37)) for the neurotransmitter GABA. This keeps the GABAAR GABA-bound for longer periods of time, which in turn causes an increase in the total number of the receptor ion channel openings.(38,39) In this way, BZDs modulate the receptor's activation by enhancing the effect of the neurotransmitter GABA. This process is known as positive allosteric modulation.(36) Scientists think that chronic potentiation of GABA might result in subsensitivity, or uncoupling between the BZD site and the GABA site on the GABAAR:
“Attempts to uncover the molecular mechanism(s) that underlie tolerance to chronic in vivo administration of BZDs began 21 years ago with the discovery that a subsensitivity of allosteric interactions between the GABA and BZD recognition sites occurs after chronic in vivo administration of diazepam to rats. This was subsequently referred to as uncoupling of allosteric interactions…Surprisingly, a single dose of diazepam results in subsensitivity after only 12 h. These results suggest that GABAAR subsensitivity is produced via an interaction of diazepam with GABA-mediated synaptic transmission because BZDs potentiate the GABAAR-mediated response.” (9)
Long-term BZD administration has been shown to cause GABAAR uncoupling through down-regulation and changes to GABAAR gene expression- where the neurons essentially swap out GABAARs with subunits that bind BZDs with ones that don’t:
“In rats given benzodiazepines chronically, the common α 1 γ2 sub-units are down-regulated, while rarer sub-units are elevated proportionately (Holt et al, 1999). It is suggested that transcription of the Gene cluster on Chromosome 5 (which encodes for α1 β2 γ2 sub-units) is inhibited on chronic benzodiazepine administration, while the transcription of the Gene cluster on Chromosome 15 is upregulated (Holt et al, 1999). In certain brain regions, the Chromosome-5-encoded receptor sub-unit proteins are replaced by those encoded in Chromosome 15, which show less sensitivity.” (4)
“Long-term treatment of rats with BZs results in so-called “uncoupling,” a decrease in the ability of BZs to potentiate the action of GABA on GABAA receptors and in a decrease in the ability of GABA to potentiate BZ binding (Gallager et al., 1984; Marley and Gallager, 1989; Tietz et al., 1989). This uncoupling might be due to changes from BZ-sensitive to -insensitive receptor subtypes (changes in receptor subunit combination) and/or changes in receptor function without changes in receptor subtype.” (5)
“During some chronic benzodiazepine treatment regimens, there is a down-regulation of receptors. By using selective ligands, it was shown that GABAA receptors containing α1 subunits are particularly affected (Galpern et al., 1990; Wu et al., 1994a, 1995). The present study used [3H]RY-80, a ligand that is selective for the benzodiazepine recognition site of GABAA receptors containing α5 subunit an (Skolnick et al., 1997). The results showed that this receptor subpopulation also plays a role in receptor down-regulation, and possibly in tolerance. Moreover, the results indicate that neurons in the hippocampal CA1 region play a prominent role in these processes.” (6)
“Tolerance induced by prolonged administration of benzodiazepines is associated with changes in GABAA receptor function.” (7)
These changes to GABAAR subunit configurations occur as a homeostatic response by the neurons to counteract the effect of the drug and may persist after the drug has been discontinued:
“Drugs used as hypnotics are the same as those used to diminish anxiety-for example, alcohol, barbiturates, and benzodiazepines and their presence leads to adaptive changes in the central nervous system, as if to counteract the drug. When the drug is stopped the induced changes persist, with resultant insomnia and anxiety.” (20)
These neuroadaptations may also negatively affect the GABAARs affinity for GABA:
“Chronic use of benzodiazepines causes compensatory adaptions which cause GABA receptors to become less sensitive to GABA.” (15)
The BZD binding site on the GABAAR may also serve as the binding site for natural peptides known as endozepines. Therefore, BZD induced down-regulation of GABAARs that are BZD sensitive might also cause a reduction in endozepine binding sites, which could theoretically reduce the natural capability of the brain to reduce anxiety:
“…some substances which are not chemically related to benzodiazepine drugs but combine with GABA/benzodiazepine receptors have been found in the brain and other tissues of a variety of animals including rats, cattle, frogs, fish and humans and in isolated rat brain slices. These agents, which are small polypeptides, have been termed endozepines and are thought to be the body's natural benzodiazepines. They have a number of actions, among which is the ability to react specifically with the benzodiazepine site of the GABA-A receptor and to modulate GABA neurotransmission in the brain. Endozepines probably interact also with other types of GABA receptors which are distributed all over the body and have many functions.
There is still much to discover about endozepines. Some inhibit diazepam binding and may therefore be anxiogenic while others appear to act like diazepam and enhance GABA activity (as explained in the Manual, Chapter 1). It seems likely that the balance between different endozepines acting at the GABA-A receptor may determine an individual's susceptibility to anxiety and response to benzodiazepine drugs by acting as 'fine-tuners' of GABA-A function.” (21)
BZD induced changes to neurons may be long lasting and perhaps irreversible, which may result in a state of protracted anxiety:
“However, some changes induced by benzodiazepines may be permanent or only very slowly reversible. Since benzodiazepines apparently inhibit learning, especially for coping with stress strategies (Gray, 1987), cessation after many years of use may expose a learning deficit, especially in the ability to cope with stress. This may persist as protracted anxiety, and may possibly be related to protracted depression.” (12)
“Between 15–44% of chronic BZD users experience protracted moderate to severe withdrawal symptoms upon cessation, including emergent anxiety and depressive symptoms.” (13)
“The mechanism of GABA-A receptor uncoupling by benzodiazepines in vitro may be a permanent conformational change in existing receptors, production of an endogenous regulatory GABA-A receptor ligand, a change in phosphorylation, or a displacement of GABA-A receptor subunits. The favored mechanism is a lasting conformational change in existing receptors.” (14)
Other BZD induced neuronal changes that can produce anxiety have been observed occurring to AMPA receptors (AMPARs) in Hippocampal CA1 pyramidal neurons after tolerance had been established and BZDs were abruptly discontinued:
“Benzodiazepine withdrawal anxiety is associated with potentiation of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) currents in hippocampal CA1 pyramidal neurons attributable to increased synaptic incorporation of GluA1-containing AMPARs.” (17)
“In summary, the present study provides evidence that AMPAR facilitation of NMDAR-mediated hippocampal pathways contributes to expression of anxiety-like behavior during withdrawal from prolonged BZ exposure.” [8]
AMPA potentiation may occur with rapid discontinuation of BZDs after changes to GABAAR subunit gene expression have occurred. This is because rapid discontinuation of the BZD does not allow time for the changes to GABAAR gene expression to reverse as happens with a slow gradual taper. The sudden removal of the drug after dependence has set up may result in a sudden drop in chloride influx into the neurons. The lack of the negatively charged chloride influx results in an increase in the neuron membrane voltage potential. The rise in voltage may in turn activate NMDA and voltage gated calcium channels and subsequently allow calcium to enter the neurons.
“A GABAR-mediated depolarizing potential, which is present in 2-day FZP-withdrawn CA1 neurons (Zeng et al, 1995), has been shown to activate NMDARs (Staley et al, 1995) and may contribute to increased postsynaptic Ca2+-mediated signal transduction.” [8]
"…Ca2+ entry during benzodiazepine withdrawal may primarily occur through an increase in high voltage-activated Ca2+-channel current; and perhaps subsequently, through the increased density of Ca2+-permeable, GluA1 homomeric AMPARs." (17)
The resulting calcium influx may then activate internal mechanisms which in turn potentiate AMPA conductance through AMPAR phosphorylation (which increases single channel conductance) and facilitating AMPAR insertion, thereby increasing synaptic density. The end result is Long-term Potentiation (LTP) like occurrences.
“Similar to mechanisms of LTP in CA1 neurons, a temporal pattern of AMPAR potentiation was observed in rats withdrawn from the benzodiazepine, FZP [flurazepam]…FZP withdrawal is correlated with synaptic incorporation of homomeric GluA1-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) in the proximal stratum radiatum of CA1 neurons. After 2 days of withdrawal, Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylates GluA1 subunits at Ser831, increasing channel conductance.” (22)
AMPA potentiation may be a major contributing factor as to why abrupt BZD discontinuation can result in an emergence of rebound anxiety more intense than before BZD administration. Results from clinical observations and double blind placebo controlled studies support these findings:
“In this double-blind, placebo-controlled study of 4 weeks of benzodiazepine treatment followed by 3 weeks of abrupt or gradual drug withdrawal, 16 patients whose benzodiazepine was withdrawn abruptly were worse (p less than .05) than 13 who had received placebo in terms of change in mean anxiety scores from the pretreatment level. The scores of seven patients (44%) whose benzodiazepine was withdrawn abruptly increased 10% or more on both the Hamilton Rating Scale for Anxiety and the Self Rating Symptom Scale. There were no cases of rebound anxiety in 14 patients whose benzodiazepine was withdrawn gradually; fewer cases of rebound anxiety were seen with a benzodiazepine that had a long half-life.” (16)
“Sixty-two anxious patients were treated under double-blind conditions for 4 weeks with either clorazepate or lorazepam. Two-thirds of each treatment group were then switched abruptly to placebo for 2 weeks, while one-third continued to receive active medication. Two major findings were obtained. About 70% of the patients maintained improvement during the 2-week placebo period. Some patients, however, experienced rebound anxiety, which appeared to be more intense and occurred earlier when placebo was substituted for a benzodiazepine with a short half-life (lorazepam) than for one with a long half-life (clorazepate).” [18]
“A group of patients suffering from anxiety, as assessed by general practitioners and psychologists using research criteria for generalised anxiety, were treated with either diazepam or placebo double blind for six weeks. This active treatment period was preceded by a one week single blind placebo "wash in" period and followed by a two week single blind placebo "wash out" period. The results suggest that diazepam can produce rebound anxiety and withdrawal symptoms when used in moderate doses and for what has previously been regarded as a safe length of time.” (19)
“A substantial proportion of patients receiving benzodiazepines also develop rebound anxiety, an intensification of previous symptoms, or withdrawal when treatment is discontinued.” (31)
In contrast to abrupt BZD cessation, gradual tapering allows the neurons to reverse changes in GABAAR subunit gene expression as the dosage declines. Therefore switching the patient from a BZD with a short half-life to one with a longer half-life in addition to a gradual tapering schedule may help prevent sudden changes in the membrane potential of the neurons (30) which may help prevent LTP-like occurrences from setting up.
Corticotropin-releasing hormone (CRH) also known as corticotropin-releasing factor (CRF) is a peptide hormone and neurotransmitter involved in the stress response. Its main function is the stimulation of the pituitary synthesis of Adrenocorticotropic hormone (ACTH) as part of the Hypothalamic-Pituitary-Adrenal (HPA) Axis.(23,24)
BZD administration has been shown to inhibit CRF and CRF receptor 1 (CRF1) receptor function:
“Previous studies revealed that chronic administration of the anxiolytic alprazolam reduced indices of CRF and CRF1 receptor function.” (24)
“Chlordiazepoxide attenuates stress-induced activation of neurons, corticotropin-releasing factor (CRF) gene transcription and CRF biosynthesis in the paraventricular nucleus (PVN)” (25)
However when BZDs are discontinued, studies have shown an increase in CRF transcription and a rebound increase in HPA Axis activity:
“Spontaneous withdrawal from the triazolobenzodiazepine Alprazolam [Xanax] increases cortical Corticotropin-Releasing Factor mRNA expression…The elevated HPA axis activity exhibited during alprazolam withdrawal may represent not only the endocrine stress response to drug withdrawal but also a rebound increase in HPA axis activity after removal of the suppressing influence of chronic benzodiazepine administration.” (24)
“Benzodiazepines profoundly suppress the basal and stress-related activation of the hypothalamic pituitary-adrenocortical (HPA) system and discontinuation of these drugs results in rebound activation.” (26)
Studies have correlated increased levels of CRF and CRF1 activity with anxiety and decreased levels with anxiolysis:
“CRHR1-deficient mice show decreased anxiety-related behavior…transgenic mice overexpressing CRH show increased anxiety-related behavior…central administration of CRHR1 antisense ODNs inhibit CRH- and social defeat–elicited anxiety-related behaviors and evoke anxiolytic-like effects in certain anxiety tests… selective (nonpeptidergic) CRHR1 antagonists NBI-27914, CRA1000, CRA1001 (all anilinopyrimidines), and CP154526 (a pyrrolopyrimidine) inhibit the anxiogenic action of CRH [under stressed conditions]” [28]
Benzo induced changes to CRF transcription along with the LTP-like occurrences observed in the CA1 region of the hippocampus discussed earlier would have a significant effect on the stress response- as cortisol levels are regulated by hypothalamus and hippocampus interactions as described below:
“Plasma cortisol levels are regulated by the hypothalamic-pituitary-adrenal (HPA) axis and the hippocampus, which interact to form a negative feedback circuit to regulate cortisol release. Cortisol's effect on the hippocampus is mediated through interactions with mineralocorticoid receptors (MR) which increase the firing rate of CA1 neurons. A rise in cortisol levels sufficient to fully saturate MR receptors induces the transcription of inhibitory glucocorticoid receptors (GR) which decrease CA1 neuronal firing in tandem with augmenting negative feedback to the HPA to decrease cortisol secretion.” (40)
As previously mentioned, BZD induced changes to GABAAR gene expression may cause uncoupling of the GABAA-benzodiazepine receptor complex. Research suggests that this may also be associated with HPA Axis hyperactivity [Note- Flumazenil binds to the BZD receptor site on the GABAAR(2)]:
“The bilateral reduction in limbic parahippocampal and right temporal [(11)C]FMZ [Flumazenil] binding found in MDD [Major Depressive Disorder] indicates decreased GABA(A)-benzodiazepine receptor complex affinity and/or number. The inverse relationship between GABA(A) binding in the temporal lobe and HPA axis activity, suggests that HPA axis hyperactivity is partly due to reduced GABA-ergic inhibition.” (27)
One BZD, alprazolam [Xanax] was shown to cause inter-dose and progressive increases in baseline AM cortisol levels which corresponded to increases in anxiety. This may be an indication of inter-dose withdrawal from the drug:
“Consistent with previous results, we found that acute and chronic administration of alprazolam (0. 5 mg) resulted in significant reductions in plasma cortisol. In addition, we found that predose, morning cortisol levels also progressively increased in the 3-week period of alprazolam (0.5 mg) b.i.d. treatment. These predose, morning elevations were correlated with increased anxiety after 2 weeks of treatment and with increased depression after 3 weeks…This increase may reflect an early stage of drug withdrawal.” (35)
Chronic administration of BZDs has been shown to be the cause of anxiety in some patients and discontinuation resulted in abatement of anxiety symptoms:
“In almost half the patients seeking advice for anxiety, panic and phobias the cause was alcohol or benzodiazepines… The only criterion for causation was that the patients lost their symptoms when they stopped taking these substances.” (29)
“Drug [BZD] discontinuation yielded a significant decrease in anxiety sensitivity and state anxiety in these long-term users.” (32)
Chronic BZD use has also been shown to worsen pre-existing anxiety:
“…the result is reduced anxiety in the moment but worse long-term anxiety reactions documented in both animal and human studies.” (33)
Some experts believe that the increase in anxiety observed with chronic BZD administration may be in part attributable to a learning deficit caused by BZDs impairment of procedural memory:
“Shanna Treworgy, Psy,D. also of Geisel medical school, said the impact on procedural memory “perhaps the worst side effect” of benzodiazepines in treatment of anxiety. “Research that has successfully pulled apart explicit and implicit memory has demonstrated significant effects on procedural learning and memory” during treatment with benzodiazepines, she said. “This happens through impairing acquisition of new memories through reduced arousal or sedative effects.” (33)
“Anxiety persisting after the acute phase of withdrawal may be partly due to the uncovering of a learning defect caused by the benzodiazepines. These drugs specifically impair the learning of new skills, including stress-coping strategies. Such skills are normally acquired continuously from childhood to middle age or later as experience of life accumulates. Their development may be blocked for a period of years during which benzodiazepines are taken. After withdrawal the ex-user is left in a vulnerable state with a decreased ability to deal with stressful situations. Full recovery may require many months of learning new stress-coping strategies to replace the years when this facility was blanketed by pills.” (34)
An example of this impairment may have been evident during a study involving flying phobia, where a single dose of BZD appeared to increase flying phobia:
“…a 1997 investigation of exposure therapy in women with flying phobia, which evaluated the acute and long-term effects of alprazolam [Xanax]. Women on alprazolam had significantly reduced levels of anxiety compared with those on placebo during the first flight. But during a second flight a week later, when the former group of women was not medicated, they had significantly increased feelings of anxiety, an increased heart rate, a desire to leave the plane, and panic, while those who had been on the placebo during both flights showed decreases in multiple measures of anxiety.” (33)
In summary, the research presented in this review shows that BZDs affect the major mechanisms involved in the stress response and may cause long lasting changes to the nervous system which may result in protracted symptoms of anxiety. The research also suggests that BZD administration might be a poor choice for treatment for anxiety disorders due to potential changes to inhibitory and excitatory neurotransmitter systems and to the HPA Axis which may be contrary to treatment goals.
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