What is the Hospital Anxiety and Depression Scale?


Hospital Anxiety and Depression Scale (HADS) was originally developed by Zigmond and Snaith (1983) and is commonly used by doctors to determine the levels of anxiety and depression that a person is experiencing.

The HADS is a fourteen item scale that generates: Seven of the items that relate to anxiety and seven that relate to depression. Zigmond and Snaith created this outcome measure specifically to avoid reliance on aspects of these conditions that are also common somatic symptoms of illness, for example fatigue and insomnia or hypersomnia. This, it was hoped, would create a tool for the detection of anxiety and depression in people with physical health problems.

Items on the Questionnaire

The items on the questionnaire that relate to anxiety are

  • I feel tense or wound up.
  • I get a sort of frightened feeling as if something awful is about to happen.
  • Worrying thoughts go through my mind.
  • I can sit at ease and feel relaxed.
  • I get a sort of frightened feeling like ‘butterflies’ in the stomach.
  • I feel restless as I have to be on the move.
  • I get sudden feelings of panic.

The items that relate to depression are:

  • I still enjoy the things I used to enjoy.
  • I can laugh and see the funny side of things.
  • I feel cheerful.
  • I feel as if I am slowed down.
  • I have lost interest in my appearance.
  • I look forward with enjoyment to things.
  • I can enjoy a good book or radio or TV programme.

Scoring the Questionnaire

Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression.

Caseness of Anxiety and Depression

A number of researchers have explored HADS data to establish the cut-off points for caseness of anxiety or depression. Bjelland et al. (2002) through a literature review of a large number of studies identified a cut-off point of 8/21 for anxiety or depression. For anxiety (HADS-A) this gave a specificity of 0.78 and a sensitivity of 0.9. For depression (HADS-D) this gave a specificity of 0.79 and a sensitivity of 0.83.

Factor Structure

There are a large number of studies that have explored the underlying factor structure of the HADS. Many support the two-factor structure but there are others that suggest a three or four factor structure. Some argue that the tool is best used as a unidimensional measure of psychological distress.


The factor structure of the HADS has been questioned. Coyne and Sonderen argue in a letter published in the same issue, that Cosco, et al. provides grounds for abandoning HADS altogether. The HADS has also been criticised for its over reliance on anhedonia as being the core symptom of depression, how single-item measures of depression may have the same predictive value as the HADS scale, as well as its use of British colloquial expressions which can be difficult to translate.

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Magic Medicine (2018)


Can magic mushrooms cure depression? This documentary follows the first medical trial to explore the use of psilocybin as a treatment for clinical depression.


In 2012 a team of medical researchers asked themselves, “what would happen if we gave psilocybin (magic mushrooms) to people suffering from severe depression”? It took them three years to get the necessary permissions to find out.

Production & Filming Details

  • Director(s):
    • Monty Wales.
  • Producer(s):
    • Lizzie Gillett.
    • Monty Wales.
  • Writer(s):
    • Monty Wales.
  • Music:
    • Christopher White.
  • Cinematography:
    • Monty Wales.
  • Editor(s):
    • John Mister.
  • Production:
    • Life Cycle Films.
  • Distributor(s):
    • Dartmouth Films (2018) (UK) (theatrical).
  • Release Date: 09 November 2018 (London, UK).
  • Running Time: 79 minutes.
  • Rating: 15.
  • Country: UK.
  • Language: English.

The Psychedelic Drug Trial (2021)


With exclusive access to a ground-breaking trial, this film asks if psychedelic drugs combined with psychological support can help tackle one of the biggest medical challenges we face – depression.


The Psychedelic Drug Trial has exclusive access to a ground-breaking new trial at Imperial College London. The trial sees, for the first time ever under controlled conditions, a psychedelic drug tested head-to-head against a standard antidepressant as a treatment for depression.

The film follows a pioneering team of scientists and psychotherapists, led by Professor David Nutt, Dr Robin Carhart-Harris and Dr Rosalind Watts, as they compare the effects of psilocybin (the active ingredient of magic mushrooms) with an antidepressant (an SSRI called escitalopram) on a small group of participants with clinical depression. This is scientific research at its most cutting edge. With over seven million people being prescribed antidepressants each year in England alone, this drug trial is an important milestone in understanding a completely different treatment for depression.

Filmed over 16 months, this film explores both the immediate and long-term impacts of the trial on the lives of participants. It investigates whether psychedelic drugs combined with psychological support could help tackle one of the biggest medical challenges faced today and what it takes to conduct research in uncharted scientific territory.

How do psychedelic drugs measure up against the industry-standard antidepressants that have been popular since the 1990s? The empirical results of the trial are explored alongside the participants’ powerful lived experience.

About the Trial

All psychedelic drug use shown in this programme was part of a carefully controlled clinical trial under the supervision of specially trained psychotherapists.

The trial was run by Professor Nutt, Dr Carhart-Harris and Dr Watts and their team at Imperial College from 2019 to 2020. Fifty-nine participants took part, the trial is now finished.

The psychedelic drugs used in the trial are illegal in the UK and not available for medical treatment. You should always consult your doctor before you stop, change or start any new treatment.

Production & Filming Details

  • Director(s):
    • Sam Eastall.
  • Producer(s):
    • Caroline Lai … line producer.
    • Alice Martineau … producer.
    • Anna Murphy … executive producer.
    • Sabine Pusch … edit producer.
    • Caroline Willis … line producer.
  • Writer(s):
  • Music:
  • Cinematography:
    • Richard Jephcote … director of photography.
  • Editor(s):
    • Zoe Davis … editor.
    • Alex Spence … assistant editor.
  • Production:
    • Grain Media.
  • Distributor(s):
    • BBC Two (2021) (UK) (TV).
    • British Broadcasting Corporation (BBC) (2021) (UK) (all media).
  • Release Date: 19 May 2021 (UK).
  • Running Time: 59 minutes.
  • Rating: Unknown.
  • Country: UK.
  • Language: English.

What is the Depression and Bipolar Support Alliance?


The Depression and Bipolar Support Alliance (DBSA), formerly the National Depressive and Manic Depressive Association (NDMDA), is a non-profit organisation providing support groups for people who live with depression or bipolar disorder as well as their friends and family.

Refer to Depression and Bipolar Support Alliance (Greater Houston).


DBSA’s scope, also includes outreach, education and advocacy regarding depression and bipolar disorder. DBSA employs a small staff and operates with the guidance of a Scientific Advisory Board.

DBSA sponsors online and “face to face” support groups. A nonrandomized study found participants in such groups reported their coping skills, medication compliance, and acceptance of their illness correlated with participation. Member hospitalization decreased by 49% (from 82% to 33%). Following an initial meeting, members were found to be 6.8 times more likely to attend subsequent meetings if accompanied by a member the first time.

DBSA is a not-for-profit 501(c)(3) organisation and receives over 21 million hits per year on their combined websites. Each month, DBSA distributes nearly 20,000 educational materials free of charge to anyone requesting information about mood disorders. DBSA reaches nearly five million people through their educational materials and programs, exhibit materials, and media activities.

What is the Depression and Bipolar Support Alliance (Greater Houston)?


The Depression and Bipolar Support Alliance (DBSA) Greater Houston is a 501(c)(3) non-profit organisation located in Houston, Texas.

DBSA provides free and confidential support groups for individuals living with, or family and friends affected by, depression or bipolar disorder. Each support group is led by a facilitator trained by the organisation. Select groups target specific populations including veterans, adolescents, and parents of adolescents, young adults, senior citizens, LGBT Community, homeless individuals and Spanish-speaking individuals.

Refer to Depression and Bipolar Support Alliance (DBSA).

Brief History

Established in 1979, the Depressive and Manic Disorder Association (DMDA) of Greater Houston sponsored up to five weekly support groups for those with depressive or manic depressive disorders. In 2003, DMDA Greater Houston changed its name to DBSA Greater Houston and formed its own 501(c) (3) corporation. Currently, DBSA Greater Houston sponsors nearly 70 weekly support groups at 50 different locations throughout the Houston metropolitan area. The Houston organisation is the largest of the nation’s DBSA chapters, serving over 1,000 support group participants annually.


The Depression and Bipolar Support Alliance of Greater Houston is a chapter member of the National Depression and Bipolar Support Alliance organisation based in Chicago, Illinois. Additionally, the organisation has developed collaborations with a number of Houston area mental health and social service providers including the Texas Department of Corrections, the Harris County judicial system, the Michael DeBakey VA Hospital, Mental Health of America, National Alliance on Mental Illness and the AIDS Foundation of Houston. Every group provided by DBSA Greater Houston is a collaboration with another organisation in the community. For a list of collaborations, visit the organisations website.


DBSA Greater Houston utilises 75 trained volunteer and professional facilitators to provide nearly 70 weekly support groups. According to an independently conducted demographics study in 2008, 64% of DBSA Greater Houston participants were female, 36% were male; 77% were diagnosed individuals while 23% were family members; 66% reported a diagnosis and/or symptoms of depression, 69% were diagnosed with bipolar disorder; 88% were prescribed psychotropic medications and 65% were in professional therapy.

The Depression and Bipolar Support Alliance of Greater Houston conducts an annual satisfaction survey for participants. In 2013, the results continued to show a high rating of satisfaction with a score of 4.28 out of a possible 5, which represents excellence. Also, it was found that the longer a person attends group, the more satisfied they are with the experience and the more skills they learn to manage their disorder.

In 2006 DBSA Greater received the Chapter of the Year award from the national Depression and Bipolar Support Alliance.

Recent Developments

On 24 September 2013, the Depression and Bipolar Support Alliance of Greater Houston hosted its second annual Help, Hope, and Healing Luncheon with speakers Jessie Close and actress, Glenn Close. Jessie lives with Bipolar Disorder and Glenn talked about the perspective of the family and gave 2 monologues.

The Depression and Bipolar Support Alliance of Greater Houston hosted its first annual Help, Hope, and Healing luncheon at the River Oaks Country Club on 24 September 2012 featuring Jane Pauley as the speaker. Jane Pauley is known for her work on Dateline NBC and the Today Show. Ms. Pauley lives with Bipolar Disorder.

In the fall of 2008, DBSA Greater Houston published an outcome study independently conducted by Dr. Ralph Culler, former Associate Dean of Research at the Hogg Foundation for Mental Health. The outcome study was designed to analyse the effectiveness of the DBSA Greater Houston support group model. The study provided tools for DBSA Greater Houston to:

  • Provide quantitative and qualitative evidence that its support group model is effective;
  • Prove DBSA Greater Houston’s accountability to individuals utilising its services; and
  • Learn how the benefits of DBSA occur.

This study provided evidenced-based results that the DBSA Greater Houston support group model was effective in a number of areas. The study used an outcome questionnaire which asked a broad range of questions regarding demographics, medical data, outcome assessments and satisfaction with the support group experience. On average 89% of group participants experienced an improvement in their quality of life as a direct benefit of their participation in the DBSA groups. 93% of participants reported high or very high satisfaction with their DBSA support group experience.

An Overview of the Biology of Depression


Scientific studies have found that different brain areas show altered activity in people with major depressive disorder (MDD), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes.

Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms.

Neural circuits implicated in depression include those involved in the generation and regulation of emotion, as well as in reward. Abnormalities are commonly found in the lateral prefrontal cortex whose putative function is generally considered to involve regulation of emotion. Regions involved in the generation of emotion and reward such as the amygdala, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and striatum are frequently implicated as well. These regions are innervated by a monoaminergic nuclei, and tentative evidence suggests a potential role for abnormal monoaminergic activity.

Genetic Factors

Difficulty of Gene Studies

Historically, candidate gene studies have been a major focus of study. However, as the number of genes reduces the likelihood of choosing a correct candidate gene, Type I errors (false positives) are highly likely. Candidate genes studies frequently possess a number of flaws, including frequent genotyping errors and being statistically underpowered. These effects are compounded by the usual assessment of genes without regard for gene-gene interactions. These limitations are reflected in the fact that no candidate gene has reached genome-wide significance.

Gene Candidates


The 5-HTTLPR, or serotonin transporter promoter gene’s short allele, has been associated with increased risk of depression; since the 1990s, however, results have been inconsistent. Other genes that have been linked to a gene-environment interaction include CRHR1, FKBP5 and BDNF, the first two of which are related to the stress reaction of the HPA axis, and the latter of which is involved in neurogenesis. Candidate gene analysis of 5-HTTLPR on depression was inconclusive on its effect, either alone or in combination with life stress.

A 2003 study proposed that a gene-environment interaction (GxE) may explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR). This hypothesis was widely-discussed in both the scientific literature and popular media, where it was dubbed the “Orchid gene”, but has conclusively failed to replicate in much larger samples, and the observed effect sizes in earlier work are not consistent with the observed polygenicity of depression.


BDNF polymorphisms have also been hypothesized to have a genetic influence, but early findings and research failed to replicate in larger samples, and the effect sizes found by earlier estimates are inconsistent with the observed polygenicity of depression.


A 2015 GWAS study in Han Chinese women positively identified two variants in intronic regions near SIRT1 and LHPP with a genome-wide significant association.

Norepinephrine Transporter Polymorphisms

Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results.

One review identified multiple frequently studied candidate genes. The genes encoding for the 5-HTT and 5-HT2A receptor were inconsistently associated with depression and treatment response. Mixed results were found for brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. Polymorphisms in the tryptophan hydroxylase gene was found to be tentatively associated with suicidal behaviour. A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein E verepsilon 2 to be protective, and GNB3 825T, MTHFR 677T, SLC6A4 44bp insertion or deletions, and SLC6A3 40 bpVNTR 9/10 genotype to confer risk.

Circadian Rhythm

Depression may be related to abnormalities in the circadian rhythm, or biological clock.

A well synchronised circadian rhythm is critical for maintaining optimal health. Adverse changes and alterations in the circadian rhythm have been associated various neurological disorders and mood disorders including depression.

Depression may be related to the same brain mechanisms that control the cycles of sleep and wakefulness.


Sleep disturbance is the most prominent symptom in depressive patients. Studies about sleep electroencephalograms have shown characteristic changes in depression such as reductions in non-rapid eye movement sleep production, disruptions of sleep continuity and disinhibition of rapid eye movement (REM) sleep. Rapid eye movement (REM) sleep – the stage in which dreaming occurs – may be quick to arrive and intense in depressed people. REM sleep depends on decreased serotonin levels in the brain stem, and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness.

Light Therapy

Research on the effects of light therapy on seasonal affective disorder suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. Sleep deprivation and light therapy both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in people who are hospitalised for MDD.

Increased and decreased sleep length appears to be a risk factor for depression. People with MDD sometimes show diurnal and seasonal variation of symptom severity, even in non-seasonal depression. Diurnal mood improvement was associated with activity of dorsal neural networks. Increased mean core temperature was also observed. One hypothesis proposed that depression was a result of a phase shift.

Daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some depression.


Monoamines are neurotransmitters that include serotonin, dopamine, norepinephrine, and epinephrine.

Illustration of the major elements in a prototypical synapse. Synapses are gaps between nerve cells. These cells convert their electrical impulses into bursts of chemical relayers, called neurotransmitters, which travel across the synapses to receptors on adjacent cells, triggering electrical impulses to travel down the latter cells.

Monoamine Hypothesis of Depression

Many antidepressant drugs acutely increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of norepinephrine and dopamine. The observation of this efficacy led to the monoamine hypothesis of depression, which postulates that the deficit of certain neurotransmitters is responsible for depression, and even that certain neurotransmitters are linked to specific symptoms. Normal serotonin levels have been linked to mood and behaviour regulation, sleep, and digestion; norepinephrine to the fight-or-flight response; and dopamine to movement, pleasure, and motivation. Some have also proposed the relationship between monoamines and phenotypes such as serotonin in sleep and suicide, norepinephrine in dysphoria, fatigue, apathy, cognitive dysfunction, and dopamine in loss of motivation and psychomotor symptoms.[31] The main limitation for the monoamine hypothesis of depression is the therapeutic lag between initiation of antidepressant treatment and perceived improvement of symptoms. One explanation for this therapeutic lag is that the initial increase in synaptic serotonin is only temporary, as firing of serotonergic neurons in the dorsal raphe adapt via the activity of 5-HT1A autoreceptors. The therapeutic effect of antidepressants is thought to arise from autoreceptor desensitization over a period of time, eventually elevating firing of serotonergic neurons.


Initial studies of serotonin in depression examined peripheral measures such as the serotonin metabolite 5-Hydroxyindoleacetic acid (5-HIAA) and platelet binding. The results were generally inconsistent, and may not generalise to the central nervous system. However evidence from receptor binding studies and pharmacological challenges provide some evidence for dysfunction of serotonin neurotransmission in depression. Serotonin may indirectly influence mood by altering emotional processing biases that are seen at both the cognitive/behavioural and neural level. Pharmacologically reducing serotonin synthesis, and pharmacologically enhancing synaptic serotonin can produce and attenuate negative affective biases, respectively. These emotional processing biases may explain the therapeutic gap.


While various abnormalities have been observed in dopaminergic systems, results have been inconsistent. People with MDD have an increased reward response to dextroamphetamine compared to controls, and it has been suggested that this results from hypersensitivity of dopaminergic pathways due to natural hypoactivity. While polymorphisms of the D4 and D3 receptor have been implicated in depression, associations have not been consistently replicated. Similar inconsistency has been found in post-mortem studies, but various dopamine receptor agonists show promise in treating MDD. There is some evidence that there is decreased nigrostriatal pathway activity in people with melancholic depression (psychomotor retardation). Further supporting the role of dopamine in depression is the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine, as well as post mortem findings of altered Dopamine receptor D3 and dopamine transporter expression. Studies in rodents have supported a potential mechanism involving stress-induced dysfunction of dopaminergic systems.

Monoamine receptors affect phospholipase C and adenylyl cyclase inside of the cell. Green arrows means stimulation and red arrows inhibition. Serotonin receptors are blue, norepinephrine orange, and dopamine yellow. Phospholipase C and adenylyl cyclase start a signalling cascade which turn on or off genes in the cell. Sufficient ATP from mitochondria is required for these downstream signalling events. The 5HT-3 receptor is associated with gastrointestinal adverse effects and has no relationship to the other monoamine receptors.


A number of lines of evidence indicative of decreased adrenergic activity in depression have been reported. Findings include the decreased activity of tyrosine hydroxylase, decreased size of the locus coeruleus, increased alpha 2 adrenergic receptor density, and decreased alpha 1 adrenergic receptor density. Furthermore, norepinephrine transporter knockout in mice models increases their tolerance to stress, implicating norepinephrine in depression.

One method used to study the role of monoamines is monoamine depletion. Depletion of tryptophan (the precursor of serotonin), tyrosine and phenylalanine (precursors to dopamine) does result in decreased mood in those with a predisposition to depression, but not in persons lacking the predisposition. On the other hand, inhibition of dopamine and norepinephrine synthesis with alpha-methyl-para-tyrosine does not consistently result in decreased mood.

Monoamine Oxidase

An offshoot of the monoamine hypothesis suggests that monoamine oxidase A (MAO-A), an enzyme which metabolises monoamines, may be overly active in depressed people. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET study, which found significantly elevated activity of MAO-A in the brain of some depressed people. In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. Contrary to the assumptions of the monoamine hypothesis, lowered but not heightened activity of MAO-A was associated with depressive symptoms in adolescents. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders. In addition, some evidence indicates that disrupted information processing within neural networks, rather than changes in chemical balance, might underlie depression.


Since the 1990s, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticised within the psychiatric community. For one thing, serotonin system dysfunction cannot be the sole cause of depression. Not all patients treated with antidepressants show improvements despite the usually rapid increase in synaptic serotonin. If significant mood improvements do occur, this is often not for at least two to four weeks. One possible explanation for this lag is that the neurotransmitter activity enhancement is the result of auto receptor desensitization, which can take weeks. Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in people with MDD. The antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known for a long time. There have also been inconsistent findings with regard to levels of serum 5-HIAA, a metabolite of serotonin. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. Another problem that presents is that drugs that deplete monoamines may actually have antidepressant properties. Further, some have argued that depression may be marked by a hyperserotonergic state. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.

Receptor Binding

As of 2012, efforts to determine differences in neurotransmitter receptor expression or for function in the brains of people with MDD using positron emission tomography (PET) had shown inconsistent results. Using the PET imaging technology and reagents available as of 2012, it appeared that the D1 receptor may be under-expressed in the striatum of people with MDD. 5-HT1A receptor binding literature is inconsistent; however, it leans towards a general decrease in the mesiotemporal cortex. 5-HT2A receptor binding appears to be unregulated in people with MDD. Results from studies on 5-HTT binding are variable, but tend to indicate higher levels in people with MDD. Results with D2/D3 receptor binding studies are too inconsistent to draw any conclusions. Evidence supports increased MAO activity in people with MDD, and it may even be a trait marker (not changed by response to treatment). Muscarinic receptor binding appears to be increased in depression, and, given ligand binding dynamics, suggests increased cholinergic activity.

Four meta analyses on receptor binding in depression have been performed, two on serotonin transporter (5-HTT), one on 5-HT1A, and another on dopamine transporter (DAT). One meta analysis on 5-HTT reported that binding was reduced in the midbrain and amygdala, with the former correlating with greater age, and the latter correlating with depression severity. Another meta-analysis on 5-HTT including both post-mortem and in vivo receptor binding studies reported that while in vivo studies found reduced 5-HTT in the striatum, amygdala and midbrain, post mortem studies found no significant associations. 5-HT1A was found to be reduced in the anterior cingulate cortex, mesiotemporal lobe, insula, and hippocampus, but not in the amygdala or occipital lobe. The most commonly used 5-HT1A ligands are not displaced by endogenous serotonin, indicating that receptor density or affinity is reduced. Dopamine transporter binding is not changed in depression.

Emotional Processing and Neural Circuits

Emotional Bias

People with MDD show a number of biases in emotional processing, such as a tendency to rate happy faces more negatively, and a tendency to allocate more attentional resources to sad expressions. Depressed people also have impaired recognition of happy, angry, disgusted, fearful and surprised, but not sad faces. Functional neuroimaging has demonstrated hyperactivity of various brain regions in response to negative emotional stimuli, and hypoactivity in response to positive stimuli. One meta analysis reported that depressed subjects showed decreased activity in the left dorsolateral prefrontal cortex and increased activity in the amygdala in response to negative stimuli. Another meta analysis reported elevated hippocampus and thalamus activity in a subgroup of depressed subjects who were medication naïve, not elderly, and had no comorbidities. The therapeutic lag of antidepressants has been suggested to be a result of antidepressants modifying emotional processing leading to mood changes. This is supported by the observation that both acute and sub-chronic SSRI administration increases response to positive faces. Antidepressant treatment appears to reverse mood congruent biases in limbic, prefrontal, and fusiform areas. dlPFC response is enhanced and amygdala response is attenuated during processing of negative emotions, the former or which is thought to reflect increased top down regulation. The fusiform gyrus and other visual processing areas respond more strongly to positive stimuli with antidepressant treatment, which is thought to reflect the a positive processing bias. These effects do not appear to be unique to serotonergic or noradrenergic antidepressants, but also occur in other forms of treatment such as deep brain stimulation.

Neural Circuits

One meta analysis of functional neuroimaging in depression observed a pattern of abnormal neural activity hypothesized to reflect an emotional processing bias. Relative to controls, people with MDD showed hyperactivity of circuits in the salience network (SN), composed of the pulvinar nuclei, the insula, and the dorsal anterior cingulate cortex (dACC), as well as decreased activity in regulatory circuits composed of the striatum and dlPFC.

A neuroanatomical model called the limbic-cortical model has been proposed to explain early biological findings in depression. The model attempts to relate specific symptoms of depression to neurological abnormalities. Elevated resting amygdala activity was proposed to underlie rumination, as stimulation of the amygdala has been reported to be associated with the intrusive recall of negative memories. The ACC was divided into pregenual (pgACC) and subgenual regions (sgACC), with the former being electrophysiologically associated with fear, and the latter being metabolically implicated in sadness in healthy subjects. Hyperactivity of the lateral orbitofrontal and insular regions, along with abnormalities in lateral prefrontal regions was suggested to underlie maladaptive emotional responses, given the regions roles in reward learning. This model and another termed “the cortical striatal model”, which focused more on abnormalities in the cortico-basal ganglia-thalamo-cortical loop, have been supported by recent literature. Reduced striatal activity, elevated OFC activity, and elevated sgACC activity were all findings consistent with the proposed models. However, amygdala activity was reported to be decreased, contrary to the limbic-cortical model. Furthermore, only lateral prefrontal regions were modulated by treatment, indicating that prefrontal areas are state markers (i.e. dependent upon mood), while subcortical abnormalities are trait markers (i.e. reflect a susceptibility).


While depression severity as a whole is not correlated with a blunted neural response to reward, anhedonia is directly correlated to reduced activity in the reward system. The study of reward in depression is limited by heterogeneity in the definition and conceptualisations of reward and anhedonia. Anhedonia is broadly defined as a reduced ability to feel pleasure, but questionnaires and clinical assessments rarely distinguish between motivational “wanting” and consummatory “liking”. While a number of studies suggest that depressed subjects rate positive stimuli less positively and as less arousing, a number of studies fail to find a difference. Furthermore, response to natural rewards such as sucrose does not appear to be attenuated. General affective blunting may explain “anhedonic” symptoms in depression, as meta analysis of both positive and negative stimuli reveal reduced rating of intensity. As anhedonia is a prominent symptom of depression, direct comparison of depressed with healthy subjects reveals increased activation of the subgenual anterior cingulate cortex (sgACC), and reduced activation of the ventral striatum, and in particular the nucleus accumbens (NAcc) in response to positive stimuli. Although the finding of reduced NAcc activity during reward paradigms is fairly consistent, the NAcc is made up of a functionally diverse range of neurons, and reduced blood-oxygen-level dependent (BOLD) signal in this region could indicate a variety of things including reduced afferent activity or reduced inhibitory output. Nevertheless, these regions are important in reward processing, and dysfunction of them in depression is thought to underlie anhedonia. Residual anhedonia that is not well targeted by serotonergic antidepressants is hypothesized to result from inhibition of dopamine release by activation of 5-HT2C receptors in the striatum. The response to reward in the medial orbitofrontal cortex (OFC) is attenuated in depression, while lateral OFC response is enhanced to punishment. The lateral OFC shows sustained response to absence of reward or punishment, and it is thought to be necessary for modifying behaviour in response to changing contingencies. Hypersensitivity in the lOFC may lead to depression by producing a similar effect to learned helplessness in animals.

Elevated response in the sgACC is a consistent finding in neuroimaging studies using a number of paradigms including reward related tasks. Treatment is also associated with attenuated activity in the sgACC, and inhibition of neurons in the rodent homologue of the sgACC, the infralimbic cortex (IL), produces an antidepressant effect. Hyperactivity of the sgACC has been hypothesized to lead to depression via attenuating the somatic response to reward or positive stimuli. Contrary to studies of functional magnetic resonance imaging response in the sgACC during tasks, resting metabolism is reduced in the sgACC. However, this is only apparent when correcting for the prominent reduction in sgACC volume associated with depression; structural abnormalities are evident at a cellular level, as neuropathological studies report reduced sgACC cell markers. The model of depression proposed from these findings by Drevets et al. suggests that reduced sgACC activity results in enhanced sympathetic nervous system activity and blunted HPA axis feedback. Activity in the sgACC may also not be causal in depression, as the authors of one review that examined neuroimaging in depressed subjects during emotional regulation hypothesized that the pattern of elevated sgACC activity reflected increased need to modulate automatic emotional responses in depression. More extensive sgACC and general prefrontal recruitment during positive emotional processing was associated with blunted subcortical response to positive emotions, and subject anhedonia. This was interpreted by the authors to reflect a downregulation of positive emotions by the excessive recruitment of the prefrontal cortex.


While a number of neuroimaging findings are consistently reported in people with major depressive disorder, the heterogeneity of depressed populations presents difficulties interpreting these findings. For example, averaging across populations may hide certain subgroup related findings; while reduced dlPFC activity is reported in depression, a subgroup may present with elevated dlPFC activity. Averaging may also yield statistically significant findings, such as reduced hippocampal volumes, that are actually present in a subgroup of subjects. Due to these issues and others, including the longitudinal consistency of depression, most neural models are likely inapplicable to all depression.

Structural Neuroimaging

Meta analyses performed using seed-based d mapping have reported grey matter reductions in a number of frontal regions. One meta analysis of early onset general depression reported grey matter reductions in the bilateral anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (dmPFC). One meta analysis on first episode depression observed distinct patterns of grey matter reductions in medication free, and combined populations; medication free depression was associated with reductions in the right dorsolateral prefrontal cortex, right amygdala, and right inferior temporal gyrus; analysis on a combination of medication free and medicated depression found reductions in the left insula, right supplementary motor area, and right middle temporal gyrus. Another review distinguishing medicated and medication free populations, albeit not restricted to people with their first episode of MDD, found reductions in the combined population in the bilateral superior, right middle, and left inferior frontal gyrus, along with the bilateral parahippocampus. Increases in thalamic and ACC grey matter was reported in the medication free and medicated populations respectively. A meta analysis performed using “activation likelihood estimate” reported reductions in the paracingulate cortex, dACC and amygdala.

GMV reductions in MDD and BD.

Using statistical parametric mapping, one meta analysis replicated previous findings of reduced grey matter in the ACC, medial prefrontal cortex, inferior frontal gyrus, hippocampus and thalamus; however reductions in the OFC and ventromedial prefrontal cortex grey matter were also reported.

Two studies on depression from the ENIGMA consortium have been published, one on cortical thickness, and the other on subcortical volume. Reduced cortical thickness was reported in the bilateral OFC, ACC, insula, middle temporal gyri, fusiform gyri, and posterior cingulate cortices, while surface area deficits were found in medial occipital, inferior parietal, orbitofrontal and precentral regions. Subcortical abnormalities, including reductions in hippocampus and amygdala volumes, which were especially pronounced in early onset depression.

Multiple meta analysis have been performed on studies assessing white matter integrity using fractional anisotropy (FA). Reduced FA has been reported in the corpus callosum (CC) in both first episode medication naïve, and general major depressive populations. The extent of CC reductions differs from study to study. People with MDD who have not taken antidepressants before have been reported to have reductions only in the body of the CC and only in the genu of the CC. On the other hand, general MDD samples have been reported to have reductions in the body of the CC, the body and genu of the CC, and only the genu of the CC. Reductions of FA have also been reported in the anterior limb of the internal capsule (ALIC) and superior longitudinal fasciculus.

Functional Neuroimaging

Studies of resting state activity have utilised a number of indicators of resting state activity, including regional homogeneity (ReHO), amplitude of low frequency fluctuations (ALFF), fractional amplitude of low frequency fluctuations (fALFF), arterial spin labelling (ASL), and positron emission tomography measures of regional cerebral blood flow or metabolism.

MDD is associated with reduced FA in the ALIC and genu/body of the CC.

Studies using ALFF and fALFF have reported elevations in ACC activity, with the former primarily reporting more ventral findings, and the latter more dorsal findings. A conjunction analysis of ALFF and CBF studies converged on the left insula, with previously untreated people having increased insula activity. Elevated caudate CBF was also reported A meta analysis combining multiple indicators of resting activity reported elevated anterior cingulate, striatal, and thalamic activity and reduced left insula, post-central gyrus and fusiform gyrus activity. An activation likelihood estimate (ALE) meta analysis of PET/SPECT resting state studies reported reduced activity in the left insula, pregenual and dorsal anterior cingulate cortex and elevated activity in the thalamus, caudate, anterior hippocampus and amygdala. Compared to the ALE meta analysis of PET/SPECT studies, a study using multi-kernel density analysis reported hyperactivity only in the pulvinar nuclei of the thalamus.

Brain Regions

Research on the brains of people with MDD usually shows disturbed patterns of interaction between multiple parts of the brain. Several areas of the brain are implicated in studies seeking to more fully understand the biology of depression:

Subgenual Cingulate

Studies have shown that Brodmann area 25, also known as subgenual cingulate, is metabolically overactive in treatment-resistant depression. This region is extremely rich in serotonin transporters and is considered as a governor for a vast network involving areas like hypothalamus and brain stem, which influences changes in appetite and sleep; the amygdala and insula, which affect the mood and anxiety; the hippocampus, which plays an important role in memory formation; and some parts of the frontal cortex responsible for self-esteem. Thus disturbances in this area or a smaller than normal size of this area contributes to depression. Deep brain stimulation has been targeted to this region in order to reduce its activity in people with treatment resistant depression.

Prefrontal Cortex

One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. The prefrontal cortex is involved in emotional processing and regulation, and dysfunction of this process may be involved in the aetiology of depression. One study on antidepressant treatment found an increase in PFC activity in response to administration of antidepressants. One meta analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in people with MDD. One study suggested that areas of the prefrontal cortex are part of a network of regions including dorsal and pregenual cingulate, bilateral middle frontal gyrus, insula and superior temporal gyrus that appear to be hypoactive in people with MDD. However the authors cautioned that the exclusion criteria, lack of consistency and small samples limit results.


The amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. The amygdala in unmedicated depressed persons tended to be smaller than in those that were medicated, however aggregate data shows no difference between depressed and healthy persons. During emotional processing tasks right amygdala is more active than the left, however there is no differences during cognitive tasks, and at rest only the left amygdala appears to be more hyperactive. One study, however, found no difference in amygdala activity during emotional processing tasks.


Atrophy of the hippocampus has been observed during depression, consistent with animal models of stress and neurogenesis.

Stress can cause depression and depression-like symptoms through monoaminergic changes in several key brain regions as well as suppression in hippocampal neurogenesis. This leads to alteration in emotion and cognition related brain regions as well as HPA axis dysfunction. Through the dysfunction, the effects of stress can be exacerbated including its effects on 5-HT. Furthermore, some of these effects are reversed by antidepressant action, which may act by increasing hippocampal neurogenesis. This leads to a restoration in HPA activity and stress reactivity, thus restoring the deleterious effects induced by stress on 5-HT.

The hypothalamic-pituitary-adrenal axis is a chain of endocrine structures that are activated during the body’s response to stressors of various sorts. The HPA axis involves three structure, the hypothalamus which release CRH that stimulates the pituitary gland to release ACTH which stimulates the adrenal glands to release cortisol. Cortisol has a negative feedback effect on the pituitary gland and hypothalamus. In people with MDD this often shows increased activation in depressed people, but the mechanism behind this is not yet known. Increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in people with MDD. Early life stress has been hypothesized as a potential cause of HPA dysfunction. HPA axis regulation may be examined through a dexamethasone suppression tests, which tests the feedback mechanisms. Non-suppression of dexamethasone is a common finding in depression, but is not consistent enough to be used as a diagnostic tool. HPA axis changes may be responsible for some of the changes such as decreased bone mineral density and increased weight found in people with MDD. One drug, ketoconazole, currently under development has shown promise in treating MDD.

Hippocampal Neurogenesis

Reduced hippocampal neurogenesis leads to a reduction in hippocampal volume. A genetically smaller hippocampus has been linked to a reduced ability to process psychological trauma and external stress, and subsequent predisposition to psychological illness. Depression without familial risk or childhood trauma has been linked to a normal hippocampal volume but localised dysfunction.

Animal Models

A number of animal models exist for depression, but they are limited in that depression involves primarily subjective emotional changes. However, some of these changes are reflected in physiology and behaviour, the latter of which is the target of many animal models. These models are generally assessed according to four facets of validity; the reflection of the core symptoms in the model; the predictive validity of the model; the validity of the model with regard to human characteristics of aetiology; and the biological plausibility.

Different models for inducing depressive behaviours have been utilised; neuroanatomical manipulations such as olfactory bulbectomy or circuit specific manipulations with optogenetics; genetic models such as 5-HT1A knockout or selectively bred animals; models involving environmental manipulation associated with depression in humans, including chronic mild stress, early life stress and learned helplessness. The validity of these models in producing depressive behaviours may be assessed with a number of behavioural tests. Anhedonia and motivational deficits may, for example, be assessed via examining an animal’s level of engagement with rewarding stimuli such as sucrose or intracranial self-stimulation. Anxious and irritable symptoms may be assessed with exploratory behaviour in the presence of a stressful or novelty environment, such as the open field test, novelty suppressed feeding, or the elevated plus-maze. Fatigue, psychomotor poverty, and agitation may be assessed with locomotor activity, grooming activity, and open field tests.

Animal models possess a number of limitations due to the nature of depression. Some core symptoms of depression, such as rumination, low self-esteem, guilt, and depressed mood cannot be assessed in animals as they require subjective reporting. From an evolutionary standpoint, the behaviour correlates of defeats of loss are thought to be an adaptive response to prevent further loss. Therefore, attempts to model depression that seeks to induce defeat or despair may actually reflect adaption and not disease. Furthermore, while depression and anxiety are frequently comorbid, dissociation of the two in animal models is difficult to achieve. Pharmacological assessment of validity is frequently disconnected from clinical pharmacotherapeutics in that most screening tests assess acute effects, while antidepressants normally take a few weeks to work in humans.


Regions involved in reward are common targets of manipulation in animal models of depression, including the nucleus accumbens (NAc), ventral tegmental area (VTA), ventral pallidum (VP), lateral habenula (LHb) and medial prefrontal cortex (mPFC). Tentative fMRI studies in humans demonstrate elevated LHb activity in depression. The lateral habenula projects to the RMTg to drive inhibition of dopamine neurons in the VTA during omission of reward. In animal models of depression, elevated activity has been reported in LHb neurons that project to the ventral tegmental area (ostensibly reducing dopamine release). The LHb also projects to aversion reactive mPFC neurons, which may provide an indirect mechanism for producing depressive behaviours. Learned helplessness induced potentiation of LHb synapses are reversed by antidepressant treatment, providing predictive validity. A number of inputs to the LHb have been implicated in producing depressive behaviours. Silencing GABAergic projections from the NAc to the LHb reduces conditioned place preference induced in social aggression, and activation of these terminals induces CPP. Ventral pallidum firing is also elevated by stress induced depression, an effect that is pharmacologically valid, and silencing of these neurons alleviates behavioural correlates of depression. Tentative in vivo evidence from people with MDD suggests abnormalities in dopamine signalling. This led to early studies investigating VTA activity and manipulations in animal models of depression. Massive destruction of VTA neurons enhances depressive behaviours, while VTA neurons reduce firing in response to chronic stress. However, more recent specific manipulations of the VTA produce varying results, with the specific animal model, duration of VTA manipulation, method of VTA manipulation, and subregion of VTA manipulation all potentially leading to differential outcomes. Stress and social defeat induced depressive symptoms, including anhedonia, are associated with potentiation of excitatory inputs to Dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) and depression of excitatory inputs to Dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs). Optogenetic excitation of D1-MSNs alleviates depressive symptoms and is rewarding, while the same with D2-MSNs enhances depressive symptoms. Excitation of glutaminergic inputs from the ventral hippocampus reduces social interactions, and enhancing these projections produces susceptibility to stress-induced depression. Manipulations of different regions of the mPFC can produce and attenuate depressive behaviours. For example, inhibiting mPFC neurons specifically in the intralimbic cortex attenuates depressive behaviours. The conflicting findings associated with mPFC stimulation, when compared to the relatively specific findings in the infralimbic cortex, suggest that the prelimbic cortex and infralimbic cortex may mediate opposing effects. mPFC projections to the raphe nuclei are largely GABAergic and inhibit the firing of serotonergic neurons. Specific activation of these regions reduce immobility in the forced swim test but do not affect open field or forced swim behaviour. Inhibition of the raphe shifts the behavioural phenotype of uncontrolled stress to a phenotype closer to that of controlled stress.

Altered Neuroplasticity

Recent studies have called attention to the role of altered neuroplasticity in depression. A review found a convergence of three phenomena:

  • Chronic stress reduces synaptic and dendritic plasticity;
  • Depressed subjects show evidence of impaired neuroplasticity (e.g. shortening and reduced complexity of dendritic trees); and
  • Anti-depressant medications may enhance neuroplasticity at both a molecular and dendritic level.

The conclusion is that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants.

Blood levels of BDNF in people with MDD increase significantly with antidepressant treatment and correlate with decrease in symptoms. Post mortem studies and rat models demonstrate decreased neuronal density in the prefrontal cortex thickness in people with MDD. Rat models demonstrate histological changes consistent with MRI findings in humans, however studies on neurogenesis in humans are limited. Antidepressants appear to reverse the changes in neurogenesis in both animal models and humans.


Various reviews have found that general inflammation may play a role in depression. One meta analysis of cytokines in people with MDD found increased levels of pro-inflammatory IL-6 and TNF-a levels relative to controls. The first theories came about when it was noticed that interferon therapy caused depression in a large number of people receiving it. Meta analysis on cytokine levels in people with MDD have demonstrated increased levels of IL-1, IL-6, C-reactive protein, but not IL-10. Increased numbers of T-Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in depression. Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. Cytokines, by manipulating neurotransmitters, are involved in the generation of sickness behaviour, which shares some overlap with the symptoms of depression. Neurotransmitters hypothesized to be affected include dopamine and serotonin, which are common targets for antidepressant drugs. Induction of indolamine-2,3 dioxygenease by cytokines has been proposed as a mechanism by which immune dysfunction causes depression. One review found normalization of cytokine levels after successful treatment of depression. A meta analysis published in 2014 found the use of anti-inflammatory drugs such as NSAIDs and investigational cytokine inhibitors reduced depressive symptoms. Exercise can act as a stressor, decreasing the levels of IL-6 and TNF-a and increasing those of IL-10, an anti-inflammatory cytokine.

Inflammation is also intimately linked with metabolic processes in humans. For example, low levels of Vitamin D have been associated with greater risk for depression. The role of metabolic biomarkers in depression is an active research area. Recent work has explored the potential relationship between plasma sterols and depressive symptom severity.

Oxidative Stress

A marker of DNA oxidation, 8-Oxo-2′-deoxyguanosine, has been found to be increased in both the plasma and urine of people with MDD. This along with the finding of increased F2-isoprostanes levels found in blood, urine and cerebrospinal fluid indicate increased damage to lipids and DNA in people with MDD. Studies with 8-Oxo-2′ Deoxyguanosine varied by methods of measurement and type of depression, but F2-Isoprostane level was consistent across depression types. Authors suggested lifestyle factors, dysregulation of the HPA axis, immune system and autonomics nervous system as possible causes. Another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity. Oxidative DNA damage may play a role in MDD.

Mitochondrial Dysfunction:

Increased markers of oxidative stress relative to controls have been found in people with MDD. These markers include high levels of RNS and ROS which have been shown to influence chronic inflammation, damaging the electron transport chain and biochemical cascades in mitochondria. This lowers the activity of enzymes in the respiratory chain resulting in mitochondrial dysfunction. The brain is a highly energy-consuming and has little capacity to store glucose as glycogen and so depends greatly on mitochondria. Mitochondrial dysfunction has been linked to the dampened neuroplasticity observed in depressed brains.

Large-Scale Brain Network Theory

Instead of studying one brain region, studying large scale brain networks is another approach to understanding psychiatric and neurological disorders, supported by recent research that has shown that multiple brain regions are involved in these disorders. Understanding the disruptions in these networks may provide important insights into interventions for treating these disorders. Recent work suggests that at least three large-scale brain networks are important in psychopathology.

Central Executive Network

The central executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal cortex. This network is involved in high level cognitive functions such as maintaining and using information in working memory, problem solving, and decision making. Deficiencies in this network are common in most major psychiatric and neurological disorders, including depression. Because this network is crucial for everyday life activities, those who are depressed can show impairment in basic activities like test taking and being decisive.

Default Mode Network

The default mode network includes hubs in the prefrontal cortex and posterior cingulate, with other prominent regions of the network in the medial temporal lobe and angular gyrus. The default mode network is usually active during mind-wandering and thinking about social situations. In contrast, during specific tasks probed in cognitive science (for example, simple attention tasks), the default network is often deactivated. Research has shown that regions in the default mode network (including medial prefrontal cortex and posterior cingulate) show greater activity when depressed participants ruminate (that is, when they engage in repetitive self-focused thinking) than when typical, healthy participants ruminate. People with MDD also show increased connectivity between the default mode network and the subgenual cingulate and the adjoining ventromedial prefrontal cortex in comparison to healthy individuals, individuals with dementia or with autism. Numerous studies suggest that the subgenual cingulate plays an important role in the dysfunction that characterizes major depression. The increased activation in the default mode network during rumination and the atypical connectivity between core default mode regions and the subgenual cingulate may underlie the tendency for depressed individual to get “stuck” in the negative, self-focused thoughts that often characterise depression. However, further research is needed to gain a precise understanding of how these network interactions map to specific symptoms of depression.

Salience Network

The salience network is a cingulate-frontal operculum network that includes core nodes in the anterior cingulate and anterior insula. A salience network is a large-scale brain network involved in detecting and orienting the most pertinent of the external stimuli and internal events being presented. Individuals who have a tendency to experience negative emotional states (scoring high on measures of neuroticism) show an increase in the right anterior insula during decision-making, even if the decision has already been made. This atypically high activity in the right anterior insula is thought to contribute to the experience of negative and worrisome feelings. In MDD, anxiety is often a part of the emotional state that characterises depression.

What is Thought Suppression?


Thought suppression is a psychological defence mechanism. It is a type of motivated forgetting in which an individual consciously attempts to stop thinking about a particular thought.

It is often associated with obsessive-compulsive disorder (OCD). OCD is when a person will repeatedly (usually unsuccessfully) attempt to prevent or “neutralise” intrusive distressing thoughts centred on one or more obsessions. It is also thought to be a cause of memory inhibition, as shown by research using the think/no think paradigm. Thought suppression is relevant to both mental and behavioural levels, possibly leading to ironic effects that are contrary to intention. Ironic process theory is one cognitive model that can explain the paradoxical effect.

When an individual tries to suppress thoughts under a high cognitive load, the frequency of those thoughts increases and becomes more accessible than before. Evidence shows that people can prevent their thoughts from being translated into behaviour when self-monitoring is high; this does not apply to automatic behaviours though, and may result in latent, unconscious actions. This phenomenon is made paradoxically worse by increasing the amount of distractions a person has, although the experiments in this area can be criticised for using impersonal concurrent tasks, which may or may not properly reflect natural processes or individual differences.

Empirical Work (1980s)

In order for thought suppression and its effectiveness to be studied, researchers have had to find methods of recording the processes going on in the mind. One experiment designed with this purpose was performed by Wegner, Schneider, Carter & White. They asked participants to avoid thinking of a specific target (e.g. a white bear) for five minutes, but if they did, they were told then to ring a bell. After this, participants were told that for the next five minutes they were to think about the target. There was evidence that unwanted thoughts occurred more frequently in those who used thought suppression compared to those who were not. Furthermore, there was also evidence that during the second stage, those who had used thought suppression had a higher frequency of target thoughts than did those who had not used thought suppression; later coined the rebound effect. This effect has been replicated and can even be done with implausible targets, such as the thought of a “green rabbit”. From these implications, Wegner eventually developed the “ironic process theory”.

Improved Methodology (1990s)

To better elucidate the findings of thought suppression, several studies have changed the target thought. Roemer and Borkovec found that participants who suppressed anxious or depressing thoughts showed a significant rebound effect. Furthermore, Wenzlaff, Wegner, & Roper demonstrated that anxious or depressed subjects were less likely to suppress negative, unwanted thoughts. Despite Rassin, Merkelbach and Muris reporting that this finding is moderately robust in the literature, some studies were unable to replicate results. However, this may be explained by a consideration of individual differences.

Recent research found that for individuals with low anxiety and high desirability traits (repressors), suppressed anxious autobiographical events initially intruded fewer times than in other groups (low, high, and high defensive anxious groups), but intruded more often after one week. This difference in coping style may account for the disparities within the literature. That said, the problem remains that the cause of the paradoxical effect may be in the thought tapping measures used (e.g. bell ringing). Evidence from Brown (1990) that showed participants were very sensitive to frequency information prompted Clarke, Ball and Pape to obtain participants’ aposterio estimates of the number of intrusive target thoughts and found the same pattern of paradoxical results. However, even though such a method appears to overcome the problem, it and all the other methodologies use self-report as the primary form of data-collection. This may be problematic because of response distortion or inaccuracy in self-reporting.

Behavioural Domain

Thought suppression also has the capability to change human behaviour. Macrae, Bodenhausen, Milne, and Jetten found that when people were asked not to think about the stereotypes of a certain group (e.g. a “skinhead”), their written descriptions about a group member’s typical day contained less stereotypical thoughts. However, when they were told they were going to meet an individual they had just written about, those in the suppression group sat significantly farther away from the “skinhead” (just by virtue of his clothes being present). These results show that even though there may have been an initial enhancement of the stereotype, participants were able to prevent this from being communicated in their writing; this was not true for their behaviour though.

Further experiments have documented similar findings. In one study from 1993, when participants were given cognitively demanding concurrent tasks, the results showed a paradoxical higher frequency of target thoughts than controls. However other controlled studies have not shown such effects. For example, Wenzlaff and Bates found that subjects concentrating on a positive task experienced neither paradoxical effects nor rebound effects – even when challenged with cognitive load. Wenzlaff and Bates also note that the beneficiality of concentration in their study participants was optimised when the subjects employed positive thoughts.

Some studies have shown that when test subjects are under what Wegner refers to as a “cognitive load” (for instance, using multiple external distractions to try to suppress a target thought), the effectiveness of thought suppression appears to be reduced. However, in other studies in which focused distraction is used, long term effectiveness may improve. That is, successful suppression may involve less distractors. For example, in 1987 Wegner, Schneider, Carter & White found that a single, pre-determined distracter (e.g. a red Volkswagen) was sufficient to eliminate the paradoxical effect post-testing. Evidence from Bowers and Woody in 1996 is supportive of the finding that hypnotised individuals produce no paradoxical effects. This rests on the assumption that deliberate “distracter activity” is bypassed in such an activity.

Cognitive Dynamics

When the cognitive load is increased, thought suppression typically becomes less effective. For example, in the white bear experiment, many general distractions in the environment (for instance a lamp, a light bulb, a desk etc.) might later serve as reminders of the object being suppressed (these are also referred to as “free distraction”). Some studies, however, are unable to find this effect for emotional thoughts in hypnotized individuals when one focused distraction is provided. In an attempt to account for these findings, a number of theorists have produced cognitive models of thought suppression. Wegner suggested in 1989 that individuals distract themselves using environmental items. Later, these items become retrieval cues for the thought attempting to be suppressed. This iterative process leaves the individual surrounded by retrieval cues, ultimately causing the rebound effect. Wegner hypothesized that multiple retrieval cues not being forged explains, in part, the effectiveness of focused distraction (i.e. a reduction of mental load). This is because there may be an ideal balance between the two processes; if the cognitive demand that is not too heavy, then the monitoring processes will not supersede it.

Individual differences may also play a role in regards to the ironic thought process.

Thought suppression has been seen as a form of “experiential avoidance”. Experiential avoidance is when an individual attempts to suppress, change, or control unwanted internal experiences (thoughts, feelings, bodily sensations, memories, etc.). This line of thinking supports relational frame theory.

Other Methodologies

Thought suppression has been shown to be a cause of inhibition in several ways. Two commonly-used methods to study this relationship are the list method and the item method. In this list method, participants study two lists of words, one after the other. After studying the first list, some participants are told to forget everything that they have just learned, while others are not given this instruction. After studying both lists, participants are asked to recall the words on both lists. These experiments typically find that participants who were told to forget the first list do not remember as many words from that list, suggesting that they have been suppressed due to the instruction to forget. In the item method, participants study individual words rather than lists. After each word is shown, participants are told to either remember or forget the word. As in experiments using the list method, the words followed by the instruction to forget are more poorly remembered. Some researchers believe that these two methods result in different types of forgetting. According to these researchers, the list method results in inhibition of the forgotten words, but the item method results in some words being remembered better than the others, without a specific relation to forgetting.

Think/No Think Paradigm

A paradigm from 2009 to study how suppression relates to inhibition is the think/no think paradigm. In these experiments, participants study pairs of words. An example of a possible word pair is roach-ordeal. After all the word pairs are learned, the participants see the first word of the pair and are either told to think about the second word (think phase) or not to think about the second word (no think phase). The no think phase is when suppression occurs. Some pairs were never presented after the initial study portion of the study, and these trials serve as the control group. At the end of the experiment, the participants try to remember all of the word pairs based on the first word. Studies could also use the “independent probe” method, which gives the category and first letter of the second word of the pair. Typically, regardless of the method used, results show that the no-think trials result in worse memory than the think trials, which supports the idea that suppression leads to inhibition in memory. Although this methodology was first done using word pairs, experiments have been conducted using pictures and autobiographical memories as stimuli, with the same results.

Research has also shown that doing difficult counting tasks at the same time as a think/no think task leads to less forgetting in the no think condition, which suggests that suppression takes active mental energy to be successful. Furthermore, the most forgetting during the no think phase occurs when there is a medium amount of brain activation while learning the words. The words are never learned if there is too little activation, and the association between the two words is too strong to be suppressed during the no think phase if there is too much activation. However, with medium activation, the word pairs are learned but able to be suppressed during the no think phase.

fMRI studies have shown two distinct patterns of brain activity during suppression tasks. The first is that there is less activity in the hippocampus, the brain area responsible for forming memories. The second is an increase of brain activity in the dorsolateral prefrontal cortex, especially in cases where suppression is harder. Researchers think that this region works to prevent memory formation by preventing the hippocampus from working.

This methodology can also be used to study thought substitution by adding an instruction during the no think phase for participants to think of a different word rather than the word being suppressed. This research shows that thought substitution can lead to increased levels of forgetting compared to suppression without a thought substitution instruction. This research also suggests that thought substitution, while used as a suppression strategy during the no think phase, may work differently than suppression. Some researchers argue that thinking of something different during the no think phase forms a new association with the first word than the original word pair, which results in interference when using this strategy, which is different than the inhibition that results from simply not thinking about something.

Dream Influence

Dreams occur mainly during the rapid eye movement (REM) sleep and are composed of images, ideas, emotions, and sensations. Although more research needs to be done on this subject, dreams are said to be linked to the unconscious mind. Thought suppression has an influence on the subject matter of the unconscious mind and by trying to restrain particular thoughts, there is a high chance of them showing up in one’s dreams.

Ironic Control Theory

Ironic control theory, also known as “ironic process theory”, states that thought suppression “leads to an increased occurrence of the suppressed content in waking states”. The irony lies in the fact that although people try not to think about a particular subject, there is a high probability that it will appear in one’s dreams regardless. There is a difference for individuals who have a higher tendency of suppression; they are more prone to psychopathological responses such as “intrusive thoughts, including depression, anxiety and obsessional thinking”. Due to these individuals having higher instances of thought suppression, they experience dream rebound more often.

Cognitive load also plays a role in ironic control theory. Studies have shown that a greater cognitive load results in an increased possibility of dream rebound occurring. In other words, when one tries to retain a heavy load of information before going to sleep, there is a high chance of that information manifesting itself within the dream. There is a greater degree of dream rebound in those with a higher cognitive load opposed to those whose load was absent. With the enhancement of a high cognitive load, ironic control theory states thought suppression is more likely to occur and lead to dream rebound.

Dream Rebound

Dream rebound is when suppressed thoughts manifest themselves in one’s dreams. Self-control is a form of thought suppression and when one dreams, that suppressed item has a higher chance of appearing in the dream. For example, when an individual is attempting to quit smoking, they may dream about themselves smoking a cigarette. Emotion suppression has also been found to trigger dream rebound. Recurrence of emotional experiences act as pre-sleep suggestions, ultimately leading to the suppressed thoughts presenting themselves within the dream. One effecting factor of dream rebound is the changes in the prefrontal lobes during rapid-eye movement sleep. Suppressed thoughts are more accessible during REM sleep, as a result of operating processes having a diminished effectiveness. This leads to pre-sleep thoughts becoming more available “with an increased activity of searching for these suppressed thought[s]”. There are other hypotheses regarding REM sleep and dream rebound. For instance, weak semantic associations, post REM sleep, are more accessible than any other time due to weak ironic monitoring processes becoming stronger. More research is needed to further understand what exactly causes dream rebound.

What is Depressive Realism?


Depressive realism is the hypothesis developed by Lauren Alloy and Lyn Yvonne Abramson that depressed individuals make more realistic inferences than non-depressed individuals.

Although depressed individuals are thought to have a negative cognitive bias that results in recurrent, negative automatic thoughts, maladaptive behaviours, and dysfunctional world beliefs, depressive realism argues not only that this negativity may reflect a more accurate appraisal of the world but also that non-depressed individuals’ appraisals are positively biased.

Refer to Defensive Pessimism.

Evidence (For)

When participants were asked to press a button and rate the control they perceived they had over whether or not a light turned on, depressed individuals made more accurate ratings of control than non-depressed individuals. Among participants asked to complete a task and rate their performance without any feedback, depressed individuals made more accurate self-ratings than non-depressed individuals. For participants asked to complete a series of tasks, given feedback on their performance after each task, and who self-rated their overall performance after completing all the tasks, depressed individuals were again more likely to give an accurate self-rating than non-depressed individuals. When asked to evaluate their performance both immediately and some time after completing a task, depressed individuals made accurate appraisals both immediately before and after time had passed.

In a functional magnetic resonance imaging (fMRI) study of the brain, depressed patients were shown to be more accurate in their causal attributions of positive and negative social events than non-depressed participants, who demonstrated a positive bias. This difference was also reflected in the differential activation of the fronto-temporal network, higher activation for non self-serving attributions in non-depressed participants and for self-serving attributions in depressed patients, and reduced coupling of the dorsomedial prefrontal cortex seed region and the limbic areas when depressed patients made self-serving attributions.

Evidence (Against)

When asked to rate both their performance and the performance of others, non-depressed individuals demonstrated positive bias when rating themselves but no bias when rating others. Depressed individuals conversely showed no bias when rating themselves but a positive bias when rating others.

When assessing participant thoughts in public versus private settings, the thoughts of non-depressed individuals were more optimistic in public than private, while depressed individuals were less optimistic in public.

When asked to rate their performance immediately after a task and after some time had passed, depressed individuals were more accurate when they rated themselves immediately after the task but were more negative after time had passed whereas non-depressed individuals were positive immediately after and some time after.

Although depressed individuals make accurate judgments about having no control in situations where they in fact have no control, this appraisal also carries over to situations where they do have control, suggesting that the depressed perspective is not more accurate overall. Note, however, that this finding alone does not imply depression as a cause; researchers did not control for philosophical factors such as determinism which could affect responses.

One study suggested that in real-world settings, depressed individuals are actually less accurate and more overconfident in their predictions than their non-depressed peers. Participants’ attributional accuracy may also be more related to their overall attributional style rather than the presence and severity of their depressive symptoms.

Criticism of the Evidence

Some have argued that the evidence is not more conclusive because no standard for reality exists, the diagnoses are dubious, and the results may not apply to the real world. Because many studies rely on self-report of depressive symptoms and self-reports are known to be biased, the diagnosis of depression in these studies may not be valid, necessitating the use of other objective measures. Due to most of these studies using designs that do not necessarily approximate real-world phenomena, the external validity of the depressive realism hypothesis is unclear. There is also concern that the depressive realism effect is merely a byproduct of the depressed person being in a situation that agrees with their negative bias.

What is Paranoid Anxiety?


Paranoid anxiety is a term used in object relations theory, particularity in discussions about the Paranoid-schizoid and depressive positions.

The term was frequently used by Melanie Klein, especially to refer to a pre-depressive and persecutory sense of anxiety characterised by the psychological splitting of objects.

Further Developments

Donald Meltzer saw paranoid anxiety as linked not only to a loss of trust in the goodness of objects, but also to a confusion between feeling and thought.

For the extreme forms of such anxiety, he coined the term ‘terror’, to convey something of the qualitatively different intensity of their nature.

External Sources

Sigmund Freud considered that there was generally a small kernel of truth hidden in the exaggerated anxiety of the paranoid – what Hanns Sachs described as an amoeba about to become monster.

The anti-psychiatrist David Cooper argued indeed that “The therapist in working with people might far more often have to confirm the reality of paranoid fears than in any sense disconfirm or attempt to modify them”, but most family therapists would probably agree that this is an extreme and one-sided position.

Defensive Functions

Idealisation (as in the transference) can be used as a defence against deeper paranoid anxieties about the actual presence of a destructive, denigrating object.

Conversely, paranoid fears, especially when systematised, may themselves serve as a defence against a deeper, chaotic disintegration of the personality.

Persecutory Anxiety State (Panic Attack) and Persecutory Delusion

Paranoid anxiety may reach the level of a persecutory anxiety state (a form of panic attack), including various levels of persecutory delusions (the preferred term to paranoid delusions).

Heavy drinking is said to sometimes precipitate acute paranoid panic – the protagonist’s unconscious hostile impulses being projected onto all those around.

Literary Examples

Hamm in Endgame by Samuel Beckett has been singled out as a character driven by paranoid anxiety.

Noboru in The Sailor Who Fell from Grace with the Sea by Yukio Mishima is shown to have persecutory anxiety.

What is the Mood Disorder Questionnaire?


The Mood Disorder Questionnaire (MDQ) is a self-report questionnaire designed to help detect bipolar disorder.

It focuses on symptoms of hypomania and mania, which are the mood states that separate bipolar disorders from other types of depression and mood disorder. It has 5 main questions, and the first question has 13 parts, for a total of 17 questions. The MDQ was originally tested with adults, but it also has been studied in adolescents ages 11 years and above. It takes approximately 5-10 minutes to complete. In 2006, a parent-report version was created to allow for assessment of bipolar symptoms in children or adolescents from a caregiver perspective, with the research looking at youths as young as 5 years old.

The MDQ has become one of the most widely studied and used questionnaires for bipolar disorder, and it has been translated into more than a dozen languages.


The MDQ was developed as a screening tool for bipolar disorder, and assesses symptoms of mania and hypomania It was developed in the hopes that it would reduce the mis-diagnosis and delayed diagnosis of bipolar disorder. The first 13 items on the measure ask about any manic/hypomanic symptoms that may have occurred during one’s lifetime. These items are based on the DSM-IV criteria for bipolar disorder. Additional items then ask if these symptoms have happened during the same period of time (an “episode”), and how severely these symptoms affected functioning (assessing impairment).

In developing this tool, the MDQ was administered to a group of bipolar patients to assess feasibility and face validity, leading to revision of the items. Following this initial study, researchers have assessed psychometric properties of the MDQ, finding that the measure possesses adequate internal consistency. The measure has also demonstrated fair sensitivity in several studies, although sensitivity may be greater in inpatient versus community settings. First built for use in adults, it has been translated into many languages and tested in a range of different settings. Researchers also have studied whether parents could use this to provide useful information about their child or adolescent. Meta-analyses have found that the MDQ is one of the best self-report tools for assessing hypomania or mania in adults, and the parent report version is one of the three best options available for parents to use about their children.


One limitation of the MDQ is that it has shown higher sensitivity when detecting bipolar I compared to other bipolar spectrum disorders. It is much less sensitive to bipolar II, often missing more than half of the cases with this diagnosis when using the recommended algorithm. Additionally, the sensitivity and specificity of the MDQ has been shown to differ by the use of a standard vs. modified cutoff (i.e. simplifies the cutoff to be based only on symptom endorsement, rather than impairment). Sensitivity and specificity of the MDQ also depend on study inclusion and exclusion criteria. Including more severe cases will increase the apparent sensitivity, because it is more likely that they will have high scores. Including healthy controls or people who are not seeking services will exaggerate the specificity of the test, as these individuals are unlikely to have manic symptoms and will score very low on the measure as a result.

Another major limitation of the MDQ is that it is not to be sensitive to treatment effects. It asks about lifetime history of symptoms, which is a strength for screening and detection, but a weakness for measuring the current severity of mood symptoms. The MDQ also uses a yes/no format for the symptoms, rather than asking about the severity of each. Other rating scales are more useful for measuring severity and treatment outcomes.

Additionally, self-report measures have some disadvantages, including bias that can stem from social desirability and demand characteristics.