Book: Stahl’s Illustrated Substance Use and Impulsive Disorders

Book Title:

Stahl’s Illustrated Substance Use and Impulsive Disorders.

Author(s): Stephen M. Stahl and Meghan M. Grady.

Year: 2012.

Edition: First (1st), Illustrated Edition.

Publisher: Cambridge University Press.

Type(s): Paperback and Kindle.

Synopsis:

All of the titles in the Stahl’s Illustrated series are designed to be fun. Concepts are illustrated by full-colour images that will be familiar to readers of Stahl’s Essential Psychopharmacology, 3rd edition, and The Prescriber’s Guide. The visual learner will find that these books make psychopharmacology concepts easy to master, while the non-visual learner will enjoy a shortened text version of complex psychopharmacology concepts. Each chapter builds on previous ones, synthesizing information from basic biology and diagnostics to building treatment plans and dealing with complications and comorbidities. Novices may want to begin by looking through all the graphics and gaining a feel for the visual vocabulary. Readers more familiar with these topics should find that going back and forth between images and text provides an interaction with which to vividly conceptualize complex pharmacologies. Each book ends with a Suggested Reading section to help guide more in-depth learning about particular concepts.

What is Generalised Anxiety Disorder (GAD)?

Introduction

Generalised anxiety disorder (GAD) is an anxiety disorder characterised by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning, and sufferers are overly concerned about everyday matters such as health, finances, death, family, relationship concerns, or work difficulties. Symptoms may include excessive worry, restlessness, trouble sleeping, exhaustion, irritability, sweating, and trembling.

Symptoms must be consistent and ongoing, persisting at least six months, for a formal diagnosis of GAD. Individuals with GAD often suffer from other disorders including other psychiatric disorders (e.g. major depressive disorder), substance use disorder, obesity, and may have a history of trauma or family with GAD. Clinicians use screening tools such as the GAD-7 and GAD-2 questionnaires to determine if individuals may have GAD and warrant formal evaluation for the disorder. Additionally, sometimes screening tools may enable clinicians to evaluate the severity of GAD symptoms.

GAD is believed to have a hereditary or genetic basis (e.g. first-degree relatives of an individual who has GAD are themselves more likely to have GAD) but the exact nature of this relationship is not fully appreciated. Genetic studies of individuals who have anxiety disorders (including GAD) suggest that the hereditary contribution to developing anxiety disorders is only approximately 30-40%, which suggests that environmental factors may be more important to determining whether an individual develops GAD.

The pathophysiology of GAD implicates several regions of the brain that mediate the processing of stimuli associated with fear, anxiety, memory, and emotion (i.e. the amygdala, insula and the frontal cortex). It has been suggested that individuals with GAD have greater amygdala and medial prefrontal cortex (mPFC) activity in response to stimuli than individuals who do not have GAD. However, the relationship between GAD and activity levels in other parts of the frontal cortex is the subject of ongoing research with some literature suggesting greater activation in specific regions for individuals who have GAD but where other research suggests decreased activation levels in individuals who have GAD as compared to individuals who do not have GAD.

Traditional treatment modalities include variations on psychotherapy (e.g. cognitive-behavioural therapy (CBT)) and pharmacological intervention (e.g. citalopram, escitalopram, sertraline, duloxetine, and venlafaxine). CBT and selective serotonin reuptake inhibitors (SSRIs) are the respectively predominant psychological and pharmacological treatment modalities; other treatments (e.g. selective norepinephrine reuptake inhibitors (SNRIs)) are often considered depending on individual response to therapy. Areas of active investigation include the usefulness of complementary and alternative medications (CAMs), exercise, therapeutic massage and other interventions that have been proposed for study.

Estimates regarding prevalence of GAD or lifetime risk (i.e. lifetime morbid risk (LMR)) for GAD vary depending upon which criteria are used for diagnosing GAD (e.g. DSM-5 vs ICD-10) although estimates do not vary widely between diagnostic criteria. In general, ICD-10 is more inclusive than DSM-5, so estimates regarding prevalence and lifetime risk tend to be greater using ICD-10. In regard to prevalence, in a given year, about two (2%) percent of adults in the United States and Europe have been suggested to suffer GAD. However, the risk of developing GAD at any point in life has been estimated at 9.0%. Although it is possible to experience a single episode of GAD during one’s life, most people who experience GAD experience it repeatedly over the course of their lives as a chronic or ongoing condition. GAD is diagnosed twice as frequently in women as in men.

Diagnosis

DSM-5 Criteria

The diagnostic criteria for GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013), published by the American Psychiatric Association, are paraphrased as follows:

  1. “Excessive anxiety or worry” experienced most days over at least six (6) month and which involve a plurality of concerns.
  2. Inability to manage worry.
  3. At least three (3) of the following occur:
    • Restlessness.
    • Fatigability.
    • Problems concentrating.
    • Irritability.
    • Muscle tension.
    • Difficulty with sleep.
    • Note that in children, only one (1) of the above items is required.
  4. One experiences significant distress in functioning (e.g. work, school, social life).
  5. Symptoms are not due to drug abuse, prescription medication or other medical condition(s).
  6. Symptoms do not fit better with another psychiatric condition such as panic disorder.

No major changes to GAD have occurred since publication of the Diagnostic and Statistical Manual of Mental Disorders (2004); minor changes include wording of diagnostic criteria.

ICD-10 Criteria

The 10th revision of the International Statistical Classification of Disease (ICD-10) provides a different set of diagnostic criteria for GAD than the DSM-5 criteria described above. In particular, ICD-10 allows diagnosis of GAD as follows:

  • A period of at least six months with prominent tension, worry, and feelings of apprehension, about everyday events and problems.
  • At least four symptoms out of the following list of items must be present, of which at least one from items (1) to (4).
    • Autonomic arousal symptoms:
      • (1) Palpitations or pounding heart, or accelerated heart rate.
      • (2) Sweating.
      • (3) Trembling or shaking.
      • (4) Dry mouth (not due to medication or dehydration).
    • Symptoms concerning chest and abdomen:
      • (5) Difficulty breathing.
      • (6) Feeling of choking.
      • (7) Chest pain or discomfort.
      • (8) Nausea or abdominal distress (e.g. churning in the stomach).
    • Symptoms concerning brain and mind:
      • (9) Feeling dizzy, unsteady, faint or light-headed.
      • (10) Feelings that objects are unreal (derealization), or that one’s self is distant or “not really here” (depersonalization).
      • (11) Fear of losing control, going crazy, or passing out.
      • (12) Fear of dying.
    • General symptoms:
      • (13) Hot flashes or cold chills.
      • (14) Numbness or tingling sensations.
    • Symptoms of tension:
      • (15) Muscle tension or aches and pains.
      • (16) Restlessness and inability to relax.
      • (17) Feeling keyed up, or on edge, or of mental tension.
      • (18) A sensation of a lump in the throat or difficulty with swallowing.
    • Other non-specific symptoms:
      • (19) Exaggerated response to minor surprises or being startled.
      • (20) Difficulty in concentrating or mind going blank, because of worrying or anxiety.
      • (21) Persistent irritability.
      • (22) Difficulty getting to sleep because of worrying.
  • The disorder does not meet the criteria for panic disorder (F41.0), phobic anxiety disorders (F40.-), obsessive-compulsive disorder (F42.-) or hypochondriacal disorder (F45.2).
  • Most commonly used exclusion criteria: not sustained by a physical disorder, such as hyperthyroidism, an organic mental disorder (F0) or psychoactive substance-related disorder (F1), such as excess consumption of amphetamine-like substances, or withdrawal from benzodiazepines.[21]

See ICD-10 F41.1

Note: For children different ICD-10 criteria may be applied for diagnosing GAD (see F93.80).

History of Diagnostic Criteria

The American Psychiatric Association introduced GAD as a diagnosis in the DSM-III in 1980, when anxiety neurosis was split into GAD and panic disorder. The definition in the DSM-III required uncontrollable and diffuse anxiety or worry that is excessive and unrealistic and persists for 1 month or longer. High rates in comorbidity of GAD and major depression led many commentators to suggest that GAD would be better conceptualised as an aspect of major depression instead of an independent disorder. Many critics stated that the diagnostic features of this disorder were not well established until the DSM-III-R. Since comorbidity of GAD and other disorders decreased with time, the DSM-III-R changed the time requirement for a GAD diagnosis to 6 months or longer. The DSM-IV changed the definition of excessive worry and the number of associated psychophysiological symptoms required for a diagnosis. Another aspect of the diagnosis the DSM-IV clarified was what constitutes a symptom as occurring “often”. The DSM-IV also required difficulty controlling the worry to be diagnosed with GAD. The DSM-5 emphasized that excessive worrying had to occur more days than not and on a number of different topics. It has been stated that the constant changes in the diagnostic features of the disorder have made assessing epidemiological statistics such as prevalence and incidence difficult, as well as increasing the difficulty for researchers in identifying the biological and psychological underpinnings of the disorder. Consequently, making specialized medications for the disorder is more difficult as well. This has led to the continuation of GAD being medicated heavily with SSRIs.

Risk Factors

Genetics, Family and Environment

The relationship between genetics and anxiety disorders is an ongoing area of research. It is broadly understood that there exists an hereditary basis for GAD, but the exact nature of this hereditary basis is not fully appreciated. While investigators have identified several genetic loci that are regions of interest for further study, there is no singular gene or set of genes that have been identified as causing GAD. Nevertheless, genetic factors may play a role in determining whether an individual is at greater risk for developing GAD, structural changes in the brain related to GAD, or whether an individual is more or less likely to respond to a particular treatment modality. Genetic factors that may play a role in development of GAD are usually discussed in view of environmental factors (e.g. life experience or ongoing stress) that might also play a role in development of GAD. The traditional methods of investigating the possible hereditary basis of GAD include using family studies and twin studies (there are no known adoption studies of individuals who suffer anxiety disorders, including GAD). Meta-analysis of family and twin studies suggests that there is strong evidence of a hereditary basis for GAD in that GAD is more likely to occur in first-degree relatives of individuals who have GAD than in non-related individuals in the same population. Twin studies also suggest that there may be a genetic linkage between GAD and major depressive disorder (MDD), which may explain the common occurrence of MDD in individuals who suffer GAD (e.g. comorbidity of MDD in individuals with GAD has been estimated at approximately 60%). When GAD is considered among all anxiety disorders (e.g. panic disorder, social anxiety disorder), genetic studies suggest that hereditary contribution to the development of anxiety disorders amounts to only approximately 30-40%, which suggests that environmental factors are likely more important to determining whether an individual may develop GAD. In regard to environmental influences in the development of GAD, it has been suggested that parenting behaviour may be an important influence since parents potentially model anxiety-related behaviours. It has also been suggested that individuals who suffer GAD have experienced a greater number of minor stress-related events in life and that the number of stress-related events may be important in development of GAD (irrespective of other individual characteristics).

Studies of possible genetic contributions to the development of GAD have examined relationships between genes implicated in brain structures involved in identifying potential threats (e.g. in the amygdala) and also implicated in neurotransmitters and neurotransmitter receptors known to be involved in anxiety disorders. More specifically, genes studied for their relationship to development of GAD or demonstrated to have had a relationship to treatment response include:

  • PACAP (A54G polymorphism): remission after 6 month treatment with Venlafaxine suggested to have a significant relationship with the A54G polymorphism (Cooper et al. (2013)).
  • HTR2A gene (rs7997012 SNP G allele): HTR2A allele suggested to be implicated in a significant decrease in anxiety symptoms associated with response to 6 months of Venlafaxine treatment (Lohoff et al. (2013)).
  • SLC6A4 promoter region (5-HTTLPR): Serotonin transporter gene suggested to be implicated in significant reduction in anxiety symptoms in response to 6 months of Venlafaxine treatment (Lohoff et al. (2013)).

Pathophysiology

The pathophysiology of GAD is an active and ongoing area of research often involving the intersection of genetics and neurological structures. GAD has been linked to changes in functional connectivity of the amygdala and its processing of fear and anxiety. Sensory information enters the amygdala through the nuclei of the basolateral complex (consisting of lateral, basal and accessory basal nuclei). The basolateral complex processes the sensory-related fear memories and communicates information regarding threat importance to memory and sensory processing elsewhere in the brain, such as the medial prefrontal cortex and sensory cortices. Neurological structures traditionally appreciated for their roles in anxiety include the amygdala, insula and orbitofrontal cortex (OFC). It is broadly postulated that changes in one or more of these neurological structures are believed to allow greater amygdala response to emotional stimuli in individuals who have GAD as compared to individuals who do not have GAD.

Individuals who GAD have been suggested to have greater amygdala and medial prefrontal cortex (mPFC) activation in response to stimuli than individuals who do not have GAD. However, the exact relationship between the amygdala and the frontal cortex (e.g. prefrontal cortex or the orbitofrontal cortex (OFC)) is not fully understood because there are studies that suggest increased or decreased activity in the frontal cortex in individuals who have GAD. Consequently, because of the tenuous understanding of the frontal cortex as it relates to the amygdala in individuals who have GAD, it’s an open question as to whether individuals who have GAD bear an amygdala that is more sensitive than an amygdala in an individual without GAD or whether frontal cortex hyperactivity is responsible for changes in amygdala responsiveness to various stimuli. Recent studies have attempted to identify specific regions of the frontal cortex (e.g. dorsomedial prefrontal cortex (dmPFC)) that may be more or less reactive in individuals who have GAD or specific networks that may be differentially implicated in individuals who have GAD. Other lines of study investigate whether activation patterns vary in individuals who have GAD at different ages with respect to individuals who do not have GAD at the same age (e.g. amygdala activation in adolescents with GAD).

Treatment

Traditional treatment modalities broadly fall into two (2) categories:

  • Psychotherapeutic; and
  • Pharmacological intervention.

In addition to these two conventional therapeutic approaches, areas of active investigation include complementary and alternative medications (CAMs), brain stimulation, exercise, therapeutic massage and other interventions that have been proposed for further study. Treatment modalities can, and often are utilised concurrently so that an individual may pursue psychological therapy (i.e. psychotherapy) and pharmacological therapy. Both cognitive behavioural therapy (CBT) and medications (such as SSRIs) have been shown to be effective in reducing anxiety. A combination of both CBT and medication is generally seen as the most desirable approach to treatment. Use of medication to lower extreme anxiety levels can be important in enabling patients to engage effectively in CBT.

Psychotherapy

Psychotherapeutic interventions include a plurality of therapy types that vary based upon their specific methodologies for enabling individuals to gain insight into the working of the conscious and subconscious mind and which sometimes focus on the relationship between cognition and behaviour. Cognitive behavioural therapy (CBT) is widely regarded as the first-line psychological therapy for treating GAD. Additionally, many of these psychological interventions may be delivered in an individual or group therapy setting. While individual and group settings are broadly both considered effective for treating GAD, individual therapy tends to promote longer-lasting engagement in therapy (i.e. lower attrition over time).

Psychodynamic Therapy

Psychodynamic therapy is a type of therapy premised upon Freudian psychology in which a psychologist enables an individual explore various elements in their subconscious mind to resolve conflicts that may exist between the conscious and subconscious elements of the mind. In the context of GAD, the psychodynamic theory of anxiety suggests that the unconscious mind engages in worry as a defence mechanism to avoid feelings of anger or hostility because such feelings might cause social isolation or other negative attribution toward oneself. Accordingly, the various psychodynamic therapies attempt to explore the nature of worry as it functions in GAD in order to enable individuals to alter the subconscious practice of using worry as a defence mechanism and to thereby diminish GAD symptoms. Variations of psychotherapy include a near-term version of therapy, “short-term anxiety-provoking psychotherapy (STAPP).

Behavioural Therapy

Behavioural therapy is therapeutic intervention premised upon the concept that anxiety is learned through classical conditioning (e.g., in view of one or more negative experiences) and maintained through operant conditioning (e.g. one finds that by avoiding a feared experience that one avoids anxiety). Thus, behavioural therapy enables an individual to re-learn conditioned responses (behaviours) and to thereby challenge behaviours that have become conditioned responses to fear and anxiety, and which have previously given rise to further maladaptive behaviours.

Cognitive Therapy

Cognitive therapy (CT) is premised upon the idea that anxiety is the result of maladaptive beliefs and methods of thinking. Thus, CT involves assisting individuals to identify more rational ways of thinking and to replace maladaptive thinking patterns (i.e. cognitive distortions) with healthier thinking patterns (e.g. replacing the cognitive distortion of catastrophising with a more productive pattern of thinking). Individuals in CT learn how to identify objective evidence, test hypotheses, and ultimately identify maladaptive thinking patterns so that these patterns can be challenged and replaced.

Acceptance and Commitment Therapy

Acceptance and commitment therapy (ACT) is a behavioural treatment based on acceptance-based models. ACT is designed with the purpose to target three therapeutic goals:

  1. Reduce the use of avoiding strategies intended to avoid feelings, thoughts, memories, and sensations;
  2. Decreasing a person’s literal response to their thoughts (e.g., understanding that thinking “I’m hopeless” does not mean that the person’s life is truly hopeless); and
  3. Increasing the person’s ability to keep commitments to changing their behaviours.

These goals are attained by switching the person’s attempt to control events to working towards changing their behaviour and focusing on valued directions and goals in their lives as well as committing to behaviours that help the individual accomplish those personal goals. This psychological therapy teaches mindfulness (paying attention on purpose, in the present, and in a non-judgemental manner) and acceptance (openness and willingness to sustain contact) skills for responding to uncontrollable events and therefore manifesting behaviours that enact personal values. Like many other psychological therapies, ACT works best in combination with pharmacology treatments.

Intolerance of Uncertainty Therapy

Intolerance of uncertainty (IU) refers to a consistent negative reaction to uncertain and ambiguous events regardless of their likelihood of occurrence. Intolerance of uncertainty therapy (IUT) is used as a stand-alone treatment for GAD patients. Thus, IUT focuses on helping patients in developing the ability to tolerate, cope with and accept uncertainty in their life in order to reduce anxiety. IUT is based on the psychological components of psychoeducation, awareness of worry, problem-solving training, re-evaluation of the usefulness of worry, imagining virtual exposure, recognition of uncertainty, and behavioural exposure. Studies have shown support for the efficacy of this therapy with GAD patients with continued improvements in follow-up periods.

Motivational Interviewing

A promising innovative approach to improving recovery rates for the treatment of GAD is to combine CBT with motivational interviewing (MI). Motivational interviewing is a strategy centred on the patient that aims to increase intrinsic motivation and decrease ambivalence about change due to the treatment. MI contains four key elements:

  • Express empathy;
  • Heighten dissonance between behaviours that are not desired and values that are not consistent with those behaviours;
  • Move with resistance rather than direct confrontation; and
  • Encourage self-efficacy.

It is based on asking open-ended questions and listening carefully and reflectively to patients’ answers, eliciting “change talk”, and talking with patients about the pros and cons of change. Some studies have shown the combination of CBT with MI to be more effective than CBT alone.

Cognitive Behavioural Therapy

Cognitive behavioural therapy (CBT) is an evidence-based type of psychotherapy that demonstrates efficacy in treating GAD and which integrates the cognitive and behavioural therapeutic approaches. The objective of CBT is to enable individuals to identify irrational thoughts that cause anxiety and to challenge dysfunctional thinking patterns by engaging in awareness techniques such as hypothesis testing and journaling. Because CBT involves the practice of worry and anxiety management, CBT includes a plurality of intervention techniques that enable individuals to explore worry, anxiety and automatic negative thinking patterns. These interventions include anxiety management training, cognitive restructuring, progressive relaxation, situational exposure and self-controlled desensitisation.

Other forms of psychological therapy include:

  • Relaxation techniques (e.g. relaxing imagery, meditational relaxation).
  • Metacognitive Therapy (MCT):
    • The objective of MCT is to alter thinking patterns regarding worry so that worry is no longer used as a coping strategy.
  • Mindfulness based stress reduction (MBSR).
  • Mindfulness based cognitive therapy (MBCT).
  • Supportive therapy:
    • This is a Rogerian method of therapy in which subjects experience empathy and acceptance from their therapist to facilitate increasing awareness.
    • Variations of active supportive therapy include Gestalt therapy, Transactional analysis and Counselling.

Pharmacotherapy

Historically, benzodiazepines (BZs) were used prominently to treat anxiety starting in the 1970s but support for this use attenuated in view of the risk for dependence and tolerance to the medication. BZs can have a plurality of effects that made them a seemingly desirable option for treating anxiety – i.e. BZs have anxiolytic, hypnotic (induce sleep), myorelaxant (relax muscles), anticonvulsant and amnestic (impair short-term memory) properties. While BZs are well appreciated for their ability to alleviate anxiety (i.e. their anxiolytic properties) shortly after administration, they are also known for their ability to promote dependence and are frequently abused. Current recommendations for using BZs to treat anxiety in GAD allow no more than 2-4 weeks of BZ exposure. Antidepressants (e.g. SSRIs/SNRIs) have become a mainstay in treating GAD in adults. First-line mediations from any drug category often include drugs that have been approved by the US Food and Drug Administration (FDA) for treating GAD because these medications have been proven safe and effective for treating GAD.

FDA-Approved Medications for Treating GAD

FDA-approved medications for treating GAD include:

  • SSRIs:
    • Paroxetine.
    • Escitalopram.
  • SNRIs:
    • Venlafaxine.
    • Duloxetine.
  • Benzodiazepines (BZs):
    • Alprazolam: Alprazolam is the only FDA-approved BZ for treating GAD.
  • Azapirones:
    • Buspirone.

Non-FDA Approved Medications

While certain medications are not specifically FDA approved for treatment of GAD, there are a number of medications that historically have been used or studied for treating GAD. Other medications that have been used or evaluated for treating GAD include:

  • SSRIs (antidepressants):
    • Citalopram.
    • Fluoxetine.
    • Sertraline.
    • Fluvoxamine (SSRI).
  • Benzodiazepines:
    • Clonazepam.
    • Lorazepam.
    • Diazepam.
  • GABA analogs:
    • Pregabalin (atypical anxiolytic, GABA analog).
    • Tiagabine.
  • Second-generation antipsychotics (SGAs):
    • Olanzapine (evidence of effectiveness is merely a trend).
    • Ziprasidone.
    • Risperidone.
    • Aripiprazole (studied as an adjunctive measure in concert with other treatment).
    • Quetiapine (atypical antipsychotic studied as an adjunctive measure in adults and geriatric patients).
  • Antihistamines:
    • Hydroxyzine (H1 receptor antagonist).
  • Vilazodone (atypical antidepressant).
  • Agomelatine (antidepressant, MT1/2 receptor agonist, 5HT2c antagonist).
  • Clonidine (noted to cause decreased blood pressure and other AEs).
  • Guanfacine (a2A receptor agonist, studied in paediatric patients with GAD).
  • Mirtazapine (atypical antidepressant having 5HT2A and 5HT2c receptor affinity).
  • Vortioxetine (multimodal antidepressant).
  • Eszopiclone (non-benzodiazepine hypnotic).
  • Tricyclic antidepressants:
    • Amitriptyline.
    • Clomipramine.
    • Doxepin.
    • Imipramine.
    • Trimipramine.
    • Desipramine.
    • Nortriptyline.
    • Protriptyline.
  • Opipramol (atypical TCA).]
  • Trazodone.
  • Monamine oxidase inhibitors (MAOIs):
    • Tranylcypromine.
    • Phenelzine.
  • Homeopathic preparations (discussed below, see complementary and alternative medications (CAMs))

Selective Serotonin Reuptake Inhibitors

Pharmaceutical treatments for GAD include selective serotonin reuptake inhibitors (SSRIs).[50] SSRIs increase serotonin levels through inhibition of serotonin reuptake receptors.

FDA approved SSRIs used for this purpose include escitalopram and paroxetine. However, guidelines suggest using sertraline first due to its cost-effectiveness compared to other SSRIs used for GAD and a lower risk of withdrawal compared to SNRIs. If sertraline is found to be ineffective, then it is recommended to try another SSRI or SNRI.

Common side effects include nausea, sexual dysfunction, headache, diarrhoea, constipation, restlessness, increased risk of suicide in young adults and adolescents, among others. Sexual side effects, weight gain, and higher risk of withdrawal are more common in paroxetine than escitalopram and sertraline. In older populations or those taking concomitant medications that increase risk of bleeding, SSRIs may further increase the risk of bleeding. Overdose of an SSRI or concomitant use with another agent that causes increased levels of serotonin can result in serotonin syndrome, which can be life-threatening.

Serotonin Norepinephrine Reuptake Inhibitors

First line pharmaceutical treatments for GAD also include serotonin-norepinephrine reuptake inhibitors (SNRIs). These inhibit the reuptake of serotonin and noradrenaline to increase their levels in the CNS.

FDA approved SNRIs used for this purpose include duloxetine (Cymbalta) and venlafaxine (Effexor). While SNRIs have similar efficacy as SSRIs, many psychiatrists prefer to use SSRIs first in the treatment of GAD The slightly higher preference for SSRIs over SNRIs as a first choice for treatment of anxiety disorders may have been influenced by the observation of poorer tolerability of the SNRIs in comparison to SSRIs in systematic reviews of studies of depressed patients.

Side effects common to both SNRIs include anxiety, restlessness, nausea, weight loss, insomnia, dizziness, drowsiness, sweating, dry mouth, sexual dysfunction and weakness. In comparison to SSRIs, the SNRIs have a higher prevalence of the side effects of insomnia, dry mouth, nausea and high blood pressure. Both SNRIs have the potential for discontinuation syndrome after abrupt cessation, which can precipitate symptoms including motor disturbances and anxiety and may require tapering. Like other serotonergic agents, SNRIs have the potential to cause serotonin syndrome, a potentially fatal systemic response to serotonergic excess that causes symptoms including agitation, restlessness, confusion, tachycardia, hypertension, mydriasis, ataxia, myoclonus, muscle rigidity, diaphoresis, diarrhoea, headache, shivering, goose bumps, high fever, seizures, arrhythmia and unconsciousness. SNRIs like SSRIs carry a black box warning for suicidal ideation, but it is generally considered that the risk of suicide in untreated depression is far higher than the risk of suicide when depression is properly treated.

Pregabalin and Gabapentin

Pregabalin (Lyrica) acts on the voltage-dependent calcium channel to decrease the release of neurotransmitters such as glutamate, norepinephrine and substance P. Its therapeutic effect appears after 1 week of use and is similar in effectiveness to lorazepam, alprazolam and venlafaxine but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychic and somatic anxiety symptoms. Long-term trials have shown continued effectiveness without the development of tolerance and additionally, unlike benzodiazepines, it does not disrupt sleep architecture and produces less severe cognitive and psychomotor impairment. It also has a low potential for abuse and dependency and may be preferred over the benzodiazepines for these reasons. The anxiolytic effects of pregabalin appear to persist for at least six months continuous use, suggesting tolerance is less of a concern; this gives pregabalin an advantage over certain anxiolytic medications such as benzodiazepines.

Gabapentin (Neurontin), a closely related medication to pregabalin with the same mechanism of action, has also demonstrated effectiveness in the treatment of GAD, though unlike pregabalin, it has not been approved specifically for this indication. Nonetheless, it is likely to be of similar usefulness in the management of this condition, and by virtue of being off-patent, it has the advantage of being significantly less expensive in comparison. In accordance, gabapentin is frequently prescribed off-label to treat GAD.

Complementary and Alternative Medicines Studied for Potential in Treating GAD

Complementary and alternative medicines (CAMs) are widely used by individuals who suffer GAD despite having no evidence or varied evidence regarding efficacy. Efficacy trials for CAM medications often suffer from various types of bias and low quality reporting in regard to safety. In regard to efficacy, critics point out that CAM trials sometimes predicate claims of efficacy based on a comparison of a CAM against a known drug after which no difference in subjects is found by investigators and which is used to suggest an equivalence between a CAM and a drug. Because this equates a lack of evidence with the positive assertion of efficacy, a “lack of difference” assertion is not a proper claim for efficacy. Moreover, an absence of strict definitions and standards for CAM compounds further burdens the literature regarding CAM efficacy in treating GAD. CAMs academically studied for their potential in treating GAD or GAD symptoms along with a summary of academic findings are given below. What follows is a summary of academic findings. Accordingly, none of the following should be taken as offering medical guidance or an opinion as to the safety or efficacy of any of the following CAMs.

  • Kava Kava (Piper methysticum) extracts:
    • Meta analysis does not suggest efficacy of Kava Kava extracts due to few data available yielding inconclusive results or non-statistically significant results.
    • Nearly a quarter (25.8%) of subjects experienced adverse effects (AEs) from Kava Kava extracts during six (6) trials.
    • Kava Kava may cause liver toxicity.
  • Lavender (Lavandula angustifolia) extracts:
    • Small and varied studies may suggest some level of efficacy as compared to placebo or other medication; claims of efficacy are regarded as needing further evaluation.
    • Silexan is an oil derivative of Lavender studied in paediatric patients with GAD.
    • Concern exists regarding the question as to whether Silexan may cause unopposed oestrogen exposure in boys due to disruption of steroid signalling.
  • Galphimia glauca extracts:
    • While Galphima glauca extracts have been the subject of two (2) randomised controlled trials (RCTs) comparing Galphima glauca extracts to lorazepam, efficacy claims are regarded as “highly uncertain.”
  • Chamomile (Matricaria chamomilla) extracts:
    • Poor quality trials have trends that may suggest efficacy but further study is needed to establish any claim of efficacy.
  • Crataegus oxycantha and Eschscholtzia californica extracts combined with magnesium:
    • A single12-week trial of Crataegus oxycantha and Eschscholtzia californica compared to placebo has been used to suggest efficacy.
    • However, efficacy claims require confirmation studies.
    • For the minority of subjects who experienced AEs from extracts, most AEs implicated gastrointestinal tract (GIT) intolerance.
  • Echium amoneum extract:
    • A single, small trial used this extract as a supplement to fluoxetine (vs using a placebo to supplement fluoxetine); larger studies are needed to substantiate efficacy claims.
  • Gamisoyo-San:
    • Small trials of this herbal mixture compared to placebo have suggested no efficacy of the herbal mixture over placebo but further study is necessary to allow definitive conclusion of a lack of efficacy.
  • Passiflora incarnata extract:
    • Claims of efficacy or benzodiazepam equivalence are regarded as “highly uncertain.”
  • Valeriana extract:
    • A single 4-week trial suggests no effect of Valeriana extract on GAD but is regarded as “uninformative” on the topic of efficacy in view of its finding that the benzodiazepine diazepam also had no effect.
    • Further study may be warranted.

Other Possible Modalities Discussed in Literature for Potential in Treating GAD

Other modalities that have been academically studied for their potential in treating GAD or symptoms of GAD are summarised below. What follows is a summary of academic findings. Accordingly, none of the following should be taken as offering medical guidance or an opinion as to the safety or efficacy of any of the following modalities.

  • Acupuncture:
    • A single, very small trial revealed a trend toward efficacy but flaws in the trial design suggest uncertainty regarding efficacy.
  • Balneotherapy:
    • Data from a single non-blinded study suggested possible efficacy of balneotherapy as compared to paroxetine.
    • However, efficacy claims need confirmation.
  • Therapeutic massage:
    • A single, small, possibly biased study revealed inconclusive results.
  • Resistance and aerobic exercise:
    • When compared to no treatment, a single, small, potentially unrepresentative trial suggested a trend toward GAD remission and reduction of worry.
  • Chinese bloodletting:
    • When added to paroxetine, a single, small, imprecise trial that lacked a sham procedure for comparison suggested efficacy at 4-weeks.
    • However, larger trials are needed to evaluate this technique as compared to a sham procedure.
  • Floating in water:
    • When compared to no treatment, a single, imprecise, non-blinded trial suggested a trend toward efficacy (findings were statistically insignificant).
  • Swedish massage:
    • When compared to a sham procedure, a single trial showed a trend toward efficacy (i.e. findings were statistically insignificant).
  • Ayurvedic medications:
    • A single non-blinded trial was inconclusive as to whether Ayurvedic medications were effective in treating GAD.
  • Multi-faith spiritually-based intervention:
    • A single, small, non-blinded study was inconclusive regarding efficacy.

Lifestyle

Lifestyle factors including: stress management, stress reduction, relaxation, exercise, sleep hygiene, and caffeine and alcohol reduction can influence anxiety levels. Physical activity has shown to have a positive impact whereas low physical activity may be a risk factor for anxiety disorders.

Substances and Anxiety in GAD

While there are no substances that are known to cause GAD, certain substances or the withdrawal from certain substances have been implicated in promoting the experience of anxiety. For example, even while benzodiazepines may afford individuals with GAD relief from anxiety, withdrawal from benzodiazepines is associated with the experience of anxiety among other adverse events like sweating and tremor.

Tobacco withdrawal symptoms may provoke anxiety in smokers and excessive caffeine use has been linked to aggravating and maintaining anxiety.

Comorbidity

Depression

In the National Comorbidity Survey (2005), 58% of patients diagnosed with major depression were found to have an anxiety disorder; among these patients, the rate of comorbidity with GAD was 17.2%, and with panic disorder, 9.9%. Patients with a diagnosed anxiety disorder also had high rates of comorbid depression, including 22.4% of patients with social phobia, 9.4% with agoraphobia, and 2.3% with panic disorder. A longitudinal cohort study found 12% of the 972 participants had GAD comorbid with MDD. Accumulating evidence indicates that patients with comorbid depression and anxiety tend to have greater illness severity and a lower treatment response than those with either disorder alone. In addition, social function and quality of life are more greatly impaired.

For many, the symptoms of both depression and anxiety are not severe enough (i.e. are subsyndromal) to justify a primary diagnosis of either major depressive disorder (MDD) or an anxiety disorder. However, dysthymia is the most prevalent comorbid diagnosis of GAD clients. Patients can also be categorised as having mixed anxiety-depressive disorder, and they are at significantly increased risk of developing full-blown depression or anxiety.

Various explanations for the high comorbidity between GAD and depressive disorders have been suggested, including genetic pleiotropy, meaning that GAD and nonbipolar depression might represent different phenotypic expressions of a common aetiology.

Comorbidity and Treatment

Therapy has been shown to have equal efficacy in patients with GAD and patients with GAD and comorbid disorders. Patients with comorbid disorders have more severe symptoms when starting therapy but demonstrated a greater improvement than patients with simple GAD.

Pharmacological approaches i.e. the use of antidepressants must be adapted for different comorbidities. For example, serotonin reuptake inhibitors and short acting benzodiazepines (BZDs) are used for depression and anxiety. However, for patients with anxiety and substance abuse, BZDs should be avoided due to their abuse liability. CBT has been found an effective treatment since it improves symptoms of GAD and substance abuse.

Compared to the general population, patients with internalising disorders such as depression, GAD and post-traumatic stress disorder (PTSD) have higher mortality rates, but die of the same age-related diseases as the population, such as heart disease, cerebrovascular disease and cancer.

GAD often coexists with conditions associated with stress, such as muscle tension and irritable bowel syndrome.

Patients with GAD can sometimes present with symptoms such as insomnia or headaches as well as pain and interpersonal problems.

Further research suggests that about 20% to 40% of individuals with attention deficit hyperactivity disorder have comorbid anxiety disorders, with GAD being the most prevalent.

Those with GAD have a lifetime comorbidity prevalence of 30% to 35% with alcohol use disorder and 25% to 30% for another substance use disorder. People with both GAD and a substance use disorder also have a higher lifetime prevalence for other comorbidities. A study found that GAD was the primary disorder in slightly more than half of the 18 participants that were comorbid with alcohol use disorder.

Epidemiology

GAD is often estimated to affect approximately 3-6% of adults and 5% of children and adolescents. Although estimates have varied to suggest a GAD prevalence of 3% in children and 10.8% in adolescents. When GAD manifests in children and adolescents, it typically begins around 8 to 9 years of age.

Estimates regarding prevalence of GAD or lifetime risk (i.e. lifetime morbid risk (LMR)) for GAD vary depending upon which criteria are used for diagnosing GAD (e.g. DSM-5 vs ICD-10) although estimates do not vary widely between diagnostic criteria. In general, ICD-10 is more inclusive than DSM-5, so estimates regarding prevalence and lifetime risk tend to be greater using ICD-10. In regard to prevalence, in a given year, about two (2%) percent of adults in the United States and Europe have been suggested to suffer GAD. However, the risk of developing GAD at any point in life has been estimated at 9.0%. Although it is possible to experience a single episode of GAD during one’s life, most people who experience GAD experience it repeatedly over the course of their lives as a chronic or ongoing condition. GAD is diagnosed twice as frequently in women as in men and is more often diagnosed in those who are separated, divorced, unemployed, widowed or have low levels of education, and among those with low socioeconomic status. African Americans have higher odds of having GAD and the disorder often manifests itself in different patterns. It has been suggested that greater prevalence of GAD in women may be because women are more likely than men to live in poverty, are more frequently the subject of discrimination, and be sexually and physically abused more often than men. In regard to the first incidence of GAD in an individual’s life course, a first manifestation of GAD usually occurs between the late teenage years and the early twenties with the median age of onset being approximately 31 and mean age of onset being 32.7. However, GAD can begin or reoccur at any point in life. Indeed, GAD is common in the elderly population.

  • US: Approximately 3.1% of people age 18 and over in a given year (9.5 million).
  • UK: 5.9% of adults were affected by GAD in 2019.
  • Australia: 3% of adults
  • Canada: 2.5%.
  • Italy: 2.9%
  • Taiwan: 0.4%.

What is Schizophrenia?

Introduction

Schizophrenia is a psychiatric disorder characterised by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganised thinking. Other symptoms include social withdrawal, decreased emotional expression, and apathy. Symptoms typically come on gradually, begin in young adulthood, and in many cases never resolve. There is no objective diagnostic test; diagnosis is based on:

  • Observed behaviour;
  • A history that includes the person’s reported experiences; and
  • Reports of others familiar with the person.

To be diagnosed with schizophrenia, symptoms and functional impairment need to be present for six months (DSM-5) or one month (ICD-11). Many people with schizophrenia have other mental disorders that often includes an anxiety disorder such as panic disorder, an obsessive compulsive disorder (OCD), or a substance use disorder.

About 0.3% to 0.7% of people are affected by schizophrenia during their lifetime. In 2017, there were an estimated 1.1 million new cases and in 2019 a total of 20 million cases globally. Males are more often affected and on average have an earlier onset. The causes of schizophrenia include genetic and environmental factors. Genetic factors include a variety of common and rare genetic variants. Possible environmental factors include being raised in a city, cannabis use during adolescence, infections, the ages of a person’s mother or father, and poor nutrition during pregnancy.

About half of those diagnosed with schizophrenia will have a significant improvement over the long term with no further relapses, and a small proportion of these will recover completely. The other half will have a lifelong impairment, and severe cases may be repeatedly admitted to hospital. Social problems such as long-term unemployment, poverty, homelessness, exploitation, and victimisation are common consequences of schizophrenia. Compared to the general population, people with schizophrenia have a higher suicide rate (about 5% overall) and more physical health problems, leading to an average decrease in life expectancy by 20 years. In 2015, an estimated 17,000 deaths were caused by schizophrenia.

The mainstay of treatment is antipsychotic medication, along with counselling, job training, and social rehabilitation. Up to a third of people do not respond to initial antipsychotics, in which case the antipsychotic clozapine may be used. In situations where there is a risk of harm to self or others, a short involuntary hospitalisation may be necessary. Long-term hospitalisation may be needed for a small number of people with severe schizophrenia. In countries where supportive services are limited or unavailable, long-term hospital stays are more typical.

Epidemiology

In 2017, the Global Burden of Disease Study estimated there were 1.1 million new cases, and in 2019 the World Health Organisation (WHO) reported a total of 20 million cases globally. Schizophrenia affects around 0.3-0.7% of people at some point in their life. It occurs 1.4 times more frequently in males than females and typically appears earlier in men – the peak ages of onset are 25 years for males and 27 years for females. Onset in childhood, before the age of 13 can sometimes occur. A later onset can occur between the ages of 40 and 60, known as late onset, and also after 60 known as very late onset.

Worldwide, schizophrenia is the most common psychotic disorder. The frequency of schizophrenia varies across the world, within countries, and at the local and neighbourhood level. This variation has been estimated to be fivefold. It causes approximately 1% of worldwide disability adjusted life years and resulted in 17,000 deaths in 2015.

In 2000, the WHO found the percentage of people affected and the number of new cases that develop each year is roughly similar around the world, with age-standardised prevalence per 100,000 ranging from 343 in Africa to 544 in Japan and Oceania for men, and from 378 in Africa to 527 in Southeastern Europe for women. About 1.1% of adults have schizophrenia in the United States. However, in areas of conflict this figure can rise to between 4.0 and 6.5%.

Brief History

Accounts of a schizophrenia-like syndrome are rare in records before the 19th century. The earliest cases detailed were reported in 1797, and 1809. Dementia praecox, meaning premature dementia was used by German psychiatrist Heinrich Schüle in 1886, and then in 1891 by Arnold Pick in a case report of hebephrenia. In 1893 Emil Kraepelin used the term in making a distinction, known as the Kraepelinian dichotomy, between the two psychoses – dementia praecox, and manic depression (now called bipolar disorder). Kraepelin believed that dementia praecox was probably caused by a systemic disease that affected many organs and nerves, affecting the brain after puberty in a final decisive cascade. It was thought to be an early form of dementia, a degenerative disease. When it became evident that the disorder was not degenerative it was renamed schizophrenia by Eugen Bleuler in 1908.

The word schizophrenia translates roughly as “splitting of the mind” and is Modern Latin from the Greek roots schizein (σχίζειν, “to split”) and phrēn, (φρεν, “mind”) Its use was intended to describe the separation of function between personality, thinking, memory, and perception.

The term schizophrenia used to be associated with split personality by the general population but that usage went into decline when split personality became known as a separate disorder, first as multiple identity disorder , and later as dissociative identity disorder. In 2002 in Japan the name was changed to integration disorder, and in 2012 in South Korea, the name was changed to attunement disorder to reduce the stigma, both with good results.

In the early 20th century, the psychiatrist Kurt Schneider listed the psychotic symptoms of schizophrenia into two groups of hallucinations, and delusions. The hallucinations were listed as specific to auditory, and the delusional included thought disorders. These were seen as the symptoms of first-rank importance and were termed first-rank symptoms. Whilst these were also sometimes seen to be relevant to the psychosis in manic-depression, they were highly suggestive of schizophrenia and typically referred to as first-rank symptoms of schizophrenia. The most common first-rank symptom was found to belong to thought disorders. In 2013 the first-rank symptoms were excluded from the DSM-5 criteria. First-rank symptoms are seen to be of limited use in detecting schizophrenia but may be of help in differential diagnosis.]

The earliest attempts to treat schizophrenia were psychosurgical, involving either the removal of brain tissue from different regions or the severing of pathways. These were notably frontal lobotomies and cingulotomies which were carried out from the 1930s. In the 1930s a number of shock therapies were introduced which induced seizures (convulsions) or comas. Insulin shock therapy involved the injecting of large doses of insulin in order to induce comas, which in turn produced hypoglycaemia and convulsions. The use of electricity to induce seizures was developed, and in use as electroconvulsive therapy (ECT) by 1938. Stereotactic surgeries were developed in the 1940s. Treatment was revolutionized in the mid-1950s with the development and introduction of the first typical antipsychotic, chlorpromazine. In the 1970s the first atypical antipsychotic clozapine, was introduced followed by the introduction of others.

In the early 1970s in the US, the diagnostic model used for schizophrenia was broad and clinically-based using DSM II. It had been noted that schizophrenia was diagnosed far more in the US than in Europe which had been using the ICD-9 criteria. The US model was criticised for failing to demarcate clearly those people with a mental illness, and those without. In 1980 DSM III was published and showed a shift in focus from the clinically-based biopsychosocial model to a reason-based medical model. DSM IV showed an increased focus to an evidence-based medical model.

Subtypes of schizophrenia classified as paranoid, disorganized, catatonic, undifferentiated, and residual type were difficult to distinguish between and are no longer recognised as separate conditions by DSM-5 (2013) or ICD-11.

Signs and Symptoms

Schizophrenia is a mental disorder characterized by significant alterations in perception, thoughts, mood, and behaviour. Symptoms are described in terms of positive, and negative, and cognitive symptoms. The positive symptoms of schizophrenia are the same for any psychosis and are sometimes referred to as psychotic symptoms. These may be present in any of the different psychoses, and are often transient making early diagnosis of schizophrenia problematic. Psychosis noted for the first time in a person who is later diagnosed with schizophrenia is referred to as a first-episode psychosis (FEP).

Positive Symptoms

Positive symptoms are those symptoms that are not normally experienced, but are present in people during a psychotic episode in schizophrenia. They include delusions, hallucinations, and disorganised thoughts and speech, typically regarded as manifestations of psychosis. Hallucinations most commonly involve the sense of hearing as hearing voices but can sometimes involve any of the other senses of taste, sight, smell, and touch. They are also typically related to the content of the delusional theme. Delusions are bizarre or persecutory in nature. Distortions of self-experience such as feeling as if one’s thoughts or feelings are not really one’s own, to believing that thoughts are being inserted into one’s mind, sometimes termed passivity phenomena, are also common. Thought disorders can include thought blocking, and disorganised speech – speech that is not understandable is known as word salad. Positive symptoms generally respond well to medication, and become reduced over the course of the illness, perhaps related to the age-related decline in dopamine activity.

Negative Symptoms

Negative symptoms are deficits of normal emotional responses, or of other thought processes. The five recognised domains of negative symptoms are:

  • Blunted affect: showing flat expressions or little emotion;
  • Alogia: a poverty of speech;
  • Anhedonia: an inability to feel pleasure;
  • Asociality: the lack of desire to form relationships; and
  • Avolition: a lack of motivation and apathy.

Avolition and anhedonia are seen as motivational deficits resulting from impaired reward processing. Reward is the main driver of motivation and this is mostly mediated by dopamine. It has been suggested that negative symptoms are multidimensional and they have been categorised into two subdomains of apathy or lack of motivation, and diminished expression. Apathy includes avolition, anhedonia, and social withdrawal; diminished expression includes blunt effect, and alogia. Sometimes diminished expression is treated as both verbal and non-verbal. Apathy accounts for around 50% of the most often found negative symptoms and affects functional outcome and subsequent quality of life. Apathy is related to disrupted cognitive processing affecting memory and planning including goal-directed behaviour. The two subdomains has suggested a need for separate treatment approaches. A lack of distress – relating to a reduced experience of depression and anxiety is another noted negative symptom. A distinction is often made between those negative symptoms that are inherent to schizophrenia, termed primary; and those that result from positive symptoms, from the side effects of antipsychotics, substance abuse, and social deprivation – termed secondary negative symptoms. Negative symptoms are less responsive to medication and the most difficult to treat. However if properly assessed, secondary negative symptoms are amenable to treatment.

Scales for specifically assessing the presence of negative symptoms, and for measuring their severity, and their changes have been introduced since the earlier scales such as the PANNS that deals with all types of symptoms. These scales are the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptom Scale (BNSS) also known as second-generation scales. In 2020, ten years after its introduction a cross-cultural study of the use of BNSS found valid and reliable psychometric evidence for the five-domain structure cross-culturally. The BNSS is designed to assess both the presence and severity and change of negative symptoms of the five recognised domains, and the additional item of reduced normal distress. BNSS can register changes in negative symptoms in relation to psychosocial and pharmacological intervention trials. BNSS has also been used to study a proposed non-D2 treatment called SEP-363856. Findings supported the favouring of five domains over the two-dimensional proposition.

Cognitive Symptoms

Cognitive deficits are the earliest and most constantly found symptoms in schizophrenia. They are often evident long before the onset of illness in the prodromal stage, and may be present in early adolescence, or childhood. They are a core feature but not considered to be core symptoms, as are positive and negative symptoms. However, their presence and degree of dysfunction is taken as a better indicator of functionality than the presentation of core symptoms. Cognitive deficits become worse at first episode psychosis but then return to baseline, and remain fairly stable over the course of the illness.

The deficits in cognition are seen to drive the negative psychosocial outcome in schizophrenia, and are claimed to equate to a possible reduction in IQ from the norm of 100 to 70-85. Cognitive deficits may be of neurocognition (non-social) or of social cognition. Neurocognition is the ability to receive and remember information, and includes verbal fluency, memory, reasoning, problem solving, speed of processing, and auditory and visual perception. Verbal memory and attention are seen to be the most affected. Verbal memory impairment is associated with a decreased level of semantic processing (relating meaning to words). Another memory impairment is that of episodic memory. An impairment in visual perception that is consistently found in schizophrenia is that of visual backward masking. Visual processing impairments include an inability to perceive complex visual illusions. Social cognition is concerned with the mental operations needed to interpret, and understand the self and others in the social world. This is also an associated impairment, and facial emotion perception is often found to be difficult. Facial perception is critical for ordinary social interaction. Cognitive impairments do not usually respond to antipsychotics, and there are a number of interventions that are used to try to improve them; cognitive remediation therapy has been found to be of particular help.

Onset

Onset typically occurs between the late teens and early 30s, with the peak incidence occurring in males in the early to mid twenties, and in females in the late twenties. Onset before the age of 17 is known as early-onset, and before the age of 13, as can sometimes occur, is known as childhood schizophrenia or very early-onset. A later stage of onset can occur between the ages of 40 and 60, known as late-onset schizophrenia. A later onset over the age of 60, which may be difficult to differentiate as schizophrenia, is known as very-late-onset schizophrenia-like psychosis. Late onset has shown that a higher rate of females are affected; they have less severe symptoms and need lower doses of antipsychotics. The tendency for earlier onset in males is later seen to be balanced by a post-menopausal increase in the development in females. Oestrogen produced pre-menopause has a dampening effect on dopamine receptors but its protection can be overridden by a genetic overload. There has been a dramatic increase in the numbers of older adults with schizophrenia. An estimated 70% of those with schizophrenia have cognitive deficits, and these are most pronounced in early onset and late-onset illness.

Onset may happen suddenly or may occur after the slow and gradual development of a number of signs and symptoms, a period known as the prodromal stage. Up to 75% of those with schizophrenia go through a prodromal stage. The negative and cognitive symptoms in the prodrome stage can precede FEP by many months and up to five years. The period from FEP and treatment is known as the duration of untreated psychosis (DUP) which is seen to be a factor in functional outcome. The prodromal stage is the high-risk stage for the development of psychosis. Since the progression to first episode psychosis is not inevitable, an alternative term is often preferred of at risk mental state Cognitive dysfunction at an early age impact a young person’s usual cognitive development. Recognition and early intervention at the prodromal stage would minimize the associated disruption to educational and social development and has been the focus of many studies. It is suggested that the use of anti-inflammatory compounds such as D-serine may prevent the transition to schizophrenia. Cognitive symptoms are not secondary to positive symptoms or to the side effects of antipsychotics.

Cognitive impairments in the prodromal stage become worse after first episode psychosis (after which they return to baseline and then remain fairly stable), making early intervention to prevent such transition of prime importance. Early treatment with cognitive behavioural therapies are the gold standard. Neurological soft signs of clumsiness and loss of fine motor movement are often found in schizophrenia, which may resolve with effective treatment of FEP.

Risk Factors

Schizophrenia is described as a neurodevelopmental disorder with no precise boundary, or single cause, and is thought to develop from gene-environment interactions with involved vulnerability factors. The interactions of these risk factors are complex, as numerous and diverse insults from conception to adulthood can be involved. A genetic predisposition on its own, without interacting environmental factors, will not give rise to the development of schizophrenia. The genetic component means that prenatally brain development is disturbed, and environmental influence affects the postnatal development of the brain. Evidence suggests that genetically susceptible children are more likely to be vulnerable to the effects of environmental risk factors.

Genetic

Estimates of the heritability of schizophrenia are between 70% and 80%, which implies that 70% to 80% of the individual differences in risk to schizophrenia is associated with genetics. These estimates vary because of the difficulty in separating genetic and environmental influences, and their accuracy has been queried. The greatest risk factor for developing schizophrenia is having a first-degree relative with the disease (risk is 6.5%); more than 40% of identical twins of those with schizophrenia are also affected. If one parent is affected the risk is about 13% and if both are affected the risk is nearly 50%. However, DSM-5 points out that most people with schizophrenia have no family history of psychosis. Results of candidate gene studies of schizophrenia have generally failed to find consistent associations, and the genetic loci identified by genome-wide association studies explain only a small fraction of the variation in the disease.

Many genes are known to be involved in schizophrenia, each with small effect and unknown transmission and expression. The summation of these effect sizes into a polygenic risk score can explain at least 7% of the variability in liability for schizophrenia. Around 5% of cases of schizophrenia are understood to be at least partially attributable to rare copy-number variations (CNVs); these structural variations are associated with known genomic disorders involving deletions at 22q11.2 (DiGeorge syndrome), duplications at 16p11.2 16p11.2 duplication (most frequently found) and deletions at 15q11.2 (Burnside-Butler syndrome). Some of these CNVs increase the risk of developing schizophrenia by as much as 20-fold, and are frequently comorbid with autism and intellectual disabilities.

The genes CRHR1 and CRHBP have been shown to be associated with a severity of suicidal behaviour. These genes code for stress response proteins needed in the control of the HPA axis, and their interaction can affect this axis. Response to stress can cause lasting changes in the function of the HPA axis possibly disrupting the negative feedback mechanism, homeostasis, and the regulation of emotion leading to altered behaviours.

The question of how schizophrenia could be primarily genetically influenced, given that people with schizophrenia have lower fertility rates, is a paradox. It is expected that genetic variants that increase the risk of schizophrenia would be selected against due to their negative effects on reproductive fitness. A number of potential explanations have been proposed, including that alleles associated with schizophrenia risk confers a fitness advantage in unaffected individuals. While some evidence has not supported this idea, others propose that a large number of alleles each contributing a small amount can persist.

Environmental

Environmental factors, each associated with a slight risk of developing schizophrenia in later life include oxygen deprivation, infection, prenatal maternal stress, and malnutrition in the mother during prenatal development. A risk is also associated with maternal obesity, in increasing oxidative stress, and dysregulating the dopamine and serotonin pathways. Both maternal stress and infection have been demonstrated to alter foetal neurodevelopment through an increase of pro-inflammatory cytokines. There is a slighter risk associated with being born in the winter or spring possibly due to vitamin D deficiency or a prenatal viral infection. Other infections during pregnancy or around the time of birth that have been linked to an increased risk include infections by Toxoplasma gondii and Chlamydia. The increased risk is about 5-8%. Viral infections of the brain during childhood are also linked to a risk of schizophrenia during adulthood.

Adverse childhood experiences (ACEs), severe forms of which are classed as childhood trauma, range from being bullied or abused, to the death of a parent. Many adverse childhood experiences can cause toxic stress and increase the risk of psychosis. Chronic trauma can promote lasting inflammatory dysregulation throughout the nervous system. It is suggested that early stress may contribute to the development of schizophrenia through these alterations in the immune system. Schizophrenia was the last diagnosis to benefit from the link made between ACEs and adult mental health outcomes.

Living in an urban environment during childhood or as an adult has consistently been found to increase the risk of schizophrenia by a factor of two, even after taking into account drug use, ethnic group, and size of social group. A possible link between the urban environment and pollution has been suggested to be the cause of the elevated risk of schizophrenia.

Other risk factors of importance include social isolation, immigration related to social adversity and racial discrimination, family dysfunction, unemployment, and poor housing conditions. Having a father older than 40 years, or parents younger than 20 years are also associated with schizophrenia. It has been suggested that apart from gene-environment interactions, environment-environment interactions also be taken into account as each environmental risk factor on its own is not enough.

Substance Use

About half of those with schizophrenia use recreational drugs, including cannabis, tobacco, and alcohol excessively. Use of stimulants such as amphetamine and cocaine can lead to a temporary stimulant psychosis, which presents very similarly to schizophrenia. Rarely, alcohol use can also result in a similar alcohol-related psychosis. Drugs may also be used as coping mechanisms by people who have schizophrenia, to deal with depression, anxiety, boredom, and loneliness. The use of cannabis and tobacco are not associated with the development of cognitive deficits, and sometimes a reverse relationship is found where their use improves these symptoms. However, substance abuse is associated with an increased risk of suicide, and a poor response to treatment.

Cannabis-use may be a contributory factor in the development of schizophrenia, potentially increasing the risk of the disease in those who are already at risk. The increased risk may require the presence of certain genes within an individual. Its use is associated with doubling the rate. The use of more potent strains of cannabis having a high level of its active ingredient tetrahydrocannabinol (THC), increases the risk further. One of these strains is well known as skunk.

Mechanisms

The mechanisms of schizophrenia are unknown, and a number of models have been put forward to explain the link between altered brain function and schizophrenia. The prevailing model of schizophrenia is that of a neurodevelopmental disorder, and the underlying changes that occur before symptoms become evident are seen as arising from the interaction between genes and the environment. Extensive studies support this model. Maternal infections, malnutrition and complications during pregnancy and childbirth are known risk factors for the development of schizophrenia, which usually emerges between the ages of 18-25 a period that overlaps with certain stages of neurodevelopment. Gene-environment interactions lead to deficits in the neural circuitry that affect sensory and cognitive functions.

The common dopamine and glutamate models proposed are not mutually exclusive; each is seen to have a role in the neurobiology of schizophrenia. The most common model put forward was the dopamine hypothesis of schizophrenia, which attributes psychosis to the mind’s faulty interpretation of the misfiring of dopaminergic neurons. This has been directly related to the symptoms of delusions and hallucinations. Abnormal dopamine signalling has been implicated in schizophrenia based on the usefulness of medications that affect the dopamine receptor and the observation that dopamine levels are increased during acute psychosis. A decrease in D1 receptors in the dorsolateral prefrontal cortex may also be responsible for deficits in working memory.

The glutamate hypothesis of schizophrenia links alterations between glutamatergic neurotransmission and the neural oscillations that affect connections between the thalamus and the cortex. Studies have shown that a reduced expression of a glutamate receptor – NMDA receptor, and glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with schizophrenia. Post-mortem studies consistently find that a subset of these neurons fail to express GAD67 (GAD1), in addition to abnormalities in brain morphometry. The subsets of interneurons that are abnormal in schizophrenia are responsible for the synchronising of neural ensembles needed during working memory tasks. These give the neural oscillations produced as gamma waves that have a frequency of between 30 and 80 hertz. Both working memory tasks and gamma waves are impaired in schizophrenia, which may reflect abnormal interneuron functionality.

Deficits in executive functions, such as planning, inhibition, and working memory, are pervasive in schizophrenia. Although these functions are separable, their dysfunction in schizophrenia may reflect an underlying deficit in the ability to represent goal related information in working memory, and to utilize this to direct cognition and behaviour. These impairments have been linked to a number of neuroimaging and neuropathological abnormalities. For example, functional neuroimaging studies report evidence of reduced neural processing efficiency, whereby the dorsolateral prefrontal cortex is activated to a greater degree to achieve a certain level of performance relative to controls on working memory tasks. These abnormalities may be linked to the consistent post-mortem finding of reduced neuropil, evidenced by increased pyramidal cell density and reduced dendritic spine density. These cellular and functional abnormalities may also be reflected in structural neuroimaging studies that find reduced grey matter volume in association with deficits in working memory tasks.

Positive symptoms have been linked to cortical thinning in the superior temporal gyrus. Severity of negative symptoms has been linked to reduced thickness in the left medial orbitofrontal cortex. Anhedonia, traditionally defined as a reduced capacity to experience pleasure, is frequently reported in schizophrenia. However, a large body of evidence suggests that hedonic responses are intact in schizophrenia, and that what is reported to be anhedonia is a reflection of dysfunction in other processes related to reward. Overall, a failure of reward prediction is thought to lead to impairment in the generation of cognition and behaviour required to obtain rewards, despite normal hedonic responses.

It has been hypothesized that in some people, development of schizophrenia is related to intestinal tract dysfunction such as seen with non-celiac gluten sensitivity or abnormalities in the gut microbiota. A subgroup of persons with schizophrenia present an immune response to gluten differently from that found in people with celiac, with elevated levels of certain serum biomarkers of gluten sensitivity such as anti-gliadin IgG or anti-gliadin IgA antibodies.

Another theory links abnormal brain lateralization to the development of being left-handed which is significantly more common in those with schizophrenia. This abnormal development of hemispheric asymmetry is noted in schizophrenia. Studies have concluded that the link is a true and verifiable effect that may reflect a genetic link between lateralisation and schizophrenia.

An important process that may be disrupted in neurodevelopment is astrogenesis – the formation of astrocytes. Astrocytes are crucial in contributing to the formation and maintenance of neural circuits and it is believed that disruption in this role can result in a number of neurodevelopmental disorders including schizophrenia.

Bayesian models of brain functioning have been utilised to link abnormalities in cellular functioning to symptoms. Both hallucinations and delusions have been suggested to reflect improper encoding of prior expectations, thereby causing expectation to excessively influence sensory perception and the formation of beliefs. In approved models of circuits that mediate predictive coding, reduced NMDA receptor activation, could in theory result in the positive symptoms of delusions and hallucinations.

Diagnosis

Refer to Diagnosis of Schizophrenia.

There is no objective test or biomarker to confirm diagnosis. Psychoses can occur in several conditions and are often transient making early diagnosis of schizophrenia difficult. Psychosis noted for the first time in a person that is later diagnosed with schizophrenia is referred to as a first-episode psychosis (FEP).

Criteria

Schizophrenia is diagnosed based on criteria in either the Diagnostic and Statistical Manual of Mental Disorders (DSM) published by the American Psychiatric Association or the International Statistical Classification of Diseases and Related Health Problems (ICD) published by the World Health Organization. These criteria use the self-reported experiences of the person and reported abnormalities in behaviour, followed by a psychiatric assessment. The mental status examination is an important part of the assessment. An established tool for assessing the severity of positive and negative symptoms is the Positive and Negative Syndrome Scale (PANSS). This has been seen to have shortcomings relating to negative symptoms, and other scales – the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptoms Scale (BNSS) have been introduced. The DSM-5, published in 2013, gives a Scale to Assess the Severity of Symptom Dimensions outlining eight dimensions of symptoms.

DSM-5 states that to be diagnosed with schizophrenia, two diagnostic criteria have to be met over the period of one month, with a significant impact on social or occupational functioning for at least six months. One of the symptoms needs to be either delusions, hallucinations, or disorganised speech. A second symptom could be one of the negative symptoms, or severely disorganised or catatonic behaviour. A different diagnosis of schizophreniform disorder can be made before the six months needed for the diagnosis of schizophrenia.

In Australia the guideline for diagnosis is for six months or more with symptoms severe enough to affect ordinary functioning. In the UK diagnosis is based on having the symptoms for most of the time for one month, with symptoms that significantly affect the ability to work, study, or to carry on ordinary daily living, and with other similar conditions ruled out.

The ICD criteria are typically used in European countries; the DSM criteria are used predominantly in the United States and Canada, and are prevailing in research studies. In practice, agreement between the two systems is high. The current proposal for the ICD-11 criteria for schizophrenia recommends adding self-disorder as a symptom.

A major unresolved difference between the two diagnostic systems is that of the requirement in DSM of an impaired functional outcome. WHO for ICD argues that not all people with schizophrenia have functional deficits and so these are not specific for the diagnosis.

Changes Made

Both manuals have adopted the chapter heading of Schizophrenia spectrum and other psychotic disorders; ICD modifying this as Schizophrenia spectrum and other primary psychotic disorders. The definition of schizophrenia remains essentially the same as that specified by the 2000 text revised DSM-IV (DSM-IV-TR). However, with the publication of DSM-5, the APA removed all sub-classifications of schizophrenia. ICD-11 has also removed subtypes. The removed subtype from both, of catatonic has been relisted in ICD-11 as a psychomotor disturbance that may be present in schizophrenia.

Another major change was to remove the importance previously given to Schneider’s first-rank symptoms. DSM-5 still uses the listing of schizophreniform disorder but ICD-11 no longer includes it. DSM-5 also recommends that a better distinction be made between a current condition of schizophrenia and its historical progress, to achieve a clearer overall characterisation.

A dimensional assessment has been included in DSM-5 covering eight dimensions of symptoms to be rated (using the Scale to Assess the Severity of Symptom Dimensions) – these include the five diagnostic criteria plus cognitive impairments, mania, and depression. This can add relevant information for the individual in regard to treatment, prognosis, and functional outcome; it also enables the response to treatment to be more accurately described.

Two of the negative symptoms – avolition and diminished emotional expression, have been given more prominence in both manuals.

Comorbidities

Many people with schizophrenia may have one or more other mental disorders, such as panic disorder, OCD, or substance use disorder. These are separate disorders that require treatment. When comorbid with schizophrenia, substance use disorder and antisocial personality disorder both increase the risk for violence. Comorbid substance abuse also increases risk for suicide.

Sleep disorders often co-occur with schizophrenia, and may be an early sign of relapse. Sleep disorders are linked with positive symptoms such as disorganised thinking and can adversely affect cortical plasticity and cognition. The consolidation of memories is disrupted in sleep disorders. They are associated with severity of illness, a poor prognosis, and poor quality of life. Sleep onset and maintenance insomnia is a common symptom, regardless of whether treatment has been received or not. Genetic variations have been found associated with these conditions involving the circadian rhythm, dopamine and histamine metabolism, and signal transduction. Limited positive evidence has been found for the use of acupuncture as an add-on.

Differential Diagnosis

To make a diagnosis of schizophrenia other possible causes of psychosis need to be excluded. Psychotic symptoms lasting less than a month may be diagnosed as brief psychotic disorder, or as schizophreniform disorder. Psychosis is noted in Other specified schizophrenia spectrum and other psychotic disorders as a DSM-5 category. Schizoaffective disorder is diagnosed if symptoms of mood disorder are substantially present alongside psychotic symptoms. Psychosis that results from a general medical condition or substance is termed secondary psychosis. Psychotic symptoms may be present in several other conditions, including bipolar disorder, borderline personality disorder, substance intoxication, substance-induced psychosis, and a number of drug withdrawal syndromes. Non-bizarre delusions are also present in delusional disorder, and social withdrawal in social anxiety disorder, avoidant personality disorder and schizotypal personality disorder. Schizotypal personality disorder has symptoms that are similar but less severe than those of schizophrenia. Schizophrenia occurs along with OCD considerably more often than could be explained by chance, although it can be difficult to distinguish obsessions that occur in OCD from the delusions of schizophrenia. There can be considerable overlap with the symptoms of post-traumatic stress disorder.

A more general medical and neurological examination may be needed to rule out medical illnesses which may rarely produce psychotic schizophrenia-like symptoms, such as metabolic disturbance, systemic infection, syphilis, HIV-associated neurocognitive disorder, epilepsy, limbic encephalitis, and brain lesions. Stroke, multiple sclerosis, hyperthyroidism, hypothyroidism, and dementias such as Alzheimer’s disease, Huntington’s disease, frontotemporal dementia, and the Lewy body dementias may also be associated with schizophrenia-like psychotic symptoms. It may be necessary to rule out a delirium, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, and indicates an underlying medical illness. Investigations are not generally repeated for relapse unless there is a specific medical indication or possible adverse effects from antipsychotic medication. In children hallucinations must be separated from typical childhood fantasies. It is difficult to distinguish childhood schizophrenia from autism.

Prevention

Prevention of schizophrenia is difficult as there are no reliable markers for the later development of the disorder. There is tentative though inconclusive evidence for the effectiveness of early intervention to prevent schizophrenia in the prodrome phase. There is some evidence that early intervention in those with first-episode psychosis may improve short-term outcomes, but there is little benefit from these measures after five years. Cognitive behavioural therapy (CBT) may reduce the risk of psychosis in those at high risk after a year and is recommended in this group, by the National Institute for Health and Care Excellence (NICE). Another preventive measure is to avoid drugs that have been associated with development of the disorder, including cannabis, cocaine, and amphetamines.

Antipsychotics are prescribed following a first-episode psychosis, and following remission a preventive maintenance use is continued to avoid relapse. However, it is recognised that some people do recover following a single episode and that long-term use of antipsychotics will not be needed but there is no way of identifying this group.

Management

The primary treatment of schizophrenia is the use of antipsychotic medications, often in combination with psychosocial interventions and social supports. Community support services including drop-in centres, visits by members of a community mental health team, supported employment, and support groups are common. The time between the onset of psychotic symptoms to being given treatment – the duration of untreated psychosis (DUP) is associated with a poorer outcome in both the short term and the long term.

Voluntary or involuntary admittance to hospital may be needed to treat a severe episode, however, hospital stays are as short as possible. In the UK large mental hospitals termed asylums began to be closed down in the 1950s with the advent of antipsychotics, and with an awareness of the negative impact of long-term hospital stays on recovery. This process was known as deinstitutionalisation, and community and supportive services were developed in order to support this change. Many other countries followed suit with the US starting in the 60s. There will still remain a few people who do not improve enough to be discharged. In those countries that lack the necessary supportive and social services long-term hospital stays are more usual.

Medication

The first-line treatment for schizophrenia is an antipsychotic. The first-generation antipsychotics, now called typical antipsychotics, are dopamine antagonists that block D2 receptors, and affect the neurotransmission of dopamine. Those brought out later, the second-generation antipsychotics known as atypical antipsychotics, can also have effect on another neurotransmitter, serotonin. Antipsychotics can reduce the symptoms of anxiety within hours of their use but for other symptoms they may take several days or weeks to reach their full effect. They have little effect on negative and cognitive symptoms, which may be helped by additional psychotherapies and medications. There is no single antipsychotic suitable for first-line treatment for everyone, as responses and tolerances vary between people. Stopping medication may be considered after a single psychotic episode where there has been a full recovery with no symptoms for twelve months. Repeated relapses worsen the long-term outlook and the risk of relapse following a second episode is high, and long-term treatment is usually recommended.

Tobacco smoking increases the metabolism of some antipsychotics, by strongly activating CYP1A2, the enzyme that breaks them down, and a significant difference is found in these levels between smokers and non-smokers. It is recommended that the dosage for those smokers on clozapine be increased by 50%, and for those on olanzapine by 30%. The result of stopping smoking can lead to an increased concentration of the antipsychotic that may result in toxicity, so that monitoring of effects would need to take place with a view to decreasing the dosage; many symptoms may be noticeably worsened, and extreme fatigue, and seizures are also possible with a risk of relapse. Likewise those who resume smoking may need their dosages adjusted accordingly. The altering effects are due to compounds in tobacco smoke and not to nicotine; the use of nicotine replacement therapy therefore has the equivalent effect of stopping smoking and monitoring would still be needed.

About 30-50% of people with schizophrenia fail to accept that they have an illness or comply with their recommended treatment. For those who are unwilling or unable to take medication regularly, long-acting injections of antipsychotics may be used, which reduce the risk of relapse to a greater degree than oral medications. When used in combination with psychosocial interventions, they may improve long-term adherence to treatment.

Research findings suggested that other neurotransmission systems, including serotonin, glutamate, GABA, and acetycholine, were implicated in the development of schizophrenia, and that a more inclusive medication was needed. A new first-in-class antipsychotic that targets multiple neurotransmitter systems called lumateperone (ITI-007), was trialled and approved by the FDA in December 2019 for the treatment of schizophrenia in adults. Lumateperone is a small molecule agent that shows improved safety, and tolerance. It interacts with dopamine, serotonin, and glutamate in a complex, uniquely selective manner, and is seen to improve negative and positive symptoms, and social functioning. Lumateperone was also found to reduce potential metabolic dysfunction, have lower rates of movement disorders, and have lower cardiovascular side effects such as a fast heart rate.

Side Effects

Typical antipsychotics are associated with a higher rate of movement disorders including akathisia. Some atypicals are associated with considerable weight gain, diabetes and the risk of metabolic syndrome. Risperidone (atypical) has a similar rate of extrapyramidal symptoms to haloperidol (typical). A rare but potentially lethal condition of neuroleptic malignant syndrome (NMS) has been associated with the use of antipsychotics. Through its early recognition, and timely intervention rates have declined. However, an awareness of the syndrome is advised to enable intervention. Another less rare condition of tardive dyskinesia can occur due to long-term use of antipsychotics, developing after many months or years of use. It is more often reported with use of typical antipsychotics.

Clozapine is associated with side effects that include weight gain, tiredness, and hypersalivation. More serious adverse effects include seizures, NMS, neutropenia, and agranulocytosis (lowered white blood cell count) and its use needs careful monitoring. Studies have found that antipsychotic treatment following NMS and neutropenia may sometimes be successfully re-challenged (restarted) with clozapine.

Clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy. A systematic review of clozapine-associated pulmonary embolism indicates that this adverse effect can often be fatal, and that it has an early onset, and is dose-dependent. The findings advised the consideration of using a prevention therapy for venous thromboembolism after starting treatment with clozapine, and continuing this for six months. Constipation is three times more likely to occur with the use of clozapine, and severe cases can lead to ileus and bowel ischemia resulting in many fatalities.

However, the risk of serious adverse effects from clozapine is low, and there are the beneficial effects to be gained of a reduced risk of suicide, and aggression. Typical antipsychotics and atypical risperidone can have a side effect of sexual dysfunction. Clozapine, olanzapine, and quetiapine are associated with beneficial effects on sexual functioning helped by various psychotherapies. Unwanted side effects cause people to stop treatment, resulting in relapses.

Treatment Resistant Schizophrenia

About half of those with schizophrenia will respond favourably to antipsychotics, and have a good return of functioning. However, positive symptoms persist in up to a third of people. Following two trials of different antipsychotics over six weeks, that also prove ineffective, they will be classed as having treatment resistant schizophrenia (TRS), and clozapine will be offered. Clozapine is of benefit to around half of this group although it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people. Between 12-20% will not respond to clozapine and this group is said to have ultra treatment resistant schizophrenia. ECT may be offered to treat TRS as an add-on therapy, and is shown to sometimes be of benefit. A review concluded that this use only has an effect on medium-term TRS and that there is not enough evidence to support its use other than for this group.

TRS is often accompanied by a low quality of life, and greater social dysfunction. TRS may be the result of inadequate rather than inefficient treatment; it also may be a false label due to medication not being taken regularly, or at all. About 16% of people who had initially been responsive to treatment later develop resistance. This could relate to the length of time on APs, with treatment becoming less responsive. This finding also supports the involvement of dopamine in the development of schizophrenia. Studies suggest that TRS may be a more heritable form.

TRS may be evident from first episode psychosis, or from a relapse. It can vary in its intensity and response to other therapies. This variation is seen to possibly indicate an underlying neurobiology such as dopamine super-sensitivity (DSS), glutamate or serotonin dysfunction, inflammation and oxidative stress. Studies have found that dopamine super-sensitivity is found in up to 70% of those with TRS. The variation has led to the suggestion that treatment responsive and treatment resistant schizophrenia be considered as two different subtypes. It is further suggested that if the subtypes could be distinguished at an early stage significant implications could follow for treatment considerations, and for research. Neuroimaging studies have found a significant decrease in the volume of grey matter in those with TRS with no such change seen in those who are treatment responsive. In those with ultra treatment resistance the decrease in grey matter volume was larger.

A link has been made between the gut microbiota and the development of TRS. The most prevalent cause put forward for TRS is that of mutation in the genes responsible for drug effectiveness. These include liver enzyme genes that control the availability of a drug to brain targets, and genes responsible for the structure and function of these targets. In the colon the bacteria encode a hundred times more genes than exist in the human genome. Only a fraction of ingested drugs reach the colon, having been already exposed to small intestinal bacteria, and absorbed in the portal circulation. This small fraction is then subject to the metabolic action of many communities of bacteria. Activation of the drug depends on the composition and enzymes of the bacteria and of the specifics of the drug, and therefore a great deal of individual variation can affect both the usefulness of the drug and its tolerability. It is suggested that parenteral administration of antipsychotics would bypass the gut and be more successful in overcoming TRS. The composition of gut microbiota is variable between individuals, but they are seen to remain stable. However, phyla can change in response to many factors including ageing, diet, substance-use, and medications – especially antibiotics, laxatives, and antipsychotics. In FEP, schizophrenia has been linked to significant changes in the gut microbiota that can predict response to treatment.

Psychosocial Interventions

A number of psychosocial interventions that include several types of psychotherapy may be useful in the treatment of schizophrenia such as: family therapy, group therapy, cognitive remediation therapy, CBT, and metacognitive training. Skills training, and help with substance use, and weight management – often needed as a side effect of an antipsychotic, are also offered. In the US, interventions for first episode psychosis have been brought together in an overall approach known as coordinated speciality care (CSC) and also includes support for education. In the UK care across all phases is a similar approach that covers many of the treatment guidelines recommended. The aim is to reduce the number of relapses and stays in hospital.

Other support services for education, employment, and housing are usually offered. For people suffering from severe schizophrenia, and discharged from a stay in hospital, these services are often brought together in an integrated approach to offer support in the community away from the hospital setting. In addition to medicine management, housing, and finances, assistance is given for more routine matters such as help with shopping and using public transport. This approach is known as assertive community treatment (ACT) and has been shown to achieve positive results in symptoms, social functioning and quality of life. Another more intense approach is known as intensive care management (ICM). ICM is a stage further than ACT and emphasises support of high intensity in smaller caseloads, (less than twenty). This approach is to provide long-term care in the community. Studies show that ICM improves many of the relevant outcomes including social functioning.

Some studies have shown little evidence for the effectiveness of CBT in either reducing symptoms or preventing relapse. However, other studies have found that CBT does improve overall psychotic symptoms (when in use with medication) and has been recommended in Canada, but it has been seen here to have no effect on social function, relapse, or quality of life. In the UK it is recommended as an add-on therapy in the treatment of schizophrenia, but is not supported for use in treatment resistant schizophrenia. Arts therapies are seen to improve negative symptoms in some people, and are recommended by NICE in the UK. This approach however, is criticised as having not been well-researched, and arts therapies are not recommended in Australian guidelines for example. Peer support, in which people with personal experience of schizophrenia, provide help to each other, is of unclear benefit.

Other

Exercise including aerobic exercise has been shown to improve positive and negative symptoms, cognition, working memory, and improve quality of life. Exercise has also been shown to increase the volume of the hippocampus in those with schizophrenia. A decrease in hippocampal volume is one of the factors linked to the development of the disease. However, there still remains the problem of increasing motivation for, and maintaining participation in physical activity. Supervised sessions are recommended. In the UK healthy eating advice is offered alongside exercise programmes.

An inadequate diet is often found in schizophrenia, and associated vitamin deficiencies including those of folate, and vitamin D are linked to the risk factors for the development of schizophrenia and for early death including heart disease. Those with schizophrenia possibly have the worst diet of all the mental disorders. Lower levels of folate and vitamin D have been noted as significantly lower in first episode psychosis. The use of supplemental folate is recommended. A zinc deficiency has also been noted. Vitamin B12 is also often deficient and this is linked to worse symptoms. Supplementation with B vitamins has been shown to significantly improve symptoms, and to put in reverse some of the cognitive deficits. It is also suggested that the noted dysfunction in gut microbiota might benefit from the use of probiotics.

Violence

Most people with schizophrenia are not aggressive, and are more likely to be victims of violence rather than perpetrators. However, though the risk of violence in schizophrenia is small the association is consistent, and there are minor subgroups where the risk is high. This risk is usually associated with a comorbid disorder such as a substance use disorder – in particular alcohol, or with antisocial personality disorder. Substance abuse is strongly linked, and other risk factors are linked to deficits in cognition and social cognition including facial perception and insight that are in part included in theory of mind impairments. Poor cognitive functioning, decision-making, and facial perception may contribute to making a wrong judgement of a situation that could result in an inappropriate response such as violence. These associated risk factors are also present in antisocial personality disorder which when present as a comorbid disorder greatly increases the risk of violence.

A review in 2012 showed that schizophrenia was responsible for 6% of homicides in Western countries. Another wider review put the homicide figure at between 5-20%. There was found to be a greater risk of homicide during first episode psychosis that accounted for 38.5% of homicides. The association between schizophrenia and violence is complex. Homicide is linked with young age, male sex, a history of violence, and a stressful event in the preceding year. Clinical risk factors are severe untreated psychotic symptoms – untreated due to either not taking medication or to the condition being treatment resistant. A comorbid substance use disorder or an antisocial personality disorder increases the risk for homicidal behaviour by 8-fold, in contrast to the 2-fold risk in those without the comorbid disorders. Rates of homicide linked to psychosis are similar to those linked to substance misuse, and parallel the overall rate in a region. What role schizophrenia has on violence independent of substance misuse is controversial, but certain aspects of individual histories or mental states may be factors.

Hostility is anger felt and directed at a person or group and has related dimensions of impulsiveness and aggression. When this impulsive-aggression is evident in schizophrenia neuroimaging has suggested the malfunctioning of a neural circuit that modulates hostile thoughts and behaviours that are linked with negative emotions in social interactions. This circuit includes the amygdala, striatum, prefrontal cortex, anterior cingulate cortex, insula, and hippocampus. Hostility has been reported during acute psychosis, and following hospital discharge. There is a known association between low cholesterol levels, and impulsivity, and violence. A review finds that people with schizophrenia, and lower cholesterol levels are four times more likely to instigate violent acts. This association is also linked to the increased number of suicides in schizophrenia. It is suggested that cholesterol levels could serve as a biomarker for violent and suicidal tendencies.

A review found that just under 10% of those with schizophrenia showed violent behaviour compared to 1.6% of the general population. An excessive risk of violence is associated with drugs or alcohol and increases the risk by as much as 4-fold. Violence often leads to imprisonment. Clozapine is an effective medication that can be used in penal settings such as prisons. However, a condition of benign ethnic neutropenia in many African-Americans excludes them from the use of clozapine the most effective medication. Cognitive deficits are recognised as playing an important part in the origin and maintenance of aggression, and cognitive remediation therapy may therefore help to prevent the risk of violence in schizophrenia.

Prognosis

Schizophrenia has great human and economic costs. It results in a decreased life expectancy of 20 years. This is primarily because of its association with obesity, poor diet, a sedentary lifestyle, and smoking, with an increased rate of suicide playing a lesser role. Side effects of antipsychotics may also increase the risk. These differences in life expectancy increased between the 1970s and 1990s. An Australian study puts the rate of early death at 25 years, and views the main cause to be related to heart disease.

Several studies indicate that almost 40% of those with schizophrenia die from complications of cardiovascular disease including heart attacks, and sudden cardiac death which is seen to be increasingly associated. An underlying factor of sudden cardiac death may be Brugada syndrome (BrS) – BrS mutations that overlap with those linked with schizophrenia are the calcium channel mutations. BrS may also be drug-induced from certain antipsychotics and antidepressants. Primary polydipsia, or excessive fluid intake, is relatively common in people with chronic schizophrenia. This may lead to hyponatremia which can be life-threatening. Antipsychotics can lead to a dry mouth, but there are several other factors that may contribute to the disorder. It is suggested to lead to a reduction in life expectancy by 13%. A study has suggested that real barriers to improving the mortality rate in schizophrenia are poverty, overlooking the symptoms of other illnesses, stress, stigma, and medication side effects, and that these need to be changed.

Schizophrenia is a major cause of disability. In 2016 it was classed as the 12th most disabling condition. Approximately 75% of people with schizophrenia have ongoing disability with relapses and 16.7 million people globally are deemed to have moderate or severe disability from the condition. Some people do recover completely and others function well in society. Most people with schizophrenia live independently with community support. About 85% are unemployed. In people with a first episode of psychosis in schizophrenia a good long-term outcome occurs in 31%, an intermediate outcome in 42% and a poor outcome in 31%. Males are affected more often than females, and have a worse outcome. Outcomes for schizophrenia appear better in the developing than the developed world. These conclusions have been questioned. Social problems, such as long-term unemployment, poverty, homelessness, exploitation, stigmatisation and victimisation are common consequences, and lead to social exclusion.

There is a higher than average suicide rate associated with schizophrenia estimated at around 5% to 6%, most often occurring in the period following onset or first hospital admission. Several times more (20 to 40%) attempt suicide at least once. There are a variety of risk factors, including male gender, depression, a high IQ, heavy smoking, and substance abuse. Repeated relapse is linked to an increased risk of suicidal behaviour. The use of clozapine can reduce the risk of suicide and aggression.

A strong association between schizophrenia and tobacco smoking has been shown in worldwide studies. Smoking is especially high in those diagnosed with schizophrenia, with estimates ranging from 80 to 90% being regular smokers, as compared to 20% of the general population. Those who smoke tend to smoke heavily, and additionally smoke cigarettes with high nicotine content. Some propose that this is in an effort to improve symptoms. Among people with schizophrenia use of cannabis is also common.

Society and Culture

In 2002, the term for schizophrenia in Japan was changed from seishin-bunretsu-byō (精神分裂病, lit. “mind-split disease”) to tōgō-shitchō-shō (統合失調症, lit. “integration-dysregulation syndrome”) to reduce stigma. The new name also interpreted as “integration disorder” was inspired by the biopsychosocial model; it increased the percentage of people who were informed of the diagnosis from 37 to 70% over three years. A similar change was made in South Korea in 2012 to attunement disorder. A professor of psychiatry, Jim van Os, has proposed changing the English term to psychosis spectrum syndrome. In 2013 with the reviewed DSM-5, the DSM-5 committee was in favour of giving a new name to schizophrenia but they referred this to WHO.

In the United States, the cost of schizophrenia – including direct costs (outpatient, inpatient, drugs, and long-term care) and non-health care costs (law enforcement, reduced workplace productivity, and unemployment) – was estimated to be $62.7 billion in 2002. In the UK the cost in 2016 was put at £11.8 billion per year with a third of that figure directly attributable to the cost of hospital and social care, and treatment.

The book A Beautiful Mind chronicled the life of John Forbes Nash who had been diagnosed with schizophrenia but who went on to win the Nobel Memorial Prize in Economic Sciences. This was later made into the film with the same name. An earlier documentary was made with the title A Brilliant Madness.

In 1964, a lengthy case study of three males diagnosed with schizophrenia who each had the delusional belief that they were Jesus Christ was published as a book. This has the title of The Three Christs of Ypsilanti, and a film with the title Three Christs was released in 2020. Such religious delusions are a fairly common feature in psychoses including schizophrenia.

Media coverage relating to violent acts by people with schizophrenia reinforces public perception of an association between schizophrenia and violence. Such sensationalist reporting stigmatizes schizophrenia more than any other mental illness. In the UK guidelines are given for the reporting of different conditions. Its campaigns have shown a reduction in negative reporting.

Research Directions

Research into schizophrenia has made use of a number of animal models in particular rats, that have shown to be useful in evaluating the different aspects of its development and pathology. Effects of early intervention is an active area of research, importantly focusing on the early detection of at-risk individuals and the development of risk calculators. Methods for large-scale population screening are also included.

Various agents have been explored for possible effectiveness in treating negative symptoms, for which antipsychotics have been of little benefit. There have been trials on medications with anti-inflammatory activity, based on the premise that inflammation might play a role in the pathology of schizophrenia.

Various brain stimulation techniques are being studied to treat the positive symptoms of schizophrenia, in particular auditory verbal hallucinations (AVHs). A 2015 Cochrane review found unclear evidence of benefit. Most studies focus on transcranial direct-current stimulation (tDCM), and repetitive transcranial magnetic stimulation (rTMS). Techniques based on focused ultrasound for deep brain stimulation could provide insight for the treatment of AVHs.

Another active area of research is the study of a variety of potential biomarkers that would be of invaluable help not only in the diagnosis but also in the treatment and prognosis of schizophrenia. Possible biomarkers include markers of inflammation, neuroimaging, BDNF, genetics, and speech analysis. Some inflammatory markers such as C-reactive protein are useful in detecting levels of inflammation implicated in some psychiatric disorders but they are not disorder-specific. However, other inflammatory cytokines are found to be elevated in first episode psychosis and acute relapse that are normalised after treatment with antipsychotics, and these may be considered as state markers. Deficits in sleep spindles in schizophrenia may serve as a marker of an impaired thalamocortical circuit, and a mechanism for memory impairment. MicroRNAs are highly influential in early neuronal development, and their disruption is implicated in several CNS disorders; circulating microRNAs (cimiRNAs) are found in body fluids such as blood and cerebrospinal fluid, and changes in their levels are seen to relate to changes in microRNA levels in specific regions of brain tissue. These studies suggest that cimiRNAs have the potential to be early and accurate biomarkers in a number of disorders including schizophrenia.

The use of choline as a supplement during pregnancy may have effect in the prevention of the later development of schizophrenia, and is an area of research.

In 2020, over 3,000 clinical trials into drugs, symptom assessment tools, and treatments related to schizophrenia were listed with some recruiting, and some newly completed.

With Regard to Mental Health & Substance Use Disorders what is the Reality of Youth in Custody?

Research Paper Title

Mental health and substance use disorders: The reality of youth in custody.

Background

Young offenders experience a higher prevalence of mental health disorders and substance use disorders than the general population, estimated to be between 70% and 90% (Indig et al. 2011; Kenny et al., 2006; Lader et al., 2000; Teplin et al., 2002). In addition, comorbidities affect many young offenders, with over 60% presenting with two or more disorders (Justice Health & Forensic Mental Health Network and Juvenile Justice NSW, 2015). The prevalence of mental health disorders is higher among females, with young female offenders more likely to be diagnosed with anxiety and depressive disorders, as well as substance‐induced disorders (Justice Health & Forensic Mental Health Network and Juvenile Justice NSW, 2015).

Aboriginal and Torres Strait Islander youth are over‐represented within the juvenile justice system. In a report by the Australian Institute of Health and Welfare, it was found that 50% of young offenders in 2016-2017 identified as Aboriginal and/or Torres Strait Islander (Australian Institute of Health and Welfare 2018). Mental health and substance use disorders are the most common non‐communicable diseases among this group with 33% reporting high to very high levels of psychological distress (Azzopardi et al. 2018). Furthermore, there is evidence to suggest that poor family cohesion and the presence of adverse events in this group of adolescents are a reliable predictor of negative mental health outcomes (Young et al. 2016).

A recent Australian study reported the strongest predictor of incarceration and re‐incarceration was problematic alcohol and drug use (Indig et al., 2016). Indig et al. found that young people who were heavy drinkers were seven times more likely to have been previously incarcerated and three times more likely to be re‐incarcerated within 18 months. Indig et al. (2016) also found that illicit substance use was a consistent predictor of incarceration and re‐incarceration.

In addition to issues with drugs and alcohol, many incarcerated young people also report experiencing adverse childhood experiences during their childhood years with as many as 90% reporting at least one traumatic event (Ford et al., 2012). A recent Australian study found that 60% of young offenders reported a history of child abuse or neglect, 20% met the criteria for posttraumatic stress disorder (PTSD) (Moore et al. 2013). A history of adverse childhood experiences is the main predictor of a diagnosis of PTSD (Moore et al. 2013). Evidence suggests a link between exposure to adverse childhood experiences and the occurrence of various mental health difficulties among young offenders (McReynolds & Wasserman, 2011; Wasserman & McReynolds, 2011; Wilson et al., 2009).

It is unfortunate that many troubled youth are not recognized as being distressed or having mental health difficulties, and so do not have access to appropriate mental health care. Furthermore, these young people and their families may have very low levels of mental health literacy. However, once these young people come to the attention of the justice system, we have an opportunity to raise mental health literacy and provide appropriate services. There is a need for programmes and services that address mental health and substance use issues to assist young people improve their health outcomes and reduce their offending behaviours. Programmes such as monthly recovery management check‐ups in the first 90 days postrelease could help to achieve this outcome (Indig et al., 2016).

Given the high rate of adverse childhood experiences in incarcerated youth and the known link to PTSD, we need to ensure that services are informed by a trauma informed approach (Moore et al. 2013). There is also an identified need to invest in prevention and early intervention for young people. Currently, there are diversion programmes offered within the local court system in NSW for adult offenders exhibiting mental health (Statewide Community & Court Liaison Service) or substance use disorders (Magistrates Early Referral Into Treatment (MERIT)). However, these programmes are not available to offenders under the age of 18 years and adolescent diversion programmes are not routinely or diversely available to young people residing outside of the Sydney metropolitan area.

The mental health and substance use issues affecting young offenders challenge us to respond with effective interventions. Mental health nurses have an important role to play in improving the services and interventions available to these young people. Changes have been made to services for young offenders but more needs to be done. Research has shown that diversion and treatment services delivered in the community using a trauma informed approach are more effective in this population (Dierkhising et al. 2013). Moving forward, mental health nurses have an opportunity to take the lead in this important area.

Reference

Usher, K., Douglas, L. & Jackson, D. (2020) Mental health and substance use disorders: The reality of youth in custody. International Journal of Mental Health Nursing. 28(3). https://doi.org/10.1111/inm.12597.

What is the Social Impact of Health Insurance Care Utilisation in Low- & Middle-Income Countries?

Research Paper Title

The impact of social, national and community-based health insurance on health care utilisation for mental, neurological and substance-use disorders in low- and middle-income countries: a systematic review.

Background

Whilst several systematic reviews conducted in Low- and Middle-Income Countries (LMICs) have revealed that coverage under social (SHI), national (NHI) and community-based (CBHI) health insurance has led to increased utilisation of health care services, it remains unknown whether, and what aspects of, these shifts in financing result in improvements to mental health care utilisation.

The main aim of this review was to examine the impact of SHI, NHI and CBHI enrolment on mental health care utilisation in LMICs.

Methods

Systematic searches were performed in nine databases of peer-reviewed journal articles: Pubmed, Scopus, SciELO via Web of Science, Africa Wide, CINAHL, PsychInfo, Academic Search Premier, Health Source Nursing Academic and EconLit for studies published before October 2018.

The quality of the studies was assessed using the Effective Public Health Practice Project quality assessment tool for quantitative studies.

Results

Eighteen studies were included in the review.

Despite some heterogeneity across countries, the results demonstrated that enrollment in SHI, CBHI and NHI schemes increased utilisation of mental health care.

This was consistent for the length of inpatient admissions, number of hospitalisations, outpatient use of rehabilitation services, having ever received treatment for diagnosed schizophrenia and depression, compliance with drug therapies and the prescriptions of more favourable medications and therapies, when compared to the uninsured.

The majority of included studies did not describe the insurance schemes and their organizational details at length, with limited discussion of the links between these features and the outcomes.

Given the complexity of mental health service utilisation in these diverse contexts, it was difficult to draw overall judgements on whether the impact of insurance enrollment was positive or negative for mental health care outcomes.

Conclusions

Studies that explore the impact of SHI, NHI and CBHI enrolment on mental health care utilisation are limited both in number and scope.

Despite the fact that many LMICs have been hailed for financing reforms towards universal health coverage, evidence on the positive impact of the reforms on mental health care utilisation is only available for a small sub-set of these countries.

Reference

Docrat, S., Besada, D., Cleary, S. & Lund, C. (2020) The impact of social, national and community-based health insurance on health care utilization for mental, neurological and substance-use disorders in low- and middle-income countries: a systematic review. Health Economics Review. 10(1), pp.11. doi: 10.1186/s13561-020-00268-x.

Book: Substance Abuse – Assessment & Diagnosis

Book Title:

Substance Abuse – Assessment & Diagnosis.

Author(s): Gerald A. Juhnke.

Year: 2002.

Edition: 1ed.

Publisher: Routledge.

Type(s): Hardcover, Paperback and Kindle.

Synopsis:

Substance abuse counselling has gone beyond being viewed as optional training; instead it is fast becoming an essential part of the education of helping professionals. In this book, Dr. Gerald Juhnke presents an innovative, practical model to be used in the assessment and diagnosing of substance abuse and related co-morbid disorders.

Substance Abuse Assessment and Diagnosis includes practical “nuts and bolts” direction on how to facilitate a thorough, multi-tiered substance abuse assessment. This book uniquely incorporates detailed examples of how to use individual and significant other clinical interviews, including the CAGE, SUBSTANCE -Q, etc, standardised specialty instruments, drug detection types, and personality instruments to accomplish this feat. This is the only book of its kind that provides practical detail on how to use and score these varied assessment instruments-including the newest “cornerstone instruments,” the MMPI-2, the SASSI-3 and the recently released SASSI-A2.

Students and practitioners alike will benefit from this comprehensive volume on the assessment and diagnosis of substance abuse.

College Students & Substance Use: Do They Require different Strategies for Prevention & Intervention?

Research Paper Title

Cumulative Risk of Substance Use in Community College Students.

Background

Substance use in community college students has been explored in only a handful of studies.

Differences in population characteristics and substance use between 2- and 4-year students suggest that different factors may promote and thwart this behaviour.

Cumulative risk is a parsimonious methodology that provides better model stability and more statistical power, yet it has only been recently used in substance use research.

The aim of this study is to investigate multiple aspects of substance use risk in a population in need of substance use prevention and intervention services.

Methods

The researchers conducted a cross-sectional study of community college students (N = 288; 75% female) examining the relative contributions of different domains of cumulative risk (eg, life stressors, academic stressors, and mental health diagnoses) to develop different profiles of risk across substance use classes (ie, alcohol, cigarette, marijuana, and hard drug use).

Results

Cumulative risk analyses indicated that alcohol and tobacco use were associated with the domains of life stressors and peer/family substance use, marijuana use with peer/family substance use and stressful childhood experiences, and hard drug use with peer/family substance use, lack of social support, low access to care, and stressful childhood experiences.

Conclusions

Different strategies for prevention and intervention may be necessary to effectively address different forms of substance use in this population.

Scientific Significance

The risk domain profiles related to specific drugs may lead to targeted interventions to reduce substance use in community college students.

Reference

Salgado García, F., Bursac, Z. & Derefinko, K.J. (2020) Cumulative Risk of Substance Use in Community College Students. The American Journal on Addictions. 29(2), pp.97-104. doi: 10.1111/ajad.12983. Epub 2020 Jan 3.

Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development.

Research Paper Title

Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development.

Background

Environmental contexts that are reliably associated with the use of pharmacologically active substances are hypothesized to contribute to substance use disorders.

In this review, the researchers provide an updated summary of parallel pre-clinical and human studies that support this hypothesis.

Methods

Research conducted in rats shows that environmental contexts that are reliably paired with drug use can renew extinguished drug-seeking behaviour and amplify responding elicited by discrete, drug-predictive cues.

Akin to drug-associated contexts, interoceptive drug stimuli produced by the psychopharmacological effects of drugs can also influence learning and memory processes that play a role in substance use disorders.

Results

Findings from human laboratory studies show that drug-associated contexts, including social stimuli, can have profound effects on cue reactivity, drug use, and drug-related cognitive expectancies.

This translationally relevant research supports the idea that treatments for substance use disorders could be improved by considering drug-associated contexts as a factor in treatment interventions.

The researchers conclude this review with ideas for how to integrate drug-associated contexts into treatment-oriented research based on 4 approaches:

  • Pharmacology;
  • Brain stimulation;
  • Mindfulness-based relapse prevention; and
  • Cognitive behavioural group therapy.

Throughout, the researchers focus on alcohol- and tobacco-related research, which are two of the most prevalent and commonly misused drugs worldwide for which there are known treatments.

Reference

LeCocq, M.R., Randall, P.A., Besheer, J. & Chaudhri, N. (2020) Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development. Neurotherapeutics. 17(1), pp.43-54. doi: 10.1007/s13311-019-00824-2.

Can CBD Capsules Treat Cannabis Addiction?

For individuals who are addicted to cannabis, one treatment option may be, paradoxically, to take pills that contain an extract of the drug.

The first test of the idea has found that indiviudals taking capsules of this extract, known as cannabidiol (CBD), nearly halved the amount of cannabis they smoked, according to recent research.

Cannabis is often seen as a soft drug, but according to one estimate about one in 10 people can become addicted, getting withdrawal symptoms such as anxiety when they try to stop using it.

The number of individuals seeking treatment because they can not quit smoking cannabis has been rising in the past decade, linked with use of the more potent form known as skunk.

There are two main psychoactive substances in cannabis:

  • The first is CBD; and
  • The second is the compound is tetrahydrocannabinol (THC).

THC is responsible for the drug’s high and, while THC tends to increase anxiety, CBD calms – it gets rid of eh toxic effects of THC.

In a recent study, Val Curran and her colleagues at the University College London, ran a trial in which participants took CBD for four weeks to alleviate withdrawal symptoms to help them quit smoking cannabis.

The trial involved 82 individuals classed as severely addicted to the drug, who were given one of three different doses of CBD in capsule form or a placebo (they all, also, had psychological support).

  • The middle dose of 400 milligrams worked best – after six months, it halved the amount of cannabis each individual used compared with placebo, as shown by tests for THC in their urine.
    • The 400 milligram dose also more than doubled the number of days when individuals had no THC in their urine.
  • The highest dose of 800 milligrams was slightly less effective than the middle one.
  • The lowest dose did not work.

A previous study has shown that individuals can also be helped to quit smoking cannabis by treatment with Sativex, a cannabis extract with both CBD and THC, deployed in a similar way to nicotine replacement therapy for tobacco users.

Academics suggest there could be advantages to using CBD alone. CBD has a variety of anti-addictive properties.

Researchers are also investigating CBD as a treatment for alcohol addiction. Two of the main features during alcohol detoxification are:

  • Severe anxiety; and
  • Risk of seizures.

It is believed that CBD has very strong anxiety-reducing properties, but this is still being researched.

Curran’s study also found preliminary evidence that CBD may help individuals to give up smoking tobacco.

CBD supplements are increasingly sold in pharmacies and health food shops as remedies for a range of illnesses, but at much lower doses than those used in Curran’s trial.

Many of the health claims made for them are not (currently) based on evidence. Therefore the current advice is that anyone who cannot stop smoking cannabis should seek medical assistance.

Reference

New Scientist. (2019) CBD Capsules May Treat Cannabis Addiction. New Scientist. 19 October 2019, pp.9.

Feeling the Pain: Substance Misuse & Generalised Anxiety Disorder

Research Paper Title

An Examination of Comorbid Generalized Anxiety Disorder and Chronic Pain on Substance Misuse in a Canadian Population-Based Survey.

Background

Chronic pain and generalized anxiety disorder (GAD) are co-occurring, and both conditions are independently associated with substance misuse.

However, limited research has examined the impact of comorbid GAD and chronic pain on substance misuse.

The aim of this article was to examine the associations between comorbid GAD and chronic pain conditions compared to GAD only with non-medical opioid use, drug abuse/dependence, and alcohol abuse/dependence in a Canadian, population-based sample.

Methods

Data came from the 2012 Canadian Community Health Survey-Mental Health (N = 25,113). Multiple logistic regressions assessed the associations between comorbid GAD and chronic pain conditions (migraine, back pain, and arthritis) on substance misuse.

Results

Comorbid GAD + back pain and GAD + migraine were associated with increased odds of non-medical opioid use compared to GAD only.

However, the relationship was no longer significant after controlling for additional chronic pain conditions.

No significant relationship was found between GAD + chronic pain conditions with drug or alcohol abuse/dependence.

Conclusions

Comorbid GAD + back pain and GAD + migraine have a unique association with non-medical opioid use in Canadians compared to GAD only, and chronic pain multi-morbidity may be driving this relationship.

Results emphasise the need for screening for substance misuse and prescription access in the context of GAD and comorbid chronic pain.

Reference

Bilevicius, E., Sommer, J.L., Keough, M.T. & El-Gabalawy, R. (2020) An Examination of Comorbid Generalized Anxiety Disorder and Chronic Pain on Substance Misuse in a Canadian Population-Based Survey. Canadian Journal of Psychiatry. doi: 10.1177/0706743719895340. [Epub ahead of print].