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DSM-5 classification

Diagnostic criteria

Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder. Substance/medication-induced anxiety disorder falls under the category of anxiety disorders in the DSM-5, not the category of substance-related and addictive disorders, even though the symptoms are due to the effects of a substance.

Diagnosis according to the DSM-5 is dependent on various criteria. Patients must present symptoms of either panic attacks or anxiety. There also must be evidence that the panic or anxiety symptoms are a direct result of the use of the intoxicating substance, which for caffeine-induced anxiety disorder would be due to the consumption of caffeine. The DSM-5 makes the distinction that the substance must be physiologically capable to leading to the anxiety and panic symptoms, thereby distinguishing the relationship between chemical agent and clinical effect. Caffeine has been proven to act as an antagonist on adenosine receptors, which acts as a stimulant and therefore fulfills this criteria. Symptoms must also not have a more likely clinical cause, such as another type of anxiety disorder, come before the ingestion of the intoxicating substance, or last for an extended amount of time after stopping the use of the substance. Diagnosis also requires that the panic attacks or anxiety due to the use of the intoxicating substance must cause a certain amount of disturbance in the patient or lead to deficiency of varying types of daily performance.

Diagnostic features

In addition to the criteria above, it is important to recognize that the diagnostic criteria are not met if the symptoms of panic come before the intoxication by the substance. In the case of caffeine-induced anxiety disorder, a diagnosis will not be made if symptoms of anxiety or panic precede the ingestion of caffeine containing substances or other means of substance consumption. Also, if symptoms persist for more than one month after substance intoxication, the diagnosis cannot be made. Persistence and continuation of symptoms beyond the initial consumption of caffeine suggest an alternate diagnosis that would better explain the long-lasting symptoms. A caffeine-induced anxiety disorder diagnosis should be made, rather than a substance abuse or intoxication diagnosis, when symptoms support section A of the criteria and panic attacks or anxiety is predominate.

Prevalence

Though exact rates of prevalence are not available, general population data shows a 0.002% prevalence over a year-long period and higher prevalence within clinical populations.

Structure of caffeine

Caffeine Structure

Caffeine is a methylxanthine, and is hydrophobic.

Caffeine absorption and excretion

The structure of caffeine allows the molecule to pass freely through biological membranes including the blood-brain barrier. Absorption in the gastrointestinal tract reaches near completion at about 99% after only 45 minutes. Half-life of caffeine for most adults is between 2.5 and 4.5 hours when consumption is limited to less than 10mg/kg. However, during neonatal development, half-life for the fetus is significantly longer and decreases exponentially after birth to reach a normal rate at about 6 months.

Metabolism

Cytochrome P-450 acts in liver microsomes to metabolize caffeine into dimethylxanthines, monomethylxanthines, dimethyl uric acids, monomethyl uric acids, trimethylallantoin, dimethylallantoin, and derivatives of uracil. Most caffeine is metabolized by 3-methyl demethylation, forming the metabolite of paraxanthine. Many metabolites, in addition to caffeine, act within the body and are partly responsible for the physiological response to caffeine.

Mechanism of caffeine action

Caffeine acts multiple ways within the brain and the rest of the body. However, due to the concentration of caffeine required, antagonism of adenosine receptors is the primary mode of action.

Mobilization of intracellular calcium

At very high concentrations, of about 1-2 mM, caffeine lowers the excitability threshold in muscle cells, leading to prolonged contraction. This allows calcium to enter the muscle cell through the plasma membrane and sarcoplasmic reticulum more readily. Influx of calcium requires at least 250 μM of caffeine, with toxic effects occurring over 200 μM and average consumption averaging less than 100 μM. This means that calcium influx and mobilization are most likely not the cause of caffeine’s effect on the central nervous system.

Inhibition of phophodiesterases

Methylxanthines such as caffeine inhibit the action of cyclic nucleotide phosphodiesterase, which normally acts to break down cAMP. The inhibition of the phosphodiesterase would lead to a buildup of cAMP and increase the amount the molecule continues on to effect other molecules. Though this mechanism is possible, it only occurs when levels of caffeine reach a toxic level, and therefore it is unlikely to explain the mechanism of caffeine in the brain.

Antagonism of adenosine receptors

There are four well-known adenosine receptors found in the body, A₁, A_2A, A_2B, and A₃. A_2B and A₃ receptors require conditions that do not occur at normal physiological levels or with normal levels of caffeine consumption.

Caffeine acts as an antagonist of adenosine A₁ and A_2A receptors. Adenosine is a normal neuromodulator that activates adenosine receptors that are g-protein coupled. The actions of A₁ and A2A receptors oppose each other, but are both inhibited by caffeine, due to its function as an antagonist.

A_2A receptors are coupled to G_s proteins which activate adenylate cyclase and some voltage gated Ca²⁺ channels. A_2A receptors are located in dopamine rich brain regions. A_2A receptor mRNA was found in the same neurons as D₂ receptors within the dorsal striatum, nucleus accumbens and tuberculum olfactorium. A_2A receptors are not found in neurons that express D₁ receptors and Substance P. Within the striatum, part of the basal ganglia, activation of A_2A receptors by adenosine increases GABA release, which is an inhibitory neurotransmitter. When caffeine binds to the receptor, less inhibitory neurotransmitter is released, supporting caffeine’s role as a central nervous system stimulant.

A₁ receptors are paired with the G-proteins of G_i-1, G_i-2, G_i-3, G_o1, and G_o2. The g-proteins of A₁ receptors continue to inhibit adenylate cyclase, some voltage gated Ca2+ channels, and activate some K⁺ channels, and phospholipase C and D. A₁ receptors are primarily located in the hippocampus, cerebral and cerebellar cortex, and particular thalamic nuclei. Adenosine acts on A₁ receptors to decrease opening of N-type Ca²⁺ channels in some hippocampal neurons, and therefore decrease the rate of firing since Ca²⁺ is necessary for neurotransmitter release. Caffeine’s antagonistic action on the A₁ receptor would then decrease the action of adenosine, allowing increase Ca²⁺ entry through N-type channels and higher rates of neurotransmitter release.

Other actions of caffeine

Though antagonism of adenosine receptors is the primary mechanism of caffeine, Introduction of the methylxanthine into the body also increases the rate of release and recycling of some monoamine neurotransmitters such as noradrenaline and dopamine. Caffeine also has an excitatory effect on mesocortical cholinergic neurons by acting as an antagonist on adenosine receptors that would normally inhibit the neuron.

Genetics of caffeine consumption

While there are many factors that contribute to individual differences in a person’s response to caffeine, such as environmental and demographic factors (i.e. age, drug use, circadian factors, etc.), genetics play an important role in individual variability. This inconsistency in responses to caffeine can take place "at the metabolic or at the drug-receptor level". The effects of genetic factors can occur either directly by "altering acute or chronic reactions to the drug" or indirectly "by affecting other psychological or physiological processes".

Some of these processes include wakefulness, stimulation, and mood and cognition enhancement. Low doses can result in psychological effects of "mild euphoria, alertness, and enhanced cognitive performance", whereas higher doses produce physiological side effects of nausea, anxiety, trembling, and jitteriness.

There are individuals who are prone to caffeine’s anxiogenic effects whilst others are susceptible to its caffeine-induced sleep disturbances and insomnia. A few studies have been done on twins in order to determine the extent to which genetics influence individual differences in response to caffeine. Homozygous twins have been found to react in more consistent ways to the caffeine than heterozygous twins. These studies find "the heritability of caffeine-related traits range between 0.36 and 0.58".

Behavioral effects

Caffeine’s benefits are "related to its mild psychostimulant properties". Widespread appeal is due primarily to its effect to increase alertness and cognitive arousal and diminish fatigue. In the majority of people, has such positive benefits as alleviating fatigue and promoting heightened cognitive arousal. It also has can produce a wide range of other symptoms, including upregulation of the cardiovascular system ranging "from moderate increases in heart rate to more severe cardiac arrhythmia". However, what is less widely known is that caffeine can induce anxiety-like symptoms in individuals, particularly when consumed in excess. Studies show that consuming caffeine in "excess produces persisting insomnia, nervousness, and mood fluctuations".

Additionally, studies show that caffeine consumption results in "subsequent dysregulation of HPA axis function", which presents in anxiety-related behavior. When undergoing stress, the body activates a system-wide response mechanism known as the HPA axis. This stress signal begins at the level of the hypothalamus in the brain and undergoes subsequent amplifications throughout the body. This system succeeds in elevating blood levels of stress hormones, which results in the body shutting down secondary bodily processes, increasing hyperawareness, and readying the body for to response to the perceived threat. Studies show that activation of this pathway is associated with "anxiety-related disorders such as panic disorder, post-traumatic stress disorder and generalized anxiety disorder".

In cases of prolonged consumption of excess amounts of caffeine, studies show that individuals exhibit a reduced response to HPA axis activation by the hormone ACTH and a generalized increase in basal levels of stress hormone corticosterone. This led the researchers to conclude "caffeine consumption decreases adrenal gland sensitivity to ACTH. A blunted HPA response to psychological stress has been seen in humans with panic disorder compared to healthy controls following administration of a psychosocial test".

Populations most susceptible

Various populations exhibit varying degrees of susceptibility to anxiety-like symptoms when consuming caffeine. Most notably, those who suffer from preexisting anxiety-related disorders, those who suffer from ADHD and adolescents are those who are at greatest risk for experiencing caffeine-induced anxiety-like symptoms. Adolescents, particularly, are at increased risk for developing anxiety disorders and anxiety-related symptoms. Studies show that when adolescents who consume caffeine chronically demonstrate "transient and sustained neurochemical and behavioral responses". This means that when consumed regularly in excess amounts, adolescents display "more lasting effects on behavioral reactivity to psychologically stressful events" and are at "increase vulnerability to the development of psychiatric disorders" in the long term.

Long-term health effects

When consumed in moderation, caffeine can have many beneficial effects. However, over the course of several years, chronic caffeine consumption can produce various long-term health deficits in individuals, "including permanent changes in brain excitability". As previously stated, long-term effects are most often seen in adolescents who regularly consume excess amounts of caffeine. This can effect their neuroendocrine functions and increase the risk of anxiety-disorder development.

Treatment

For individuals prescribed anti-anxiety medications such as alprazolam (Xanax), caffeine can introduce further problems by increasing rates of cytotoxicity and cell death by necrosis. This leads to these medications being essentially ruled out as viable treatments for caffeine-induced anxiety. Due to caffeine’s negative interaction with anti-anxiety medications such as benzodiazepines, treatment for caffeine-induced anxiety disorder tend to revolve around abstinence from or a reduction of caffeine intake and behavioral therapy. Some doctors actually recommend a continuance of caffeine consumption, but with the provision that the patient actively takes note of physiological changes that happen after caffeine intake. The goal of this approach is to help patients better understand the effects of caffeine on the body and to distinguish threatening symptoms from normal reactions.