Study Guide with article summaries for Clinical Psychology at Leiden University - 24/25

Why is comorbidity between major depressive disorder and physical diseases a problem?

People with major depressive disorder (MDD) have a greater risk for many physical diseases, and at the same time, populations with physical diseases experience much higher rates of MDD. This comorbidity causes negative outcomes, such as reduced adherence to treatment, greater health care costs, and increased mortality. It also causes clinical difficulties, such as difficulties pertaining adaptive health behaviors, drug interactions, and more complicated therapeutic treatments.

Which diseases appear to be comorbid to MDD?

Major depressive disorder is a risk factor for a range of physical diseases and there is a bidirectional relationship. Identified comorbid diseases are cardiovascular disease, diabetes, metabolic syndrome, cancer, neurological diseases, and osteoporosis. Both MDD and these physical diseases are associated with increases in mortality, and their coexistence increases that risk.

Is there a comorbid relationship between MDD and COVID-19?

An increase in MDD due to COVID-19 has been suggested, but this is still controversial and needs further investigation. Long COVID has been associated with an increased risk of a range of physical diseases and MDD, but this risk may be similar to non-COVID severe respiratory infections. COVID-19 has been related to certain biological processes that are relevant to MDD and physical diseases, such as immune activation and small brain changes (structural and functional alterations in the hippocampus).

What socio-environmental factors serve as both shared risk and protective factors?

Lifestyle and behavioral risk factors. The causality of these relationships is unclear and probably bidirectional: physical inactivity, smoking, impaired sleep etc. are associated with an increased risk of MDD, but it is also known that MDD has a negative impact on sleep quality, motivation for physical activity, and a propensity to self-medicate with substances.

Stressful life events. Childhood traumas can have negative consequences on mental and physical health across the lifespan, but can be mediated via resilience (the ability to successfully adapt to difficult, challenging, or disrupting life events). Resilience can be promoted through, for example, social belongingness, positive parenting, and supportive relationships. These factors may have a protective effect on the risk for MDD.

Social risk and protective factors are interwoven at multiple levels with some occurring at different times while others persist across the life course. Risk factors are, among others, poverty, discrimination, racial or sexual minority status, and intergenerational trauma. Their effects are influenced by other social factors, such as peer relationships, parenting styles, access to resources, and consistent relationships.

What biological pathways are identified as playing a role in the comorbidity between MDD and physical diseases?

Several biological pathways contribute to disease outcomes. Pathogenesis is unlikely to be caused by one pathway alone, but instead by the interaction of multiple pathways that affect both mental and physical health.

• Neuroprogression is the psychiatric disease acceleration and its underlying operative factors (reduced neurogenesis, increased apoptosis, hypothalamic-pituitary-adrenal dysfunction). It shows via impaired cognitive function, structural neuroimaging changes, and declining treatment response.
• Somatoprogression refers to the pathways that play a parallel role in the genesis and progression of many physical comorbidities and neuroprogression of MDD. It involves the accumulation of a physical comorbidity that often occurs parallel to neuroprogression.
• Genetics. Separately, MDD and physical diseases have their own genetic risk factors. But there are also several shared genetic factors between MDD and physical diseases, such as BMI, coronary artery disease, and type 2 diabetes.
• MDD is associated with inflammation, and chronic low-grade inflammation is also a feature of a variety of physical diseases (such as cardiovascular diseases, cancer, arthritis).
• Hypothalamic-pituitary-adrenal axis. There appears to be co-occurence of HPA axis dysregulation, MDD and physical diseases, but more clinical studies need to be done.
• Mitochondria are dynamic organelles that generate adenosine triphosphate. They are involved in calcium homeostasis and play an important role in the redox state of the cell and apoptosis. Mitochondrial function plays a factor in the pathophysiology of MDD and a variety of physical conditions.
• Oxidative stress occurs when there is an excess of reactive oxygen species. These reactive oxygen species play a role in cell signaling and cells need them, but a sustained excess is associated with MDD and physical disease. 
• The gut microbiome affects the gut-brain axis through several mechanisms, such as signaling within and between the enteric and central nervous system via neuromodulatory metabolites and immunomodulatory responses, and regulating physiological homeostasis via the autonomic nervous system and the HPA axis. Although the gut microbiome is associated with MDD and physical diseases, the strength for microbial causation varies across conditions.
• Brain structure and function. Common neural circuitries can influence the liability to MDD and physical diseases, or mediate the mechanisms in causal relationships between MDD and physical diseases. Examples are alterations in the interoceptive network and hippocampal atrophy.

Why is diagnosing comorbidity of MDD and physical diseases difficult?

Several depressive symptoms overlap with symptoms of the physical diseases, and physical diseases can lead to symptoms that seem to be indicating MDD when actually they are appropriate reactions to suffering from the physical diseases. Diagnostic overshadowing refers to the tendency for clinicians to misattribute physical symptoms such as pain to a person's mental disorder rather than to a potential comorbid physical disease.

How can comorbid MDD be treated?

Pharmacotherapies and psychotherapies are effective treatments. Also the introduction of lifestyle interventions as well as collaborative care models and digital technologies provide promising strategies for improving management. Psychotherapies such as cognitive behavioral therapy, compassion-focused therapies, mindfulness-based interventions, and problem-solving therapy appear to effectively treat MDD in people with physical diseases. In the treatment of comorbid MDD there must be interdisciplinary care (communication between the clinicians), patient-related factors need to be considered (e.g. age, pain), and there needs to be ongoing management.

What is especially difficult for the clinician in the treatment of comorbid MDD?

The clinician needs to balance the potential antidepressant effects of pharmacotherapy with possible side effects. The clinician also needs to consider potential drug-drug interactions.

Can MDD treatments influence physical disease outcomes?

Antidepressants can improve depressive symptoms, but also have positive effects of physical disease outcomes. SSRIs improve fasting glucose/HbA1c and pain, glycemic control, motor function after a stroke, and motor symptoms in Parkinson's disease. Additionally, psychotherapies can lead to increased engagement in lifestyle behaviors that positively influence physical health.

Can physical disease treatments influence MDD outcomes?

Certain medicines appear to have positive effects when added to antidepressants, such as non-steroidal anti-inflammatory drugs, cytokine inhibitors, and angiotensin-converting enzyme inhibitors. However, many treatments for physical disease can cause depressive symptoms as a side effect.

Why is the relationship between the big five personality traits and stress of scientific interest?

Conceptualizations and measurements of stress vary widely and it is still unknown if the personality-stress link varies depending on how stress is conceptualized. There is also a need for a theoretical basis for understanding how different domains of the big five personality traits are associated with stress. Understanding individual differences in stress could identify those at higher risk of suffering from stress than others and may lead to better health and aging management. Finally, the magnitude and direction of the relations between personality and stress are inconsistent. A meta-analysis allows for studies into between-study heterogeneity.

What is stress?

Stress can be defined in different ways as it is a process with multiple stages and dimensions and therefore can refer to different components of the process. A few examples of definitions of stress:

• External environmental events or conditions that are potentially demanding, challenging, or threatening.
• Responses to external environmental exposures that involve physiological and/or psychological reactions.
• Psychological stress is caused by the appraisal of external situations and coping resources, when a person evaluates the demands of their circumstance as exceeding their ability to manage it.
• Allostasis refers to physiological stress and describes the biological processes that maintain homeostasis when facing environmental or physiological challenges such as stress. It involves the activation of multiple systems such as the hypothalamic-pituitary-adrenocotrical axis, cardiovascular system, and the autonomic nervous system.

Which theoretical bases are there linking personality traits and stress?

There are three main theories that link personality traits to stress:

• Stress generation hypothesis supposes a transactional relation between personality and exposure to stress. Some individuals are more likely to be exposed to stress due to their personality. Individuals actively create their own environment and are thus more vulnerable to higher rates of stress.
• The transdisciplinary model of stress states that personality influences the way in which stressors are perceived and how people respond physiologically and psychologically to stress. 
• Integrative models state that personality traits act as risk or resilience factors for exposure to stress and are precursors for stress reactivity.

How can the degree of stressor-dependency cause differential associations between personality traits and stressor exposure?

Stressor exposure, physiological stress response and psychological stress response show different association patterns with personality traits. Many stressors depend on someone's personality, but studies usually only look at stressors that are dependent (e.g. interpersonal stressors) and independent (e.g. disasters) of someone's personality. But since independent stressors are usually driven by environmental influences, they can weaken the relationship between stressor and personality.

What does the Five Factor Model (FFM) teach us about the relationship between personality and stress?

The FFM is an organizational model of personality traits that identifies five main personality traits: neuroticism, agreeableness, extraversion, conscientiousness, and openness. The five traits have different relationships with stress experiences:

• Neuroticism shows a positive association with stress, possibly because people high on neuroticism play a role in generating their own stressors and then react to events in negative ways and then overreact.
• Extraversion, conscientiousness, and agreeableness are negatively related to stress. These individuals tends to have good regulation abilities, resilience, more positive social interactions (increasing their perceived social resources), more self control, and are less likely to create their own stressors.

Which factors moderate the relations between personality traits and stress?

Three factors moderate the relations between personality traits and stress:

• Stress domain. For example, people high on neuroticism find themselves in stressful circumstances across a variety of life domains, and high extraversion is negatively related to stress (possibly due to more positive social interactions), 
• Culture. The moderating role of culture in links between personality and stress could be explained by differences in behaviors and lifestyle. For example, high extraversion may be a protective factor for stressor exposure in eastern culture.
• Perceived Stress Scale. The associations between personality and stress were larger when they were assessed by the Perceived Stress Scale compared to other types of psychological stress perception scales. This shows it is important to use standardized measures with high reliability to achieve better validity.

What is the heroin overdose mystery?

The term overdose implies that someone has taken a dose too high, but many victims of overdose are actually self-administering addicts who took a dose which would not be expected to be fatal for them as they are drug-experienced and drug-tolerant. There is then not really a true pharmacological overdose of narcotics and it is yet a mystery as to why these people died.

What are the usual interpretations of overdose?

Different hypotheses have been proposed to explain these overdoses:

• The fatal reaction may be the result of the combined effects of heroin and other abused depressant drugs, because heroin addicts sometimes take other central nervous depressants as well (like alcohol and benzodiazepines).
• It may be an allergic or other type of reaction to contaminants, because heroin is often bulked up with various adulterants (like caffeine and sucrose).
• It may be an accidental overdose after a period of abstinence. The tolerance of prolonged drug use can have dissipated during the period of abstinence. 

Why should we look at the environment in which a drug is taken?

Research indicates that the majority of overdoses happen in new environments, an environment in which the drug user normally does not take the drug. Altering the context of drug administration increases drug-induced mortality.

How do acute and chronic tolerance protect the drug user from overdosing?

Acute tolerance refers to the decrease in the effect of a drug over the course of a single administration. Taking drugs disturbs the body in many ways (suppressing the cough reflex, respiratory depression, decreased pain sensitivity, etc.), but the body also detects these threats and starts homeostatic counter-responses. With repeated drug use, tolerance becomes enhanced and creates chronic tolerance. Rather than just responding reflexively to the drug, addicts show homeostatic compensations even when they just anticipate a drug.

How can Pavlovian conditioning explain accidental overdoses?

For repeated drug users, cues that are present at the time of taking the drug become conditional stimulus and the homeostatic drug-compensatory responses become the unconditional response. The drug-compensatory responses are elicited by drug-predictive cues and contribute to chronic tolerance and explain why an experienced addict can normally survive a high drug dose. When a drug is then taken in a new environment and some of the drug-predictive cues are not there, the conditional response is not initiated, chronic tolerance is not as high, and an addict can overdose.

What symptoms comprise Alice in Wonderland syndrome? 

Alice in Wonderland syndrome (AIWS) was first described in 1955 by the psychiatrist John Todd, and its symptoms include various distortions of sensory perception, including visual distortions, and distortions of time and self. These distortions differ from hallucinations and illusions in the sense that they are based in the real world but involve very specific alterations to sensory input. AIWS currently comprises 42 visual symptoms (called metamorphopsias) and 16 non-visual symptoms. The two most common symptoms are micropsia; seeing things as smaller than they really are, and macropsia; seeing things as larger than they really are. 58.6% of AIWS patients suffer from micropsia while 45% suffer from macropsia. A few other visual symptoms include kinetopsia, in which people see stationary objects as moving, and prosopometamorphopsia, in which eyes are seen as much larger than they are. Symptoms sometimes include feelings of levitation and alterations in the passage of time, among others. It is most common for people with AIWS to only experience one symptom, although many people experience up to four. Generally, AIWS symptoms tend to be short-lived, lasting a few minutes to a few days. Years-long or lifelong symptoms occur rarely.

What are the causes of AIWS? 

There are many possible causes of AIWS, and more will likely be added as more cases are identified. The causes differ between young people and adults. For youths, the most common cause of AIWS is encephalitis (inflammation of brain tissues). Encephalitis can be caused by various infections, but the Epstein-Barr virus is the one most frequently cited in cases of encephalitis-induced AIWS. In adults, neurological disorders were cited most often as the medical cause for AIWS, with migraines being the most common among them. However, symptoms of AIWS are sometimes unassociated with any type of medical disorder or pathology. Symptoms of this syndrome are caused by functional and/or structural abnormalities in the perceptual system.

What are the prevalences of AIWS in the population? 

Although AIWS is thought of as a rare syndrome, some of its symptoms are seen quite regularly in the general population. In fact, singular symptoms of AIWS unrelated to another disorder or medical condition have been experienced by around 30% of all adolescents. When considering specific symptoms, it was found that 5.6% of male adolescents and 6.2% of female adolescents have experienced micropsia and/or macropsia. It was also found that 15% of patients with migraines suffer from AIWS.

What are the treatment methods and prognoses for AIWS? 

Patients with AIWS often suffer from underlying medical conditions like encephalitis, migraines, or epilepsy. When this is the case, pharmacological treatment is used in an attempt to diminish or eliminate the underlying cause. Typically, medication is only necessary in medically-induced cases, and this treatment must target the medical condition rather than the symptoms themselves. Generally, these treatments include antiepileptic medication, antibiotics, antiviral medication, or migraine medication. Oftentimes in medical cases of AIWS, symptoms disappear and return in coordination with the severity of the disease at the time. In most cases of non-medically-induced AIWS, a helpful treatment can consist merely of reassurance from a clinician that the symptoms they are experiencing are benign. Chronic cases may warrant functional neuroimaging to better understand specific symptoms. Almost all cases of AIWS are considered benign and treatable, as full remission of symptoms is often achieved both in medically-induced and non-medically induced cases. This can occur either spontaneously or after treatment. However, the prognosis for patients with epilepsy or migraine-induced AIWS is poorer — these patients rarely achieve full remission due to the difficulty of treating their underlying conditions.

Why is AIWS so regularly discounted in scientific literature and clinical practice? 

It is estimated that AIWS is severely underdiagnosed. This is partially due to its apparent similarities to schizophrenia spectrum disorders, as patients’ perceptual distortions may be attributed to hallucinations. The diagnosis of AIWS is also made more difficult because it is not featured in either the DSM-5 or the ICD-10. In practice, symptoms of AIWS may not be recognized because of this factor. It is suggested that AIWS should be included in the next versions of the DSM and ICD under the categorization of nervous system disorders or perceptual disorders. An international database that documents cases of AIWS and their treatments would also be extremely helpful for clinicians trying to learn about and diagnose this syndrome.

What is emotional processing theory (EPT)?

Emotional processing theory (EPT) proposes a hypothetical sequence of fear-reducing changes that is evoked by emotional engagement with the memory of a significant event (the trauma). It is based around the concept of a fear structure. The fear structure is a type of mental framework for reaction to threat that includes information about a feared stimulus (e.g. a spider), physiological and behavioral responses (e.g. sweating, rapid heartbeat), and the meaning of the stimulus and response elements (e.g. the spider will bite me and I am afraid). The fear structure can be changed by activating it and presenting information that is incompatible with its elements that through prolonged exposure is integrated into the fear structure and replaces the pathological elements.

What is Ehlers and Clark´s (2000) cognitive model of PTSD?

The cognitive model of PTSD suggests that negative appraisals, disjointed trauma memories, and unhelpful coping strategies maintain PTSD.

• Patients with PTSD often have excessively negative meanings of the trauma that become more embedded over time. Perceived external threats can result from appraisals about impending danger (e.g. ¨I am not safe anywhere¨). Perceived internal threats often come from negative appraisals of one´s behavior, emotions, or reactions during the trauma (e.g. ¨I did nothing to stop it, it is my fault¨).
• Disjointed trauma memories refer to the subjectively worst moments of the trauma being excessively elaborated in memory and poorly integrated into the context of the trauma and previous and subsequent experiences. This induces a sense of threat similar to the one experienced during the trauma and causes the same feelings and emotions as though the trauma were occurring now rather than being a memory.
• Unhelpful coping strategies (e.g. excessive precautions, avoidance of reminders, rumination) prevent change in the negative appraisals and disjointed trauma memories and may increase symptoms.

Which six elements should effective trauma-focused psychological treatment have?

Effective trauma-focused psychological treatment should include:

• Psychoeducation about the nature and course of posttraumatic stress.
• Exposure either in vivo, through imaginal reliving, or narrative writing.
• Changing negative meanings of the trauma for the patient's view of themselves, other people, and the future.
• Dealing with a range of emotions that have different underlying beliefs that need to be identified and treated.
• Emotion regulation improvement, for example through breathing training.
• Changing memories by creating a coherent narrative of the trauma that helps the patient see the trauma in the context of other events in their lives.

What is imaginal reliving?

Patients visualize the traumatic event, usually with their eyes closed. They start with the first perception that something was wrong and end at a point when they were reasonably safe again. The patient describes moment by moment what is happening and what they are thinking and feeling. Imaginal reliving facilitates emotional engagement with the memory and gives access to details of the memory. The therapist supports the patient in maintaining awareness of the present surroundings.