Pharmacology of anxiety
58 important questions on Pharmacology of anxiety
What is the commonality between alcohol, barbiturates, and benzodiazepines?
- All work primarily via facilitation of GABA transmission.
What is the most important role of GABA as a neurotransmitter?
- Acts as the most important inhibitory neurotransmitter in the brain
- Activation of GABA receptor unit leads to influx of Cl- ions
- Results in hyperpolarization of the cell
- Activation of GABA receptor unit leads to influx of Cl- ions
- Results in hyperpolarization of the cell
What is the role of GABAA receptor subtype in the effects of alcohol, sedatives, and anxiolytics?
- GABAA receptor subtype mediates the effects of alcohol, sedatives, and anxiolytics
- Activation of GABA binding opens Cl- channels, leading to hyperpolarization
- The receptor consists of subunits with 19 variants
- Activation of GABA binding opens Cl- channels, leading to hyperpolarization
- The receptor consists of subunits with 19 variants
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How does the sensitivity of GABAA receptor to substances depend on its subunits?
- Sensitivity to substances is determined by the subunits in the GABAA receptor
- Subunits include 6α, 3β, 3γ, δ, ε, π, θ, ρ variants
- Receptors containing γ2/3 and α1/2/3 subunits are benzodiazepine sensitive
- Subunits include 6α, 3β, 3γ, δ, ε, π, θ, ρ variants
- Receptors containing γ2/3 and α1/2/3 subunits are benzodiazepine sensitive
How does alcohol act as an allosteric modulator at the GABAA receptor?
• Alcohol binds to extra-synaptic GABAA receptor with α4/6, γ1, and/or δ subunits
• Alcohol facilitates effects of GABA
• Alcohol facilitates effects of GABA
Apart from GABA, what other systems are affected by alcohol?
• Alcohol affects: glutamate, dopamine, serotonin, and the cannabinoid system
Which GABAA receptor subunits are sensitive to benzodiazepines (BDZ)?
- γ2/3
- α1/2/3
These are postsynpatic GABAa receptors
- α1/2/3
These are postsynpatic GABAa receptors
What is the effect of benzodiazepines (BDZ) on the GABAA receptor's channel?
- Increases GABA binding potential
- Enhances the frequency of opening (but not the duration) of the permeability of Cl- ions
- Enhances the frequency of opening (but not the duration) of the permeability of Cl- ions
What are the endogenous benzodiazepine ligands and what are they called?
- Called 'endozepines'
What are some examples of benzodiazepines often prescribed as traditional anxiolytics?
- diazepam (Valium)
- alprazolam (Xanax)
- oxazepam (Seresta)
- alprazolam (Xanax)
- oxazepam (Seresta)
What are the differences in kinetics among benzodiazepines?
- Time to peak effect and duration of effect vary
- Differences depend on diffusion and half-life
- Presence of active metabolites
- Differences depend on diffusion and half-life
- Presence of active metabolites
What is the primary indication for the use of benzodiazepines based on effect duration?
The primary effect lies in enhancing GABA's binding potential, which works particularly well with low GABA concentrations due to a natural limit.
- With high GABA levels, binding is optimal
- With low GABA levels, binding is suboptimal
- Enhancement by endo/benzodiazepines improves binding
- With high GABA levels, binding is optimal
- With low GABA levels, binding is suboptimal
- Enhancement by endo/benzodiazepines improves binding
How does the binding potential of GABA receptors affect the use of benzodiazepines?
- With high GABA levels, binding is optimal
- With low GABA levels, binding is suboptimal
- Enhancement by endo/benzodiazepines improves binding
- With low GABA levels, binding is suboptimal
- Enhancement by endo/benzodiazepines improves binding
In comparison to barbiturates, why are benzodiazepines considered relatively safe?
- Enhance GABA's binding potential with low GABA concentration
- Produce a more subtle and specific effect
- Have a much higher therapeutic index compared to barbiturates
- Produce a more subtle and specific effect
- Have a much higher therapeutic index compared to barbiturates
What are the (undesired) side effects of traditional Anxiolytics like Benzodiazepines?
- Verwarring
- Duizeligheid
- Versuftheid
- Verminderde coördinatie
- Apathie
- Geheugenproblemen
- Duizeligheid
- Versuftheid
- Verminderde coördinatie
- Apathie
- Geheugenproblemen
For what conditions are traditional Anxiolytics like Benzodiazepines obviously desired for use?
- Epilepsy
- Insomnia
- Muscle spasms
- Insomnia
- Muscle spasms
What are the findings from studies in mice regarding the α1 and α2 GABAA subunits?
- α1 subunit removal: benzodiazepines' sedative effects are absent
- α2 subunit removal: benzodiazepines' anxiolytic effects are absent
- α2 subunit removal: benzodiazepines' anxiolytic effects are absent
What is the significance of the α2 subunit in relation to anxiolytics in mice?
Absence of α2 subunit in mice results in no anxiety-reducing effect of diazepam, emphasizing the importance of α2 subunit in anxiolytics.
What is the role of the α2 subunit in GABAA receptors?
α2 subunit is responsible for the regulation of anxiety.
Why was the clinical development of the anxiolytic TPA023 halted?
The development of TPA023 was halted due to preclinical toxicity (cataract) in long-term dosing studies, despite its promising effectiveness in Phase II trials for generalized anxiety disorder.
What is the importance of the α1 subunit in the context of hypnotics like zolpidem and other 'Z-drugs'?
- The presence of α1 subunit allows binding of zolpidem and 'Z-drugs' to GABAA receptors
- This selective binding enables specific treatment of insomnia with low tolerance or dependence
- This selective binding enables specific treatment of insomnia with low tolerance or dependence
What is the effect of serotonergic substances on anxiety?
- Serotonergic neurons can inhibit outputs of the amygdala
- Little is known about pharmacotherapeutic effects on anxiety systems
- Serotonergic substances have an inhibiting effect on the amygdala output
- Little is known about pharmacotherapeutic effects on anxiety systems
- Serotonergic substances have an inhibiting effect on the amygdala output
What is the serotonin hypothesis related to SSRIs and fear/anxiety?
- Stahl highlights the increase in 5-HT turn-over due to receptor adaptations.
- Increased turn-over of 5-HT inhibits hyperactive circuits in the amygdala and other relevant nuclei.
- SSRIs are used to combat anxiety by inhibiting the reuptake of serotonin.
- Increased turn-over of 5-HT inhibits hyperactive circuits in the amygdala and other relevant nuclei.
- SSRIs are used to combat anxiety by inhibiting the reuptake of serotonin.
What are some examples of medicines used against anxiety?
- SSRIs (Selective Serotonin Reuptake Inhibitors).
- Buspirone, a partial 5-HT1A agonist, is also used.
- Different serotonergic substances act on various 5-HT receptors like 5-HT1A-F and 5-HT2A-C.
- Buspirone, a partial 5-HT1A agonist, is also used.
- Different serotonergic substances act on various 5-HT receptors like 5-HT1A-F and 5-HT2A-C.
What is the effect of SSRIs usually like, and why does it take time to observe this effect?
- SSRIs inhibit the reuptake of serotonin in synapses.
- Effects are not immediate but delayed due to unknown precise mechanisms.
- It takes 2-6 weeks to see the intended effects of SSRIs, similar to the treatment of depression.
- Effects are not immediate but delayed due to unknown precise mechanisms.
- It takes 2-6 weeks to see the intended effects of SSRIs, similar to the treatment of depression.
What initial impact might be observed when starting treatment with SSRIs for anxiety?
- Initial increased anxiety may be observed.
- Receptor adaptations such as desensitization and downregulation take time.
- Combined treatment with a benzodiazepine may be necessary initially to counteract increased anxiety.
- Receptor adaptations such as desensitization and downregulation take time.
- Combined treatment with a benzodiazepine may be necessary initially to counteract increased anxiety.
What is the precise effect of anxiolytics in an experimental model?
- Startle probe during context (safe)
- Startle probe during CS (threat)
- Difference: Fear Potentiated Startle (FPS)
- Reduces contextual anxiety but not cued fear in healthy volunteers
- Startle probe during CS (threat)
- Difference: Fear Potentiated Startle (FPS)
- Reduces contextual anxiety but not cued fear in healthy volunteers
What is the mechanism of action of Buspirone in anxiolytic treatment?
- Buspirone = partial agonist at 5-HT1A receptor (Presynaptic: autoreceptor)
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What is the effect of buspirone after 1-2 weeks of use?
Partial activation of autoreceptor 'stop production' signal
Acute: decrease in 5-HT activity
Delayed effect through down regulation of autoreceptors and/or regulation of post-synaptic receptors due to changed presynaptic activity
Effect depends on neurotransmitter concentrations
Acute: decrease in 5-HT activity
Delayed effect through down regulation of autoreceptors and/or regulation of post-synaptic receptors due to changed presynaptic activity
Effect depends on neurotransmitter concentrations
What is the effect of a partial agonist with low concentrations of endogenous transmitter?
- Too little endogenous transmitter to occupy all receptors
- Partial agonist contributes to agonist effect
- Works best when combined with SSRI’s
- Partial agonist contributes to agonist effect
- Works best when combined with SSRI’s
What is the effect of a partial agonist with high concentrations of endogenous transmitter after desensitization?
- Partial agonists occupy receptors
- Partial blocking of the effect of endogenous transmitter
- Net antagonistic effect
- (Partial) release of the break on 5-HT signaling
- Partial blocking of the effect of endogenous transmitter
- Net antagonistic effect
- (Partial) release of the break on 5-HT signaling
What is the primary indication for buspirone?
- GAD
- Mainly affects 'psychological' complaints
- Less effect on somatic symptoms
- No effect on social anxiety/panic disorder
- Mainly affects 'psychological' complaints
- Less effect on somatic symptoms
- No effect on social anxiety/panic disorder
Why was buspirone initially developed?
- Antipsychotic
- Affinity for dopamine
- Affinity for dopamine
How often is buspirone used in clinical practice in the Netherlands?
- Not used very often
How does activation of the sympathetic system relate to anxiety symptoms?
- Activation prepares for energy use in danger
- Over-activation leads to peripheral symptoms like shaking, red spots
- Can be blocked by β-blockers like Propranolol
- Over-activation leads to peripheral symptoms like shaking, red spots
- Can be blocked by β-blockers like Propranolol
How does Pregabalin contribute to anxiolysis?
- Acts as an anticonvulsant
- EMA approved for GAD
- Binds to α2δ subunits of voltage-sensitive calcium channels
- Reduces release of neurotransmitters like glutamate, noradrenaline
- EMA approved for GAD
- Binds to α2δ subunits of voltage-sensitive calcium channels
- Reduces release of neurotransmitters like glutamate, noradrenaline
What are some routes to anxiolysis for symptom reduction?
- GABA-ergic drugs: Deze medicijnen werken door de activiteit van de neurotransmitter gamma-aminoboterzuur (GABA) te versterken, wat resulteert in een kalmerend effect op het zenuwstelsel
- Blockers of voltage-sensitive calcium channels (VSCCs): Deze medicijnen remmen de instroom van calcium in de cellen, wat kan leiden tot een verminderde neurotransmitterafgifte. Door het reguleren van neurotransmissie kunnen VSCC-blockers helpen bij het verminderen van angst.
- ANS - noradrenaline, e.g. propranolol; Propranolol is een bètablokker die werkt door het blokkeren van de effecten van noradrenaline. Hierdoor kan het de fysieke symptomen van angst verminderen, zoals een verhoogde hartslag en trillen.
- Other pathways: 5-HT (Serotonin), new targets like glutamate and cannabinoids
- Blockers of voltage-sensitive calcium channels (VSCCs): Deze medicijnen remmen de instroom van calcium in de cellen, wat kan leiden tot een verminderde neurotransmitterafgifte. Door het reguleren van neurotransmissie kunnen VSCC-blockers helpen bij het verminderen van angst.
- ANS - noradrenaline, e.g. propranolol; Propranolol is een bètablokker die werkt door het blokkeren van de effecten van noradrenaline. Hierdoor kan het de fysieke symptomen van angst verminderen, zoals een verhoogde hartslag en trillen.
- Other pathways: 5-HT (Serotonin), new targets like glutamate and cannabinoids
What is the role of glutamatergic transmission in anxiolysis?
Glutamatergic transmission is crucial in the extinction of conditioned fear.
How does blocking NMDA affect the extinction of fear?
Blocking NMDA with intra-amygdala infusions of NMDA receptor antagonist leads to less extinction of fear.
Blocking NMDA receptors impairs the extinction of fear by disrupting the synaptic plasticity mechanisms necessary for forming new inhibitory memories. This leads to continued expression of learned fear responses despite repeated exposure to the conditioned stimulus without the aversive outcome. Enhancing NMDA receptor function, on the other hand, may offer therapeutic benefits for improving fear extinction in clinical settings.
Blocking NMDA receptors impairs the extinction of fear by disrupting the synaptic plasticity mechanisms necessary for forming new inhibitory memories. This leads to continued expression of learned fear responses despite repeated exposure to the conditioned stimulus without the aversive outcome. Enhancing NMDA receptor function, on the other hand, may offer therapeutic benefits for improving fear extinction in clinical settings.
What is the relationship between anxiolytics and psychotherapy?
There is no consensus on the combination of anxiolytics and psychotherapy, with pros arguing it increases success chances, while cons point out it may reduce motivation for therapy.
What is the mechanism that underlies the beneficial effects of exposure therapy?
- Extinction is the mechanism
- Extinction is the exposure to the conditioned stimulus (CS) without reinforcement
- Extinction training is crucial in exposure therapy
- Extinction is the exposure to the conditioned stimulus (CS) without reinforcement
- Extinction training is crucial in exposure therapy
What substance is sought after for enhancing glutamatergic transmission via the NMDA receptor?
- D-cycloserine is sought after
- D-cycloserine is a partial agonist at the NMDA receptor
- D-cycloserine has original indication for TBC treatment
- D-cycloserine is a partial agonist at the NMDA receptor
- D-cycloserine has original indication for TBC treatment
When does D-cycloserine facilitate extinction?
- D-Cycloserine facilitates extinction only during extinction training (exposure to the CS without reinforcement)
- Just exposure to the context without extinction training does not work
- D-Cycloserine is effective in the extinction process
- Just exposure to the context without extinction training does not work
- D-Cycloserine is effective in the extinction process
What crucial points are associated with D-Cycloserine in relation to extinction?
- D-Cycloserine does not change the basal anxiety level
- D-Cycloserine is effective when the extinction process is activated through exposure trials
- Clinical application of D-Cycloserine mainly supports the aim of exposure therapy
- D-Cycloserine is effective when the extinction process is activated through exposure trials
- Clinical application of D-Cycloserine mainly supports the aim of exposure therapy
Why may CBT and traditional anxiolytics not work for all patients with anxiety?
CBT as well as ‘traditional’ anxiolytics may have side effects and may not work for all patients with anxiety.
What are some new ideas in pharmacotherapy for anxiety?
Some new ideas include new target receptors and a new approach to treatment that involves supporting learning during psychotherapy.
What genetic factor is referred to in the strong comorbidity between GAD and depression?
- Genetic variant of the serotonin transporter gene
What system involved in anxiety is normalized by noradrenaline reuptake inhibitors?
- Locus coeruleus-noradrenergic system
- Regulation of anxiety
- Reduction of hyperarousal and stress responses
- Regulation of anxiety
- Reduction of hyperarousal and stress responses
Why are substances with longer half-life preferred for treating anxiety over those with short half-life?
- Low risk of dependence and rebound symptoms
- Active metabolites provide pharmacodynamic effect
- Active metabolites provide pharmacodynamic effect
What is an important reason to avoid prolonged use of benzodiazepines?
- Risk of physiologic dependence
- Discontinuation symptoms (rebound)
- Worsening of insomnia and distress
- Discontinuation symptoms (rebound)
- Worsening of insomnia and distress
What factors influence the duration of the effect of diazepam (Valium)?
- Drug's lipid solubility
- Tissue-binding properties
- Half-life increases up to 60-100 hours with repeated use
- Elimination half-life of one dose is 30 hours
- Tissue-binding properties
- Half-life increases up to 60-100 hours with repeated use
- Elimination half-life of one dose is 30 hours
What causes potentially strong side effects with the use of benzodiazepines in the elderly? Is this a pharmacodynamic effect or a pharmacokinetic effect, and what does this effect consist of exactly?
- Slowed hepatic metabolism and increased pharmacodynamic sensitivity
- Reduced metabolism and clearance due to aging
- Accumulation of benzodiazepines in the bloodstream
- Reduced metabolism and clearance due to aging
- Accumulation of benzodiazepines in the bloodstream
What explains the broad side effects profile of benzodiazepines?
- Dosage use and sensitivity of the individual being treated
- Impact on alertness, cognition (attention, memory), motor coordination
- Impact on alertness, cognition (attention, memory), motor coordination
What is pregabalin (Lyrica) and its approved uses?
- Anti-epileptica ligand of the α-2-δ subunit of voltage-gated calcium channels
- Approved for GAD by the European Commission
- FDA approval for neuropathic pain, postherpetic neuralgia, and epilepsy augmentation
- Approved for GAD by the European Commission
- FDA approval for neuropathic pain, postherpetic neuralgia, and epilepsy augmentation
How does pregabalin provide efficacy for the treatment of GAD?
- Relief of emotional symptoms like depressive symptoms and panic
- Relief of physical symptoms like headaches and muscle aches
- Rapid and sustained efficacy shown in placebo-controlled studies
- Relief of physical symptoms like headaches and muscle aches
- Rapid and sustained efficacy shown in placebo-controlled studies
What is the working mechanism of beta-blockers?
- Competitive antagonist of norepinephrine and epinephrine at B-adrenergic receptors
- Peripherally sympatholytic
Dit betekent dat ze concurreren met deze neurotransmitters om te binden aan de receptoren, waardoor de effecten van norepinefrine en epinefrine worden geblokkeerd. Hierdoor remmen beta-blokkers de activiteit van het sympathische zenuwstelsel, wat leidt tot een vermindering van de hartslag, bloeddruk en zuurstofverbruik door het hart. Deze perifeer sympatholytische werking maakt beta-blokkers nuttig bij de behandeling van aandoeningen zoals hypertensie, angina pectoris en hartritmestoornissen.
- Peripherally sympatholytic
Dit betekent dat ze concurreren met deze neurotransmitters om te binden aan de receptoren, waardoor de effecten van norepinefrine en epinefrine worden geblokkeerd. Hierdoor remmen beta-blokkers de activiteit van het sympathische zenuwstelsel, wat leidt tot een vermindering van de hartslag, bloeddruk en zuurstofverbruik door het hart. Deze perifeer sympatholytische werking maakt beta-blokkers nuttig bij de behandeling van aandoeningen zoals hypertensie, angina pectoris en hartritmestoornissen.
How does lipophilicity affect the effects of beta-blockers in the body?
- Lipophilic substances have stronger central effects
- Less lipophilic substances have primarily peripheral effects
- Less lipophilic substances have primarily peripheral effects
How are panic disorder, OCD, and PTSD treated?
- Antidepressants or benzodiazepines are the main treatments
- In serious cases, where patients avoid going out or leaving their homes, a full range of antidepressants options are considered
- In serious cases, where patients avoid going out or leaving their homes, a full range of antidepressants options are considered
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