Psychotic depression

Abstract

Major depressive disorder (MDD) stands as the third leading cause of disease burden worldwide, a position projected to escalate to the top spot by 2030, according to the World Health Organization. In the UK, depression ranks as the third most common reason for consulting with a GP. This article focuses on one of the most severe manifestations of depression/psychotic depression, also known as MDD with psychotic features which represents the extreme end of the depressive spectrum, characterised by the co-occurrence of psychosis in the context of severe depression. However, despite its clinical severity, it is often underdiagnosed and undertreated. This article aims to guide assessment and diagnosis of patients in primary care, covering key aspects including aetiology, clinical presentation, referral pathways, management strategies, and prognosis.

Clinical case scenario

A 68-year-old female, Adeline, presents to your morning surgery with sleeplessness, pervasively low mood, loss of appetite and anhedonia in the aftermath of the death of her husband. Her daughter who attends with her says her mother has expressed concerns that her internal organs have stopped working and are rotting. She often wakes in the middle of the night due to the smell of rotting flesh. Adeline has little insight into how unwell she is.

She speaks fondly of her deceased husband Jack and mentions since his passing she does not want to be here anymore.

What concerns you most about Adeline’s presentation?

What wider issues might be considered in Adeline’s case?

Aetiology

The cause of depression is unknown, but is likely to result from a multifaceted interaction of biological, psychological, and social factors. Similarly, the clinical definitions and nosology of psychotic depression harbour ambiguity. Various disparities have been proposed between psychotic and non-psychotic depression, spanning age, gender, familial predispositions and even a low sports grade in school may be a risk factor (Nietola et al., 2020).

Psychotic depression is stratified into mild, moderate, or severe categories, with classification contingent upon the intensity and frequency of symptoms, duration, presence of additional features, and impact on daily functioning and social interactions. Typically, psychotic symptoms emerge after episodes of depression without psychosis, with an average onset age ranging between 20 and 40 years. Furthermore, relatives of individuals afflicted with psychotic depression exhibit heightened susceptibility to both psychotic depression and schizophrenia (Hales et al., 2008).

Classification

In ICD-11, diagnosing a depressive episode requires the presence of two out of the three core symptoms: depressed mood, loss of interest and enjoyment, and reduced energy level. A diagnosis of severe depression is warranted when these symptoms are markedly distressing and significantly disrupt normal functioning. The emergence of psychotic symptoms within a depressive illness automatically classifies patients as experiencing a severe depressive episode.

Clinical case scenario (continued)

On further questioning Adeline’s daughter tells you that Adeline has been refusing to eat because she says her organs are decaying. She has purged to prove the food she eats is not being digested. As a result, she has lost a significant amount of weight and is constantly feeling extremely weak and lethargic. Furthermore, she is now currently refusing to urinate and defecate, as she believes her bowels and bladder are dysfunctional.

Clinical features

In psychotic depression, patients typically exhibit symptoms of a major depressive episode alongside additional indicators (Box 1). Identifying key clinical features and understanding the significance of early diagnosis play crucial roles in ensuring effective treatment and mitigating serious adverse outcomes. Box 1.

Symptoms in psychotic depression.

Non psychotic symptoms

Anxiety

Flat affect

Severe anhedonia

Significant change in weight and appetite

Psychomotor retardation or agitation

Absence of any diurnal pattern in mood and energy

Significantly disrupted sleep or excessive sleep

Poor concentration and marked indecisiveness

Negative thinking styles and hopelessness about the future

Self-harm/suicide

Psychotic symptoms

Hallucinations – can be auditory, visual, olfactory, tactile, and are congruent with delusional material

Delusions – common themes of mood congruent delusions include paranoia, guilt, persecution, punishment, worthlessness or disease

Poverty of thought, jumbled thoughts which can impact on how a patient describes their current situation

Feelings of their head being full/empty or as if their thoughts cannot be controlled

Catatonia – life-threatening, rare presentation

Depression is characterised by persistent low mood and diminished pleasure in most activities, accompanied by a spectrum of emotional, cognitive, physical, and behavioural symptoms. The term ‘psychosis’ encompasses various symptoms indicating significant alterations in perception, thoughts, mood, and behaviour. Typically, a prodromal phase of emotional turmoil precedes the onset of psychotic depression. Recognising psychosis is critical, as it serves as a red flag symptom demanding immediate attention.

Patients often conceal or fail to recognise psychotic symptoms as abnormal. According to the National Collaborating Centre for Mental Health (2010), accurate diagnosis of psychotic depression is challenging due to the ‘subtle, intermittent, or concealed’ nature of psychosis. This poses a risk of primary care professionals overlooking vital symptoms, potentially leading to delayed diagnosis and treatment. Essentially for diagnosis, the GP and the secondary care teams will be looking for the affective symptoms being present and usually pre-dating the psychotic ones.

In more severe instances of psychotic depression, patients may lack insight, and initial contact may arise from concerned family members, as in the case mentioned above. Such concerns should always be taken seriously, with urgent efforts made to engage the patient. It is crucial to note that command hallucinations in psychotic depression can lead to suicidal behaviour or harm to others (though homicide is rare), while delusions of having a terminal illness (nihilistic delusions) may result in severe neglect.

Depression shares intricate ties with physical health, with many risk factors associated with depression—such as alcohol and drug abuse or sedentary lifestyles—overlapping with those linked to cardiovascular disease, cancer, diabetes, and respiratory ailments. Conversely, individuals grappling with these chronic health conditions often find themselves battling depression due to the challenges inherent in managing their illnesses. Suicide also looms as a particularly acute risk in cases of psychotic depression, persisting even post-recovery. The lingering guilt and fear of recurrence often fuel suicidal ideation, necessitating vigilant monitoring and support.

Recognition of postpartum psychosis is also paramount, due to risks posed to both mother and baby. GPs often serve as the first point of contact if there are concerns about mothers’ post-birth. This presents as a highly concerning clinical scenario, often featuring mood congruent delusions that can be challenging to detect. Beliefs about being a ‘bad mother’ are common after birth, but it is essential to discern when these beliefs become delusional, overwhelming, and potentially unsafe.

Mothers may be hesitant to disclose psychotic symptoms for fear of potential repercussions such as involvement of social services or losing custody of their baby. Consequently, concerns regarding this may be relayed to the GP by either the health visitor or midwife. Table 1 provides suggestions for tactful questioning techniques to elicit these concerns. Psychotic depression in a mother with a baby constitutes a medical emergency, necessitating immediate referral to psychiatric services (with potential involvement of social services if alternative childcare is unavailable).

Table 1.

History taking example questions of mood congruent hallucinations and delusions which predominate in psychotic depression.

Symptom	Relevant questions to ask patients to elicit symptom
Hallucinations	Does anyone or anything ever say that you that you are a bad or worthless person?
	Does anyone or anything ever say that you should harm yourself or others?
	Do you ever feel that you smell or that other people can smell you?
Delusions	Do you have any beliefs that are not shared by others you know?
	Do you ever feel that people are watching or following you?
	Are you worried that you have an incurable illness?
	Do you have concerns that you are dead or that your insides are rotting away or not working properly?
General	Is there anything that worries you at present?
	Do you sometimes have thoughts that others tell you are false?
	Would you say your thoughts your own?
	Some people can worry about changes to their thoughts such as feeling other people or beings are taking thoughts out of your head or putting them in? – is this happening to you?
	Can anyone hear your thoughts? For example, can I hear what you are thinking right now?
	Do you ever hear your own thoughts echoed or repeated?
	How do you feel your relationship is going at present? Do you worry about infidelity?
	How are you bonding with your baby, do you have any doubts or concerns about your baby’s wellbeing?

Lastly, we want to touch upon Othello syndrome or delusional jealousy. This condition is often linked with depressive presentations, but is much harder and riskier to elicit. The core belief is that the partner is engaged in a secretive affair. Armed with this belief, the affected individual may repeatedly question their partner, exacerbating relationship breakdowns and worsening depressive symptoms. In some cases, the pursuit of evidence of an affair can lead to concerning behaviours such as stalking, searching belongings, or hiring detectives. In other instances, it may escalate to acts of violence towards the partner, the individual accused, or even themselves. A truly holistic approach to assessment is necessary. Diagnosis can be challenging, as the core delusional belief of infidelity cannot readily be disproved. Table 1 illustrates open-ended questions to facilitate discussion.

The most commonly used depression rating scales in primary care include the PHQ-9, (HAD) Scale, and the Beck Depression Inventory. However, these scales have limited utility in diagnosing psychotic depression. If psychotic features are present, the depression is categorically ‘severe’, irrespective of the score. Additional questions about mood congruent hallucinations and delusions, which are predominant in psychotic depression, are outlined in Table 1, with the differential diagnoses of psychotic depression being provided in Box 2. Box 2.

Differential diagnosis of psychotic depression.

The major differential is a physical health problem manifesting with primarily mental health symptoms which could include hypothyroidism, calcium disorders, head injury, intracranial masses, hypoactive delirium, Parkinson’s disease etc.

Schizoaffective disorder

Alcoholic hallucinosis

Bipolar disorder

Drug-induced psychosis

Clinical case scenario (continued)

You examine Adeline in practice. Her observations are stable and she weighs 55 kg. Her documented weight from 12 months ago was 71 kg. You undertake a full physical examination and take some bloods including a full blood count, urea and electrolytes, liver function, thyroid function, C- reactive protein, a bone profile and B12 and folate levels. A urinalysis shows ketones ++.

There is nothing acutely abnormal on her vitals or clinical examination today. On mental state examination you notice signs of self-neglect, unkempt appearance, a strong smell of urine and what appears to be faecal soiling on her fingernails. She appears underweight and there is pallor.

There is psychomotor retardation, poverty of speech and delayed responses to your questions. Adeline makes little eye contact with you. Her mood is low both subjectively and objectively, with a flat affect.

There is evidence of thought blocking and nihilistic delusions ‘My organs are rotting; can you smell the rot too’ and ‘I am dead inside’.

There is ongoing suicidal ideation “I want to die and go to my husband, I am all rot now from the inside, I do not want to be here”.

You establish there is little insight by Adeline into how unwell she is and you speak to both her and her daughter about an informal admission under the psychiatric team. With some prompting and reassurance from her daughter, Adeline thankfully agrees. You refer her to the on-call community mental health team (CMHT) for a same-day urgent assessment.

In hospital, the members of the psychiatric team arrange more blood work and brain magnetic resonance imaging. They also initiate medication including quetiapine and mirtazapine as well as intravenous fluids to rehydrate Adeline.

Management

The GP plays a crucial role in ruling out physical causes of the presentation. These include, hypothyroidism, disorders of calcium metabolism, or hypoactive delirium—especially in the elderly. Thus, it is entirely appropriate for the GP to conduct a physical examination and appropriate blood investigations to eliminate other differentials. Although brain imaging can be beneficial, we acknowledge that not all GPs will have access to this resource.

According to the National Institute for Health and Care Excellence (NICE), the initial presentation of psychosis warrants urgent same-day assessment to assess the risk of harm to self and others. NICE advises treatment should include a risk assessment, an assessment of needs, a programme of coordinated multidisciplinary care and access to psychological treatments, after improvement of acute psychotic symptoms.

GPs often possess detailed knowledge of their patients, facilitating decisions regarding the potential use of compulsory powers. Their role may also involve arranging or conducting assessments for potential compulsory admission to hospital. Informal admission should always be considered as the primary option and a crisis resolution or home treatment/early intervention team would typically be the first point of contact for GPs. However, in some areas of England, access to these services may be limited. In such cases, GPs may consider consulting with the local CMHT to determine the most appropriate course of action.

GPs must discuss treatment options and for those with capacity, we should reach a shared decision based on their clinical needs and preferences. Finally, it is important to recognise here that in some patients, depressive symptoms and cognitions may lead to neglecting comorbid conditions such as diabetes or acute severe infections, potentially necessitating admission through physicians initially.

Compulsory admission may be warranted under Sections 2 or 4 of the Mental Health Act 1983, although it is important to note that this does not apply uniformly across the UK. This option should be considered for patients at significant risk of suicide, self-harm, harm to others, self-neglect, or complications related to their treatment—especially older individuals with medical comorbidities. Family members can often assist in communicating with patients who decline treatment or lack capacity— their involvement is invaluable and should not be overlooked.

Before applying for admission to hospital, two doctors in England (one of whom should ideally have prior knowledge of and familiarity with the patient) must provide a ‘medical recommendation.’ One of these doctors must be approved under the Mental Health Act, typically a consultant psychiatrist (although a GP can seek approval under Section 12(2) of the Mental Health Act).

A Section 2 admission for assessment lasts for 28 days and cannot be renewed whereas a Section 4 admission for emergency treatment lasts for up to 72 hours and must be deemed an urgent necessity. It is utilised when admission under Section 2 would cause undesirable delay and is typically converted into a Section 2 before expiration. In Scotland, GPs may utilise an emergency detention certificate or request a psychiatrist approved under Section 22 to issue a short-term detention certificate authorised under the Mental health (Care and Treatment) (Scotland) Act 2003, as amended in 2015.

Medication

Pharmacological treatment for psychotic depression is heavily under-studied. A Cochrane database systemic review done by Kruizinga et al. (2021) illustrated that there is some evidence to suggest combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone. NICE tell us initiating dual therapy with an antipsychotic and antidepressant constitutes first-line treatment in psychotic depression, and they specifically mention olanzapine or quetiapine in their updated 2022 guidance.

There is also evidence supporting the effectiveness of electroconvulsive therapy (ECT) in treating psychotic depression. A study conducted in 2001 reported a 95% remission rate in individuals with psychotic depression following bilateral ECT (Petrides et al., 2001). NICE tell us to consider ECT in severe depression if the person chooses this in preference to other treatments based on past experience of ECT being successful, treatment resistant illness or if a rapid response is needed, as with Adeline, our case where the depression is life-threatening because she is not eating or drinking.

GPs should refrain from initiating antipsychotic drug treatment in primary care while awaiting specialist assessment unless advised by a consultant psychiatrist. However, those with experience or a specialist interest in mental health may proceed if confident and if there is an urgent need to alleviate distress or if there might be a delay in the patient’s assessment. Before initiating an antipsychotic, we need to check the patient’s baseline pulse, blood pressure, weight, nutritional status, diet, level of physical activity, fasting blood glucose or HbA1c and fasting lipids NICE (2022). Finally, it may be appropriate for GPs to prescribe a short course of benzodiazepines in primary care if the patient is highly distressed or anxious and if the GP feels competent to do so.

NICE (2022) further stipulates that the secondary care team should oversee the monitoring of the individual’s physical health and the effects of any antipsychotic medication for the first 12 months of treatment, or until the individual’s condition has stabilised (whichever duration is longer). Subsequently, responsibility for monitoring may transition to primary care, contingent upon locally agreed shared care guidelines or the individual’s care plan. Ongoing primary care management points are detailed in Box 3, with common side effects of medications being outlined in Table 2. Box 3.

Ongoing primary care management of psychotic depression.

Prescribing and monitoring medication initiated in secondary care:

Monitoring symptoms, and if necessary, following crisis plans and liaising with secondary care

Reviewing the person’s physical health, mental health, and medication at least annually

Asking the person about the support they receive from family and carers, and considering referral to the community mental health service for family intervention to manage any conflict or difficulties that could trigger a relapse

Ensuring that people with psychotic disorders and their family and/or carers are informed about support available to help them back into work or education, their housing options, entitlement to benefits, and entitlement to drive

Give advice about guided self-help groups, support groups and other local and national resources. Guided self-help may include:

○ Self-help leaflets or books, using cognitive behavioural therapy principles.

○ Self-help computer programmes or the internet.

○ Exercise sessions (three each week for up to 1 hour), for 10–12 weeks

If a person with a psychotic disorder is being managed solely in primary care, re-refer them to secondary care if:

○ There is a poor or partial response to treatment or treatment adherence is poor

○ The person’s functioning declines significantly

○ They develop intolerable or medically important adverse effects from medication

○ Comorbid alcohol or drug misuse is suspected

○ There is potential risk to the person or others

Source: NICE (2022).

Table 2.

Side effects of various medications.

Extrapyramidal symptoms	Occur most frequently with first-generation antipsychotics
	Four common extrapyramidal syndromes are recognised, namely parkinsonism, akathisia, acute dystonia and tardive dyskinesia
	It is important to note akathisia can often be misinterpreted as a worsening of the underlying condition
Weight gain	More frequent with second-generation antipsychotics, clozapine and olanzapine have the greatest potential to cause weight gain
Dyslipidaemia	Chlorpromazine, clozapine, olanzapine, quetiapine, and risperidone all have the potential to increase lipid levels.
Hyperprolactinaemia	Can present with galactorrhoea, amenorrhoea, gynaecomastia, hypogonadism, sexual dysfunction and an increased risk of osteoporosis.
Hyperprolactinaemia	Most frequently associated with risperidone, amisulpiride and sulpiride
Sedation	Chlorpromazine, clozapine, promazine, and zotepine cause the highest rate of sedation.
Anticholinergic effects	(Dry mouth, blurred vision, urinary retention, constipation, and cutaneous flushing) — Chlorpromazine and clozapine are the main culprits.
Anticholinergic effects	Cholinergic side effects can cause cognitive slowing/poor concentration, mimicking underlying condition.
Reduced seizure threshold	Risk of seizures increases with higher doses of antipsychotics.
Hypertension	Most commonly reported with clozapine
Impaired glucose tolerance	More common in people with schizophrenia than in the general population, and has been associated with both first- and second-generation antipsychotics
QT interval prolongation	The most widely reported cardiac conduction defect in antipsychotics – safe practice to ensure a baseline ECG is done on initiation
Stroke risk	Olanzapine and risperidone especially are associated with an increased risk, especially in the elderly with dementia.
Antidepressant specific	Decreased alertness, nausea, headaches, sexual problems, suicidal feelings, syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Serotonin syndrome	Presents as a combination of neuromuscular, autonomic and mental state symptoms. Most cases involve two drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) or monoamine oxidase inhibitors (MAOIs)
Neuroleptic malignant syndrome	Rare but potentially fatal. Watch for fever, increased sweating, rigidity, confusion, fluctuating consciousness, fluctuating blood pressure, tachycardia, raised CK, leucocytosis, and raise liver function tests
Neutropenia	It is desirable to get baseline measurements of routine blood tests prior to commencing antipsychotic medication
Neutropenia	Stop antipsychotic if neutrophils fall below 1.5 × 109/L and contact secondary care for urgent advice.
Abnormal liver function tests (LFTs)	Stop the suspected drug if LFTs suggest hepatitis (transaminases rise to three times normal) or prothrombin time or albumin are abnormal.

Source: NICE (2021).

We acknowledge that GPs may not typically refer patients to psychological therapies in such acute or serious scenarios. However, in secondary care, individual cognitive behavioural therapy (CBT) or individual behavioural activation for psychotic depression, as well as family intervention, are almost always considered. Lastly, it is essential to note that psychotic depression necessitates refraining from driving during an acute episode of psychosis and notifying the Driver and Vehicle Licensing Agency (DVLA) and —failure to do so may render their insurance invalid. The DVLA will make a case-by-case decision regarding whether the patient can retain their licence and continue driving.

Complications of psychotic depression include worsening pain, disability, and distress, as well as a diminished quality of life and increased morbidity and mortality in various concurrent conditions such as coronary artery disease and diabetes mellitus. There is also noted association with a heightened risk of substance abuse in these patients NICE (2022).

The prognosis of psychotic depression is diverse. The likelihood of recurrence is notably high, with this risk escalating with each subsequent episode. Up to 27% of individuals fail to achieve recovery and progress to develop a chronic depressive illness. Features such as psychosis, significant anxiety, concurrent personality disorders, and particularly severe symptoms all portend a worse prognosis in psychotic depression (Heslin and Young, 2018). Box 4 is a list of organisations that offer support and materials to patients with depression. Box 4.

Organisations that offer materials and/or support to people with depression.

MIND: www.mind.org.uk.

Depression Alliance: www.depressionalliance.org.

Depression UK: www.depressionuk.org.

Mental Health Foundation: www.mentalhealth.org.uk

Samaritans telephone helpline: 08457 90 90 90.

SaneLine telephone helpline: 0845 767 8000.

Clinical case scenario (continued)

8 weeks later you get a discharge summary from the local CMHT.

Adeline is discharged into a nursing home, stable on her medication. She responded well to emergency ECT as her depression was deemed life-threatening due to her refusal to eat or drink.

Adeline is attending weekly individual CBT and currently there are no residual psychotic thoughts.

Key points

Psychotic depression leads to premature death due to higher rates of suicide, cardiovascular disease and type 2 diabetes

GPs should undertake a physical examination and appropriate blood investigations to help rule out physical disease differentials

Assessment requires screening questions to elicit paranoia, hallucinations, social isolation and suicidal risk and these patients need prompt referral to specialist services for early intervention

Psychotic depression in a new mother with a baby is a medical emergency until proven otherwise

The mainstay of treatment is dual therapy with an antipsychotic and an antidepressant, with evidence that ECT is also effective in resistant or life-threatening cases

Individual CBT and family intervention have a role in psychotic depression

Footnotes

ORCID iD

Dr Sythra Razaq

References

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Yudofsky

Gabbard

(2008) The American Psychiatric Publishing Textbook of Psychiatry. Washington DC: American Psychiatric Publishing, Inc.

Heslin

Young

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NICE (2021) Clinical knowledge summaries; Psychosis and schizophrenia. Available at: https://cks.nice.org.uk/topics/psychosis-schizophrenia (accessed 14 April 2024).

NICE (2022) Depression in adults: Treatment and management. Available at: www.nice.org.uk/guidance/ng222 (accessed 14 April 2024).

NICE (2023) Clinical knowledge summaries: Depression. Available at: https://cks.nice.org.uk/depression (accessed 14 April 2024).

Petrides

Fink

Husain

,et al. (2001) ECT remission rates in psychotic versus nonpsychotic depressed patients: A report from CORE. The Journal of Electroconvulsive Therapy 17(4): 244–53. DOI: 10.1097/00124509-200112000-00003.

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Liemburg

Burger

, et al. (2021) Pharmacological treatment for psychotic depression. Cochrane Database of Systematic Reviews 12: art. no.: CD004044. DOI: 10.1002/14651858.CD004044.pub5.

Nietola

Huovinen

Heiskala

, et al. (2020) Early childhood and adolescent risk factors for psychotic depression in a general population birth cohort sample. Social Psychiatry and Psychiatry Epidemiology 55(9): 1179–1186. DOI: 10.1007/s00127-020-01835-7.

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World Health Organization (2004/2008) The global burden of disease: 2004 Update. 2008. Available at: https://iris.who.int/bitstream/handle/10665/43942/9789241563710_eng.pdf (accessed 14 April 2024).