In this review, we describe six medical conditions (ordered alphabetically) that not only produce psychiatric symptoms but also mimic psychiatric disorders to the point where clinicians might fail to understand the underlying illness. In these cases, accurate diagnosis is essential to getting your patients well. Keep these conditions in mind when patients present with puzzling physical symptoms or when the time course of their illness seems unusual.

Acute intermittent porphyria

Acute intermittent porphyria (AIP) is a rare genetic disorder caused by a deficiency of the enzyme porphobilinogen deaminase, essential for heme production. This deficiency leads to the accumulation of porphyrins, which are intermediates in the heme synthesis pathway, and can cause episodes or “attacks” of severe abdominal pain, nausea, and neurological issues like confusion, seizures, and even paralysis. AIP attacks can be triggered by factors that lower heme levels and trigger the production of porphyrins, like CYP450 inducers (eg, barbiturates, antiepileptics, smoking, and alcohol), low-calorie diets, stress, and hormonal changes like those seen in the menstrual cycle.

Keys to diagnosis 

We maintain a high index of suspicion for AIP in any cases of psychiatric symptoms with histories of unexplained acute abdominal pain. It’s also helpful to obtain a thorough family history, as AIP is an inherited disorder. A urine sample during an acute attack showing porphobilinogen levels greater than 6 mg/L confirms the diagnosis. 

Treatment

Treatment involves IV heme and carbohydrate loading (either as IV glucose or as a high-carbohydrate diet). The production of heme is tightly connected with the availability of energy in the body. When the body is under stress, or when it doesn’t have enough energy (eg, when fasting or on a low-calorie diet), it tries to make more heme as a way to boost the energy-producing processes. However, in AIP, this leads to an accumulation of porphyrins and triggers an attack. Administering glucose (or other carbohydrates) provides the body with energy so it doesn’t need to boost heme production, and this helps to alleviate the symptoms. 

Treatment of acute attacks usually relieves the psychiatric symptoms. However, patients’ depression and anxiety sometimes continue even after the acute attacks have ended, and we provide psychiatric treatment in these cases (Millward LM et al, J Inherit Metab Dis 2005;28(6):1099-10107).

Other considerations

Many medications can trigger acute AIP attacks, including benzodiazepines (eg, chlordiazepoxide, clonazepam), antidepressants (eg, phenelzine, venlafaxine), sleeping medications (eg, ramelteon, trazodone), antiepileptic drugs (eg, carbamazepine, topiramate), and antipsychotic medications (eg, quetiapine, ziprasidone). Always check the American Porphyria Foundation’s Drug Safety Database before prescribing medications to patients with AIP—you’ll be surprised to see the wide range of psychiatric medications that carry warnings. We do have some safe options, though, including amitriptyline, chlorpromazine, diphenhydramine, fluoxetine, fluphenazine, gabapentin, haloperidol, lithium, and lorazepam. For a full list, see: www.tinyurl.com/2x32uy9d. 

Anti-NMDA receptor encephalitis

Anti-NMDA receptor encephalitis is an autoimmune encephalitis characterized by immunoglobulin G (IgG) antibodies against NMDA receptors in the central nervous system. This syndrome affects both sexes but is more common in young females. In many cases, an ovarian teratoma is the source of the antibodies.

Symptoms

Patients typically present with a prodromal viral illness followed by a quick progression to prominent psychiatric symptoms (within weeks), including agitation, catatonia, delusions, hallucinations, insomnia, and mania. Symptoms can quickly progress to life-threatening blood pressure and heart rate fluctuations, dyskinesias (uncontrolled, involuntary writhing), and seizures. Patients typically require intensive care ­admission. 

Keys to diagnosis

Misdiagnosis is common in the early phases, and patients are often mistakenly diagnosed with schizoaffective disorder or other psychotic illnesses. You’ll need to obtain cerebrospinal fluid (CSF), which can be tricky as patients may need significant sedation to remain still for a lumbar puncture. Be cautious with serum NMDA receptor antibody testing, because it has lower sensitivity than CSF testing and can be falsely low if patients are started on IV immunoglobulins or plasmapheresis before a sample is obtained. The presence of IgG antibodies in the CSF is diagnostic for anti-NMDA receptor encephalitis.

Treatment

Prompt aSLEdministration of immunosuppressive therapies (IV immunoglobulins, corticosteroids, and plasmapheresis) is critical. If a teratoma is present, it must be removed for treatment to be successful.

The usefulness of antipsychotics for agitation in these cases is inconclusive and may worsen dyskinesias (Chapman MR et al, Am J Psychiatry 2011;168:3245–3251). We use benzodiazepines when catatonic features are present, but they can exacerbate confusion and delirium. Treatment should be tailored to each patient as guidelines for psychiatric management are still lacking (Warren N et al, Psychological Medicine 2021;51(3):435–440). Most patients recover, especially with early intervention, but full recovery can take months or years.

Lupus 

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disorder that affects multiple organ systems and follows a relapsing and remitting course. Primarily diagnosed in women of childbearing age, SLE affects an estimated 1.5 million patients in the US. Patients with family histories of autoimmune disorders are at elevated risk. 

Symptoms

Typical symptoms include a characteristic butterfly-shaped rash over the face and nose and discoid skin lesions (round scaly red plaques, typically on the face, scalp, or ears), as well as fatigue, fever, joint pain, and swelling. Some patients also experience mood symptoms, delusions, and hallucinations that can be indistinguishable from schizophrenia, bipolar disorder, or delirium. 

Keys to diagnosis

Consider SLE in patients with psychiatric symptoms who also report the characteristic symptoms of SLE listed above, especially if there’s a family history of autoimmune illnesses. We’ve occasionally encountered patients whose main symptom was psychosis with no other physical symptoms, but on further exploration uncovered a recent history of classic SLE symptoms like rashes or joint pain. If you suspect SLE, obtain a rheumatology consult. A positive antinuclear antibody titer of at least 1:80 indicates autoimmune disorder involvement but is nonspecific for SLE. The presence of anti-double-stranded DNA antibodies confirms the diagnosis. 

Treatment

Treatment consists of immunosuppressive therapies (eg, high-dose glucocorticoids, cyclophosphamide, rituximab) and plasmapheresis for more refractory cases. These help reduce mood or psychotic symptoms, but we also prescribe antidepressants, antipsychotics, or mood stabilizers as needed to speed up recovery (Yoon S et al, J Rheum Dis 2019;26(2):93–103). Most patients show improvement in SLE symptoms, including neuropsychiatric manifestations, within eight weeks of treatment; however, some cases improve slowly over six to 24 months.

Lyme disease

Lyme disease, or Lyme borreliosis, is a tick-borne illness with 30,000 new cases reported each year. Ticks thrive in wooded, shrubby, and grassy habitats and are endemic to northeast and mid-Atlantic states (Virginia to Maine), northern central states (Wisconsin and Minnesota), and northern California. 

Symptoms

Early-stage symptoms such as cognitive clouding, fatigue, and poor appetite may be mistaken for depressive or adjustment disorders. 

Later-stage symptoms like dizziness, irregular heartbeat, neuropathic pain, shortness of breath, and tremor may be misdiagnosed as an anxiety disorder.

Keys to diagnosis

Consider Lyme disease in outdoorsy patients who report fever, joint pain, or malaise, especially if they develop a gradually expanding “bullseye” rash, which occurs around the tick bite in most cases. Though less common, facial paralysis—like Bell’s palsy—sometimes occurs one to three weeks after the tick bite.

Treatment

Collaborate with the patient’s PCP to screen using serological testing that looks for antibodies against the bacterium. The CDC recommends a two-step process: After positive antibodies are found on screening, confirmation is made using a Western blot to detect B. burgdorferi proteins. A short course of antibiotics, like amoxicillin or doxycycline, cures most cases, although severe presentations may need IV antibiotics. For unknown reasons, about 10% of patients continue to experience fatigue, pain, and poor concentration after completing antibiotic treatment (Ścieszka J et al, Reumatologia 2015;53(1):46–48). This condition, termed post-treatment Lyme disease syndrome (PTLDS), can last for months and, unsurprisingly, can lead to anxiety and depression. Consider treating with anxiolytics or antidepressants in these cases.

Other considerations

Even among individuals who don’t experience PTLDS, a history of Lyme disease appears to significantly increase their risk of mood disorders in the months following infection. One study reported a 75% higher rate of suicide among patients treated for Lyme disease compared with controls for three years following diagnosis (Fallon BA et al, Am J Psychiatry 2021;178(10):921–931). Reasons for the higher rate of mood instability following infection remain unclear but may be related to effects of inflammation on the central nervous system. Regardless, we develop safety plans with our patients and provide them and their families with psychoeducation about warning signs.

Neuroendocrine tumors 

Neuroendocrine tumors (NETs) are rare solid malignant cancers that originate from hormone-secreting tissues, such as those found in the adrenal and thyroid glands and pancreas. NETs secrete metabolically active substances into the systemic circulation, including hormones and neurotransmitters. Adrenocortical and thyroid carcinomas overproduce cortisol and thyroid hormones, respectively, and pheochromocytomas overproduce catecholamines. Carcinoid syndrome (CS) is an NET that typically originates in the gastrointestinal system or, less often, in the lungs. CS diverts tryptophan, the precursor to serotonin and niacin, to overproduce serotonin, so patients become niacin deficient.

Symptoms

For adrenocortical and thyroid carcinomas and pheochromocytomas, symptoms include:

• Anxiety
• Insomnia
• Rapid heartbeat 
• Restlessness
• Shortness of breath
• Sweating
• Tremor

For CS, symptoms include:

• Diarrhea
• Dizziness 
• Flushing
• Respiratory difficulties

Watch for niacin deficiency, which can lead to pellagra—a severe nutritional deficiency that produces fatigue, abdominal pain, loss of appetite, tremor, mouth sores, and cognitive impairment.

Keys to diagnosis

We ask about weight loss, respiratory difficulties, flushing, diarrhea, tachycardia, and dizziness, and maintain a low index of suspicion for further workup and referral to medical services. 

Treatment

Symptom improvement and time course will depend on the location of the tumor, the type of tumor, the patient’s stage of disease, and the treatment modality. Successful surgical resection will have a shorter recovery period, and psychiatric symptoms typically resolve within eight weeks. For patients needing chemotherapy, treatment for the tumor may take many months to produce visible improvement. In some advanced cases, oncology interventions may only manage the psychiatric symptoms or dampen the progression of illness; unfortunately, resolution may not be achieved for these patients. 

Syphilis

Syphilis is a sexually transmitted disease caused by the bacterium Treponema pallidum. Often called the “great imitator,” its presentation can mimic many other diseases.

Symptoms

Primary stage

• 10–90 days after exposure, sores or “chancres” develop in the genitals or mouth. These are usually firm, round, and painless.

Secondary stage

• After the sores go away, patients develop a pink and brown rash all over their body. In 50% of cases, it is present on the palms and soles. 
• Mucous patches resembling “snail trails” can be seen in the mouth. 
• Ocular neurosyphilis can affect any part of the eye but most commonly presents as uveitis.
• Syphilitic meningitis can occur and produces stiff neck, headache, and vertigo; it can also lead to stroke and ­seizures. 
• Other symptoms include fatigue, fever, and swollen lymph glands.

Latent and tertiary stages

• Without treatment, the infection moves into a latent stage that can last for years, during which patients are free of any outward symptoms. Many people stay in this latent stage indefinitely, but if left untreated, about 30% go on to the tertiary stage.
• The tertiary stage involves invasion of the spirochete into the central nervous system and can present with general paresis (eg, memory loss, mood changes, psychosis, seizures, dementia); it has a very poor prognosis. Irritability, depression, anxiety, apathy, and agitation are common. 

Keys to diagnosis

Early detection of syphilis is crucial, so we screen all new patients admitted to the psychiatric unit. Populations at highest risk include men who have sex with men, individuals engaging in commercialized sex, and those with substance use disorders. Initial testing consists of a non-treponemal test such as rapid plasma reagin or venereal disease research laboratory test (VDRL). If the results are reactive with titers >1:4, proceed with a confirmatory treponemal test like fluorescent treponemal antibody absorption or T. pallidum particle agglutination. New-onset mood and psychotic symptoms, especially in elderly patients, raise our suspicion for neurosyphilis. A combination of clinical symptoms, CSF abnormalities (pleocytosis, elevated protein, positive VDRL), and brain imaging showing cerebral atrophy help distinguish neurosyphilis from primary psychiatric illness. Keep in mind that syphilitic infection of the central nervous system, or neurosyphilis, can occur at any stage of the illness. 

Treatment

For primary, secondary, and early latent stages, we use a single dose of long-acting intramuscular penicillin G. In late latent stages, three doses of intramuscular penicillin G are given at weekly intervals, and in neurosyphilis, patients require intravenous penicillin G for 10–14 days. If a patient has a penicillin allergy, it’s best to get an infectious disease consultation. In general, for primary, secondary and latent stages, we can use oral doxycycline. If a patient is pregnant, doxycycline should not be used and desensitization and treatment with penicillin G is needed. For neurosyphilis, IV ceftriaxone can be used. 

Keep in mind that patients can develop fever and flu-like symptoms within the first 24 hours of any syphilis treatment, called the Jarisch-Herxheimer reaction. This should not be confused with a true penicillin allergy and is self-limiting, needing only supportive treatment. 

Second-generation antipsychotic medications like aripiprazole, olanzapine, and quetiapine help reduce mood and psychotic symptoms in the tertiary stage. However, once patients progress to general paresis, their response to treatment is poor.

Carlat Verdict 

Many medical diagnoses present with prominent psychiatric symptoms. Consider medical causes for psychiatric illnesses when your patients report co-occurring physical symptoms, like rashes, joint pain, abdominal distress, autonomic instability, or weakness. A thorough review of systems and medical and family history are important for broadening your differentials and alerting you to the appropriate screening tests.